Compiled by JianMin LI
Med Pediatr Oncol 1999 Feb;32(2):117-23 Related Articles, Books, LinkOut
Outcomes and prognostic factors of Chinese children with acute lymphoblastic leukemia in Hong Kong: preliminary results.
Shing MM, Li CK, Chik KW, Lam TK, Lai HD, Ng MH, Cheung AY, Yuen PM.
Lady Pao Children's Cancer Centre, Department of Pediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT. mk-shing@cuhk.edu.hk.hk
BACKGROUND: The Chinese population is the biggest ethnic group in the world. However, there are few reports on the treatment outcome of childhood acute lymphoblastic leukaemia (ALL) among the Chinese population. PROCEDURE: Sixty-five children with ALL were treated with a modified protocol of the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia protocol X(MRC UKALL X) at the Prince of Wales Hospital, Hong Kong. Most patients were ethnic Chinese. They were divided into groups A and B, depending on whether their presenting leucocyte count being was less or greater than 50 x 10(9)/l, respectively. Group A patients of received induction, early intensification (week 5), cranial irradiation, and maintenance for 3 years. Group B patients received an additional late intensification (week 20). RESULTS: The median follow-up duration was 6.8 years(range: 3.4-10.1 years). The event-free and overall survival rates of all patients at 7 years were 66% (confidence interval [CI] 53-76) and 75% (CI 63-84), respectively. The event-free survival rates of groups A and B at 7 years were 67% (CI 52-79) and 60% (CI 32-80), respectively (P= 0.39). The overall survival rates of groups A and B at 7 years were 80% (CI 66-89) and 60% (CI 32-80), respectively (P = 0.07). With this treatment protocol, the factors which adversely affected the outcome were age (<2 years and >10 years) and T-cell subtype. Sex, white blood count at diagnosis, and FAB subtypes were not statistically significant prognostic factors. CONCLUSIONS: The treatment outcomes were comparable with those reported from the MRC UKALL X trials.
PMID: 9950200 [PubMed - indexed for MEDLINE]
Haematologica 1998 Nov;83(11):967-73 Related Articles, Books, LinkOut
Clinical relevance of CD10 expression in childhood ALL. The Italian Association for Pediatric Hematology and Oncology (AIEOP).
Consolini R, Legitimo A, Rondelli R, Guguelmi C, Barisone E, Lippi A, Cantu-Rajnoldi A, Arico M, Conter V, Cocito MG, Putti MC, Pession A, Masera G, Biondi A, Basso G.
Istituto di Clinica Pediatrica, Universita di Pisa.
BACKGROUND AND OBJECTIVE: Previous studies have considered the prognostic significance of CD10 expression in childhood acute lymphoblastic leukemia (ALL) and showed its linkage to a more favorable prognosis. The aim of this study was to assess the independent significance of CD10 expression in a large population of ALL patients. DESIGN AND METHODS: We revised the independent clinical relevance of CD10 expression in 2038 children with acute lymphoblastic leukemia (ALL), who were consecutively entered in 4 sequential trials of the Italian Association for Pediatric Hematology and Oncology (i.e. AIEOP studies 82, 87, 88, 91); 1142 were males and 896 females, age ranged between 1 and 14 years (yrs) at diagnosis. Of the whole group, 1471 children (72.2%) were defined as having standard risk, 567 (27.8%) as having a high risk. RESULTS: CD10 was detected in blast cells from 1706 of 1784 (95.6%) patients with B-lineage ALL and 46 of 254 (18.1%) with T-cell ALL. In the B-lineage subgroup CD10 expression was associated with presenting features such as age < 9 yrs and inclusion in the standard risk category. No significant differences were found between CD10+ and CD10- cases in T-lineage ALL, concerning presenting features, except for FAB L2 in the former group. We compared the event-free survival (EFS) rates for patients with T-ALL or B-lineage ALL, regarding CD10 positivity, overall and by individual study. Patients with T-ALL fared worse than those with B-lineage ALL (5 and 10 yrs EFS: 46.8% vs. 68.5% and 44.5% vs. 63.7% respectively, p = 0.0001). In multivariate analysis of B-lineage subgroup poorer EFS was associated with male sex, higher WBC (> or = 20 x 10(9)/L), age > 9 yrs. Only WBC > or = 20 x 10(9)/L and age > 9 yrs were parameters linked to poorer EFS in the T-lineage subgroup. Finally, we compared EFS rates for four groups of patients categorized as having high or standard risk, and according to CD10+ and CD10- expression. High-risk patients fared statistically worse than standard risk patients both in the CD10- and in the CD10+ groups (42% vs. 50.7% and 63.6% vs. 66.8%, respectively). INTERPRETATION AND CONCLUSIONS: CD10 expression does not have independent prognostic significance in either the larger subgroup of B-ALL patients or in T-cell ALL.
PMID: 9864914 [PubMed - indexed for MEDLINE]
Blood 1998 Dec 1;92(11):4072-9 Related Articles, Books, LinkOut
Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia.
Knechtli CJ, Goulden NJ, Hancock JP, Grandage VL, Harris EL, Garland RJ, Jones CG, Rowbottom AW, Hunt LP, Green AF, Clarke E, Lankester AW, Cornish JM, Pamphilon DH, Steward CG, Oakhill A.
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, UK.
The efficacy of allografting in acute lymphoblastic leukemia (ALL) is heavily influenced by remission status at the time of transplant. Using polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis, we have investigated retrospectively the impact of submicroscopic leukemia on outcome in 64 patients receiving allogeneic bone marrow transplantation (BMT) for childhood ALL. Remission BM specimens were taken 6 to 81 days (median, 23) before transplant. All patients received similar conditioning therapy; 50 received grafts from unrelated donors and 14 from related donors. Nineteen patients were transplanted in first complete remission (CR1) and 45 in second or subsequent CR. MRD was analyzed by PCR of Ig or T-cell receptor delta or gamma rearrangements, electrophoresis, and allele-specific oligoprobing. Samples were rated high-level positive (clonal band evident after electrophoresis; sensitivity 10(-2) to 10(-3)), low-level positive (MRD detected only after oligoprobing; sensitivity 10(-3) to 10(-5)), or negative. Excluding 8 patients transplanted in CR2 for isolated extramedullary relapse (all MRD-), MRD was detected at high level in 12 patients, low level in 11, and was undetectable in 33. Two-year event-free survival for these groups was 0%, 36%, and 73%, respectively (P <.001). Follow-up in patients remaining in continuing remission is 20 to 96 months (median, 35). These results suggest that MRD analysis could be used routinely in this setting. This would allow identification of patients with resistant leukemia (who may benefit from innovative BMT protocols) and of those with more responsive disease (who may be candidates for randomized trials of BMT versus modern intensive relapse chemotherapy).
PMID: 9834212 [PubMed - indexed for MEDLINE]
Blood 1998 Nov 15;92(10):3569-77 Related Articles, Books, LinkOut
Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study.
Balis FM, Holcenberg JS, Poplack DG, Ge J, Sather HN, Murphy RF, Ames MM, Waskerwitz MJ, Tubergen DG, Zimm S, Gilchrist GS, Bleyer WA.
Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; and the Children's Cancer Group, Arcadia, CA, USA. balisf@nih.gov
We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 micromol*h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 micromol*h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P =.007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P =.043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.
Publication Types: Multicenter Study
PMID: 9808549 [PubMed - indexed for MEDLINE]
Crit Rev Oncol Hematol 1998 Aug;28(2):97-113 Related Articles, Books, LinkOut
Use of L-asparaginase in childhood ALL.
Muller HJ, Boos J.
Abteilung fur Padiatrische Hamatologie, Munster, Deutschland. hmuller@uni-muenster.de
Owing to the high efficacy of L-asparaginase in the treatment of acute lymphatic leukaemia the enzyme was introduced into the chemotherapy schedules for remission induction of this disease shortly after results of large-scale clinical trials had become available. Since asparaginase monotherapy was associated with a high response rate but short remission duration, the enzyme is currently employed within the framework of combination chemotherapy schedules which achieve treatment response in about 90% and long-term remissions in the majority of patients. Recently initiated clinical trials have still confirmed the eminent value of asparaginase in the combination chemotherapy of acute lymphatic leukaemia and of some subtypes of non-Hodgkin lymphoma, and its important role as an essential component of multimodal treatment protocols. Despite the unique mechanism of action of this cytotoxic substance which shows relative selectivity with regard to the metabolism of malignant cells, some patients experience toxic effects during asparaginase therapy. Immunological reactions toward the foreign protein include enzyme inactivation without any clinical manifestations as well as anaphylactic shock. Severe functional disorders of organ systems result from the impaired homeostasis of the amino acids asparagine and glutamine. The changes affecting the proteins of the coagulation system have considerable clinical impact as they may induce bleeding as well as thromboembolic events and may be associated with life-threatening complications when the central nervous system is involved. Risk factors predisposing to thromboembolic complications are hereditary resistance against activated protein C and any other hereditary thrombophilia. Other organ systems potentially affected by relevant functional disorders are the central nervous system, the liver, and the pancreas, with patients who have a history of pancreatic disorders carrying an especially high risk of developing pancreatitis. Studies on the mechanisms of action and the occurrence of resistance phenomena have shown that a treatment response may only be expected if the malignant cells are unable to increase their asparagine synthetase activity to an extent providing enough asparagine to the cell; one may thus conclude that the enzyme-induced asparagine depletion of the serum constitutes the decisive cytotoxic mechanism. Independent of the asparagine depletion related cytotoxicity however, there are other mechanisms of clinical relevance like induction of apoptosis. Besides this, further influences on signal transduction cannot be excluded. Only few publications have dealt with the question of minimum trough activities to be ensured before each subsequent asparaginase dose in order to maintain uninterrupted asparagine depletion under treatment, and answers to this problem are not definitive. Clinical studies using enzymes from E. coli strains indicate that a trough activity of 100 U/l will suffice for complete asparagine depletion of the fluid body compartments with the preparations studied. These findings have been transferred to enzymes from other E. coli strains as well as those isolated from Erwinia chrysanthemi and to the PEG-conjugated E. coli asparaginases. It might be desirable to countercheck the results for confirmation or correction. The dosage and administration schedule of the various enzyme preparations required for complete asparagine depletion over a period of time have been insufficiently defined. While pharmacokinetic studies showed clinically relevant differences in biological activity and activity half-lives for enzymes from different biological sources, the findings of recently published clinical trials indicate that the therapeutic efficacy is affected when different asparaginase preparations are given by identical therapy schedules. (ABSTRACT TRUNCATED)
Publication Types: Review Review, Tutorial
PMID: 9768345 [PubMed - indexed for MEDLINE]
Leukemia 1998 Oct;12(10):1534-8 Related Articles, Books, LinkOut
Duration of first remission predicts remission rates and long-term survival in children with relapsed acute myelogenous leukemia.
Stahnke K, Boos J, Bender-Gotze C, Ritter J, Zimmermann M, Creutzig U.
University Children's Hospital, Ulm, Germany.
Although treatment of childhood acute myelogenous leukemia (AML) has substantially improved in the last 15 years, in nearly half of the patients disease recurs. The aim of this study was to establish the prognosis of relapsed childhood AML and to identify prognostic factors for achievement of second remission and survival. From February 1988 to July 1996, 134 children with first relapse of AML were reported to the study center of the AML-BFM group. 102 patients treated intensively to induce second remission were prospectively followed. With various regimens, complete remission was achieved in 52 of 102 patients (51%), 27 children were alive in median 2.5 years (range, 0.4-7 years) after relapse. Disease-free survival was observed in seven of 16 patients transplanted from a matched sibling donor, one of four after matched unrelated bone marrow transplantation, 10 of 22 after autologous transplantation and five of nine patients after chemotherapy alone (two patients were lost to follow-up). Time until relapse reflecting the duration of first remission is the only variable correlating CR and survival rates. Defining early relapse as less than 1.5 years from diagnosis to relapse resulted in a 5-year survival of 10%, s.e. 5% for early relapses and 40%, s.e. 10% for late relapses (P-logrank test, 0.0001). Duration of first remission is a strong predictor for achievement of second CR and survival. It should be considered in reporting results of experimental therapies.
PMID: 9766496 [PubMed - indexed for MEDLINE]
Blood 2002 Jan 1;99(1):375-7 Related Articles, Books, LinkOut
Preferential loss of maternal 9p alleles in childhood acute lymphoblastic leukemia.
Morison IM, Ellis LM, Teague LR, Reeve AE.
Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand. ian.morison@otago.ac.nz
Germ-line events, such as paternal mutation or genomic imprinting, contribute to the early onset of childhood cancers such as retinoblastoma, Wilms tumors, and neuroblastoma. Given the high frequency of deletion involving chromosome 9p in childhood acute lymphoblastic leukemia (ALL), this study investigated whether 9p deletion might reflect preexisting germ-line gene inactivation. To do this the parental origin of deletion was determined in 10 cases of ALL with 9p21 loss of heterozygosity. Of these cases, 9 showed loss of the maternally derived allele, suggesting that a germ-line event involving a 9p gene may play a role in the onset of childhood ALL.
27: Blood 1998 Oct 1;92(7):2334-7 Related Articles, Books, LinkOut
Late relapsing childhood lymphoblastic leukemia.
Vora A, Frost L, Goodeve A, Wilson G, Ireland RM, Lilleyman J, Eden T, Peake I, Richards S.
Molecular Haematology Unit, Children's and Royal Hallamshire Hospital, Sheffield, UK. A.J.Vora@Sheffield.ac.uk
Childhood lymphoblastic leukemia (ALL) is usually assumed to have been permanently eradicated in patients in long-term remission, but occasionally can recur after many years. To learn more about the problem, we studied a group of children whose leukemia had been in remission for 10 or more years before relapse and tried to determine whether they had true recurrences or second malignancies. We studied children treated on Medical Research Council ALL protocols between 1970 and 1984 and followed up by the Clinical Trial Service Unit in Oxford. Detailed clinical and laboratory data was collected from the centers concerned on all who were reported to have had a recurrence of their leukemia after 10 or more years from the time of achieving first complete remission (CR1). To prove that the relapse was a true recurrence rather than a second or secondary leukemia, DNA extracted from archived marrow smears was subjected to polymerase chain reaction (PCR) analysis for the presence of an identical Ig heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement at initial diagnosis and subsequent relapse. A total of 1,134 of 2,746 children had survived 10 years or more (range, 10 to 24 years) in CR1 and of those, 12 (approximately 1%) had subsequently relapsed. Relapse blast cells were shown to express the common ALL antigen (CD 10) in all cases and an identical clonal IgH or TCR gene rearrangement was found on PCR analysis of DNA from diagnosis and relapse in all eight cases where DNA extraction was successful. A further program of therapy was successful in inducing a second CR in all patients, four of whom have succumbed to a second relapse after 12 to 27 months. The remaining eight are in continuing CR2 at a follow-up of 12 to 108 months (median, 52) from relapse. Although the risk of relapse of childhood ALL after 10 years in remission appears to be small (around 1%), it persists. This raises questions about how blasts can survive quiescent for so long and when we can truly be confident of cure, if ever.
PMID: 9746771 [PubMed - indexed for MEDLINE]
Cancer Chemother Pharmacol 1998;42(4):266-72 Related Articles, Books, LinkOut
Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine.
Erb N, Harms DO, Janka-Schaub G.
Department of Pediatric Hematology and Oncology, Children's University Hospital, Hamburg, Germany.
Mercaptopurine (6MP) has been the standard drug for maintenance therapy of acute lymphoblastic leukemia. In a multicenter study we investigated whether thioguanine (6TG), which is converted more directly to the cytotoxic thioguanine nucleotides (TGN), offers a therapeutic advantage over 6MP. In this study (COALL-92), 6TG was randomized versus 6MP in maintenance therapy, whereby the doses of both drugs had to be adjusted to a white blood cell (WBC) count of between 2 and 3/nl. In 19 children the plasma levels of both drugs and/or the accumulation of their metabolites in red blood cells (RBC) were measured during intensive treatment in two consecutive chemotherapy blocks, and in 54 children the metabolites in RBC were measured every 3 months during daily treatment in maintenance therapy. There was a marked interindividual difference in the plasma kinetics of the two drugs; after identical doses of 100 mg/m2 an about 4-fold higher peak concentration of the parent drug was reached with 6MP. The main metabolites of 6TG were thioguanine nucleotides (TGN), whereas during 6MP treatment, methylated thioinosine nucleotides (TIN) predominated in erythrocytes. In patients receiving 6TG during maintenance therapy (22 patients) the concentration of methylated TGN reached about 40% of that of unmethylated TGN; after 6MP administration (32 patients) the methylated TIN were concentrated about 26-fold higher in RBC than were TGN. In contrast to 6TG, for 6MP the pattern of metabolites shifted toward the methylated ones with increasing dose. The median TGN concentration was about 7-fold higher in the TG branch, although the median dose was only about 70% of that of 6MP. The WBC values were equivalent in the two treatment groups. Our results suggest that the cytotoxic effect of 6MP is not based solely on the formation of TGN.
Publication Types: Clinical Trial Multicenter Study Randomized Controlled Trial
PMID: 9744770 [PubMed - indexed for MEDLINE]
Br J Haematol 1998 Aug;102(3):729-39 Related Articles, Links
Critical study of prognostic factors in childhood acute lymphoblastic leukaemia: differences in outcome are poorly explained by the most significant prognostic variables. Fralle group. French Acute Lymphoblastic Leukaemia study group.
Donadieu J, Auclerc MF, Baruchel A, Leblanc T, Landman-Parker J, Perel Y, Michel G, Cornu G, Bordigoni P, Sommelet D, Leverger G, Hill C, Schaison G.
Departement de Biostatistique et d'Epidemiologie, Institut Gustave Roussy, Villejuif, France.
We determined the proportion of survival variability explained by the usual prognostic factors in childhood acute lymphoblastic leukaemia (ALL) during a prognostic study of 1552 patients enrolled in three consecutive Fralle group protocols (Fralle 83, Fralle 87 and Fralle 89). The event-free survival rates at 5 years were 54.8% (SD 1.9), 43.1%) (SD 2.7) and 55.6% (SD 2.2), respectively. In the univariate analysis the following variables were predictive of poor outcome: male gender, elevated leucocytosis (> 50 x 10(9)/l), circulating blastosis. haemoglobin >12 g/dl, platelet count <100 x 10(9)/l, age under 1 year or over 9 years, enlarged mediastinum, nodes, spleen and liver, T phenotype, absence of CD10+ cells; testicular and meningeal involvement, poor response to induction therapy (CCSG M3), and LDH >400 U/l. Among the cytogenetic features, hyperdiploidy had a protective effect, whereas hypodiploidy, translocation and other structural abnormalities had a negative influence, particularly in cases of t(9;22) or t(4;11). Multivariate analysis summarized the prognostic information in terms of four variables: age, gender, leucocytosis and cytogenetic features. Missing data had little influence on the results. However, despite their significance in the multivariate analysis, these four variables each had very low predictive power (1.1% for gender, 2.0% for age, 3.5% for leucocytosis, and 1.6% for cytogenetic features). Thus, the most significant prognostic factors in childhood ALL each explain no more than 4% of the variability in prognosis. This may explain the disappointing practical value of these factors and underlines the need for prognostic tools in childhood ALL.
Publication Types: Multicenter Study
PMID: 9722300 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1998 Aug;22(4):325-30 Related Articles, Books, LinkOut
Outcome of acute lymphoblastic leukaemia in Danish children after allogeneic bone marrow transplantation. Superior survival following transplantation with matched unrelated donor grafts.
Lausen BF, Heilmann C, Vindelov L, Jacobsen N.
Paediatric Clinic II, Rigshospitalet, University of Copenhagen, Denmark.
Outcome of allogeneic BMT for childhood ALL performed at a national centre was evaluated for the period between 1985 and 1996. Sixty-seven patients representing all Danish children and adolescents (1-19 years) transplanted for ALL, were evaluated. Patients transplanted with a family donor (n = 51) had a 3-year probability of leukaemia-free survival (P-LFS) of 56% (95% confidence limits 41-69%) and patients receiving marrow from a matched unrelated donor (MUD) (n = 16) had a 3-year P-LFS of 67% (34-86%) (P = 0.38). Relapse was responsible for 48% of the deaths and occurred with increasing frequency among children transplanted with marrow from HLA-identical siblings. Patients transplanted with family donors from 1985-1989 had P-LFS of 72% (54-84%) compared to patients transplanted after 1990 who revealed a significantly reduced P-LFS of 28% (10-49%, P = 0.01). Furthermore, the risk of relapse was increased (65% (24-88%)) (P = 0.02) in the later period. In contrast, patients transplanted with marrow from a MUD (1990-1996) had a lower risk of relapse (11%, 5-20%) (P = 0.002) but a comparable risk of transplant-related mortality. Children who experience relapse after modern, intensive treatment for ALL may have an increased propensity for relapse even after BMT. Therefore, when performing BMT for childhood ALL, there may be a benefit in overall survival from the increased graft-versus-leukaemia effect that follows less intensive GVHD prophylaxis or transplantation with a MUD.
PMID: 9722066 [PubMed - indexed for MEDLINE]
1: J Clin Oncol 1998 Aug;16(8):2854-63 Related Articles, Books, LinkOut
Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.
Shuster JJ, Wacker P, Pullen J, Humbert J, Land VJ, Mahoney DH Jr, Lauer S, Look AT, Borowitz MJ, Carroll AJ, Camitta B.
Department of Pediatrics, University of Geneva, Switzerland. jon@pog.ufl.edu
PURPOSE: In childhood B-precursor acute lymphoblastic leukemia (ALL), possible interactions among sex, time, and widely used prognostic factors (age, WBC count, and DNA index) were investigated for the first 5 years after diagnosis. PATIENTS AND METHODS: All eligible patients aged 1 to less than 22 years, registered between February 1986 and September 1994 in two B-precursor ALL studies from the Pediatric Oncology Group (POG), were included in the analysis. Cutpoints for age (3.0, 5.0, and 10.0 years), WBC count (10, 50, and 100 x 10(9)/L), and DNA index (DI; 1.16) were defined. Four time periods after diagnosis (years 1, 2, 3, and 4 and 5 combined) were selected for the study of prognostic significance over time. The cut-off date for analysis was April 1996. RESULTS: A total of 3,717 children (2,010 boys and 1,707 girls) were included in the outcome analysis. No major differences between the sexes were observed in age, duration of symptoms before registration, WBC count, hemoglobin level, platelet count, ploidy, presence of CNS disease at diagnosis, or induction failure rate. Event-free survival (EFS) differences between sexes became significantly different from 2 years following diagnosis. At 5 years, in all subsets analyzed, boys fared worse than girls, although not all differences were statistically significant. Major sex differences in EFS were observed in older children (10 to 22 years), in patients with intermediate WBC counts (10 to 50 x 10(9)/ L), and in children who fit both of these subgroups, in whom the 2-year EFS was almost 20% higher in girls than in boys, reaching a 38% difference at 5 years. CONCLUSION: This study shows an outcome interaction among sex, time, and commonly used prognostic variables. The important sex difference observed at 2 and 5 years suggests that more intensive consolidation and/or maintenance therapy in some boys with B-precursor ALL should be investigated.
Publication Types: Multicenter Study
PMID: 9704739 [PubMed - indexed for MEDLINE]
Clin Lab Haematol 1998 Apr;20(2):123-4
Severe vincristine toxicity in combination with itraconazole.
Gillies J, Hung KA, Fitzsimons E, Soutar R.
Department of Haematology, Monklands District General Hospital, Airdrie, UK.
We report two patients with acute lymphoblastic leukaemia (ALL) who were entered into the current MRC adult ALL trial (UKALL XII) in whom unusually severe vincristine induced neurotoxicity developed. This appeared to be the result of an interaction with itraconazole suspension.
PMID: 9681224 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1998 May;21(10):1015-21 Related Articles, Books, LinkOut
Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in Italy. AIEOP/FONOP-TMO Group. Italian Association of Paediatric Haemato-Oncology.
Comment in: Bone Marrow Transplant. 2000 Nov;26(10):1136-7.
Messina C, Cesaro S, Rondelli R, Rossetti F, Locatelli F, Pession A, Miniero R, Dini G, Uderzo C, Dallorso S, Meloni G, Vignetti M, Andolina M, Porta F, Amici A, Favre C, Basso G, Sotti G, Varotto S, Destro R, Gazzola MV, Pillon M, Petris MG, Rabusin M, Scarzello G, et al.
Clinica Onco-Ematologia Pediatrica, Universita di Padova, Italy.
From January 1984 to December 1994, ABMT was performed on 154 children (101 males, 53 females; median age 10, range 3-21 years) with ALL and registered for BMT by the AIEOP (Italian Association of Paediatric Haemato-Oncology). All patients were in CR: 98 were in 2nd CR and 56 were in >2nd CR. Fifteen children (9.7%) died of transplant-related mortality. Ninety-five patients (61.6%) relapsed at a median of 5 (range 1-42) months after ABMT. The 8-year EFS according to pre-BMT status was 34.6% (s.e. 4.9) for 2nd CR patients and 10.6% (s.e. 5.6) for patients in >2nd CR. By univariate analysis, site of relapse (isolated extramedullary (IE) vs BM: EFS = 68.5% vs 18.2%; P < 0.0001) and TBI containing regimen (TBI vs no TBI: EFS = 48.1 vs 15.4%; P = 0.0023) were significant factors for 2nd CR patients. When the 2nd CR subset with BM involvement was analysed, TBI became insignificant (EFS = 25.4 vs 11.8%). No factors influenced EFS in patients in >2nd CR. By multivariate analysis, site of relapse was the only significant factor in 2nd CR patients (P < 0.0001). In conclusion, ABMT is an effective treatment after one early IE relapse. Few patients can be rescued after BM relapse.
PMID: 9632275 [PubMed - indexed for MEDLINE]
Hematol Oncol 1997 Aug;15(3):141-9 Related Articles, Books, LinkOut
Clinical presentation, hematologic features and treatment outcome of childhood acute lymphoblastic leukemia: a review of 73 cases in Hong Kong.
Ma SK, Chan GC, Ha SY, Chiu DC, Lau YL, Chan LC.
Department of Pathology, University of Hong Kong, Queen Mary Hospital.
Seventy-three consecutive cases of childhood acute lymphoblastic leukemia (ALL) diagnosed and managed in Queen Mary Hospital over a 10-year period from 1985 to 1994 were retrospectively analysed for their presenting features and treatment outcome. The 48 boys and 25 girls ranged in age from 0.4 to 14.2 years (median: 4.3 years). Bone and joint pain was a relatively common presenting feature besides fever, hepatosplenomegaly and lymphadenopathy. Immunophenotyping of blast cells showed: 51 B-cell precursor ALL, one B-ALL, 10 T-ALL and three myeloid-antigen positive ALL. Eight cases were unclassified since immunophenotyping had not been performed. Out of the 73 patients, treatment outcome was analysed in 20 cases treated with UKALL-VIII regimen and 28 cases treated with either the UKALL-XI regimen or the Hong Kong Children Cancer Study Group (HKCCSG) protocol which was modelled upon UKALL-XI. Although complete remission rates were similar between the two groups, patients treated with the former regimen that was less intensified suffered more relapses than the latter (56 per cent versus 21 per cent, P = 0.04). There were, however, no significant differences both in event-free survival (38.2 +/- 11.2 per cent versus 71.3 +/- 9.3 per cent, P = 0.12) and overall survival (70.0 +/- 10.2 per cent versus 79.6 +/- 8.3 per cent, P = 0.41) between the two groups at 3 years by long-rank test. With the use of risk-directed therapy and improved supportive care, two-thirds of our patients are able to enjoy long-term event-free survival.
Publication Types: Review Review, Multicase
PMID: 9600113 [PubMed - indexed for MEDLINE]
Br J Haematol 1998 Apr;101(1):94-103 Related Articles, Books, LinkOut
Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia.
Wheeler K, Richards S, Bailey C, Chessells J.
Department of Paediatrics, Oxford Radcliffe Hospital.
We examined the outcome of the 489 children with acute lymphoblastic leukaemia (ALL) who relapsed in the UKALL X trial, and produced graphical displays of adjusted comparisons of event-free survival (EFS) for chemotherapy versus bone marrow transplantation (BMT) from a sibling or volunteer unrelated donor, and autologous BMT (ABMT). EFS at 5 years was only 3% (95% CI 0-6%) for children who relapsed in the bone marrow (BM) within 2 years of diagnosis, irrespective of type of post-relapse treatment, whereas for those with late extramedullary relapse it was 66% (95% CI 48-85%). Comparison of the types of treatment did not show benefit for ABMT. For allogeneic BMT the overall reduction in the odds of an event was 26% (95% CI 1-51%) (2P= 0.05), resulting in an absolute increase in 5-year event-free survival of 14% (from 26.4% to 40.7%). New approaches are needed for children with early BM relapses whose prognosis is virtually hopeless with current therapy; however, a conventional chemotherapy approach may be justifiable for late extramedullary relapses. For the remaining patients (71%), with later BM or early extramedullary relapses, the optimal treatment is still not clear. This uncertainty warrants a formal randomized comparison of BMT and chemotherapy, to avoid the biases due to unmeasurable selection factors.
PMID: 9576189 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1997 Dec;20(11):939-44 Related Articles, Books, LinkOut
Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: a conceivable alternative?
Borgmann A, Baumgarten E, Schmid H, Dopfer R, Ebell W, Gobel U, Niethammer D, Gadner H, Henze G.
Department of Paediatric Haematology and Oncology of the Virchow Medical Center, Berlin, Germany.
In the BFM Relapse Study registry we retrospectively identified 136 patients with a first marrow relapse who had undergone BMT in second complete remission (CR2) (group A) and 33 patients who received transplants only after a 2nd bone marrow (BM) relapse had occurred (group B). Event-free survival (EFS) rates at 6 years after BMT were 0.49 +/- 0.05 and 0.48 +/- 0.09 for patients transplanted in CR2 and CR3, respectively. In context with the BFM chemotherapy trials for relapsed childhood ALL there is a clear benefit from BMT in 2nd CR for children with unfavorable prognostic features (isolated early BM relapse, very early BM relapse or BM relapse of T cell ALL). Similar control of leukemia can be achieved with either chemotherapy or BMT in late BM relapse of ALL. Assuming a 60% failure rate with chemotherapy for patients in second relapse, a third remission can be achieved in about 60% of patients who have received chemotherapy, rendering them eligible for BMT in 3rd CR. With this strategy 58% of these patients would survive and late sequelae of BMT be restricted to a minority. To withhold BMT in CR2 and not perform BMT before a 2nd BM relapse has occurred, may be a conceivable alternative for children with late ALL BM relapse, at least if no related donor is available.
PMID: 9422472 [PubMed - indexed for MEDLINE]
Intern Med 1997 Nov;36(11):819-21
Acute lymphoblastic leukemia with isolated adrenocorticotropic hormone deficiency.
Yamaguchi H, Nakamura H, Mamiya Y, Yamamoto Y, Tajika K, Sugihara H, Gomi S, Inokuchi K, Hasegawa S, Shibazaki T, Dan K, Wakabayashi I.
Department of Internal Medicine, Nippon Medical School, Sendagi, Tokyo.
A 57-year-old female was admitted to our hospital because of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). On admission, disturbance of consciousness and hyponatremia were recognized. The patient's endocrinological data showed low levels of adrenocorticotropic hormone (ACTH) (less than 5 pg/ml) and cortisol (5.9 microg/dl). Other anterior pituitary hormones were normal. Plasma ACTH and cortisol did not respond to the corticotropin releasing factor (CRF) test. A diagnosis of isolated ACTH deficiency was made. This is a rare case of isolated ACTH deficiency complicated with hematological malignancies.
PMID: 9392357 [PubMed - indexed for MEDLINE]
Zhonghua Liu Xing Bing Xue Za Zhi 1996 Aug;17(4):229-32 Related Articles, Books, LinkOut
[A case-control study of childhood leukemia]
[Article in Chinese]
Lu JC, Shi LY.
Guangzhou Medical College.
A 1:1 matched case-control study was conducted to investigate the etiological factors of childhood leukemia. It was found that there were five risk factors: (1) children living in the environmental pollution area, OR (95% CI) = 2.84 (1.14-7.10); (2) exposure to extreme low frequency electronmagnetic field (ELF), OR (95% CI) = 2.01 (1.18-3.42); (3) history of postnatal X-ray exposure, OR (95% CI) = 4.53 (1.68-12.21); (4) history of taking chloramphenicol, OR (95% CI) = 3.60 (1.62-8.01); (5) history of taking, antipyretic or analgesic drugs, OR (95% CI) = 1.93 (1.09-3.42). A protective factor was also discovered. Mothers often eating fish, pork and other meat foods, OR (95% CI) = 0.33 (0.18-0.59). The analysis of the population attributable risk showed that 91% of the childhood leukemia cases might attribute to these five risk factors. The interaction among these etiological factors was estimated. Results showed that there was a positive interaction between the X-ray exposure and chloramphenicol on additive model, the relative excess risk due to interaction (RERI) of childhood leukemia was 3.04.
PMID: 9387589 [PubMed - indexed for MEDLINE]
Br J Haematol 1997 Sep;98(4):999-1001 Related Articles, Links
Cell birth and death in childhood acute lymphoblastic leukaemia: how fast does the neoplastic cell clone expand?
Hirt A, Leibundgut K, Luthy AR, von der Weid N, Wagner HP.
Department of Paediatrics, Inselspital, University of Berne, Switzerland.
In 23 children with untreated precursor B-cell acute lymphoblastic leukaemia (ALL), the daily growth rate of the malignant cell clone was calculated. Cell birth expanded the leukaemic cell clone an average 10-11% per day, programmed cell death or apoptosis reduced the leukaemic cell mass by some 4% per day. From these two variables a net increase in the size of the leukaemic cell population of 6.9+/-7.3% (range -1.2-27.3%) per day could be calculated. The daily growth rate correlated negatively with the logarithm of the duration of clinical symptoms before the diagnosis of ALL was established (r=-0.680; P=0.0004). A long history, especially in children with undefined bone pain and arthralgias, was associated with a very slow expansion of the neoplastic cell clone.
PMID: 9326202 [PubMed - indexed for MEDLINE]
Br J Haematol 1997 Sep;98(4):945-51 Related Articles, Links
Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia.
Chessells JM, Harrison G, Lilleyman JS, Bailey CC, Richards SM.
Haematology/Oncology Department, Institute of Child Health, London.
The relationship between the prescribed dose of drugs during continuing (maintenance) therapy, the degree of marrow suppression caused, and subsequent event-free survival was examined in a cohort of 740 children with lymphoblastic leukaemia treated on MRC UKALL X. Girls, younger children, and patients who had received intensification treatment, were prescribed lower doses of mercaptopurine, became neutropenic more readily, and had more interruptions of treatment. Children who had one or more episodes of neutropenia with a count of <0.5 x 10(9)/l had a better prognosis than those who never became neutropenic. We conclude that early intensification treatment influences the probability of neutropenia during continuing treatment and that patients exhibiting myelosuppression during this phase of treatment have a better chance of prolonged remission.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 9326194 [PubMed - indexed for MEDLINE]
Med Pediatr Oncol 1997 Dec;29(6):534-40 Related Articles, Books, LinkOut
Bone marrow transplantation versus chemotherapy for maintenance of second remission of childhood acute lymphoblastic leukemia: a study of the Children's Cancer Group (CCG-1884).
Feig SA, Harris RE, Sather HN.
UCLA Children's Hospital, Los Angeles, CA, USA.
BACKGROUND: Maintenance of second remission of childhood acute lymphoblastic leukemia (ALL) with intensive chemotherapy is often unsuccessful. The major cause of treatment failure is relapse. MATERIALS AND METHODS: Of 96 children with ALL who relapsed in the marrow while on or within 1 year of completing initial therapy, 62 achieved a second remission. Nineteen patients underwent bone marrow transplantation in second remission, 11 from a human leukocyte antigen (HLA)-matched related donor, seven using autologous marrow, and one from a matched unrelated donor. The event-free survival (EFS) of transplanted patients was compared to that of patients treated with intensive chemotherapy using high-dose cytarabine, vincristine, escalating dose methotrexate, L-asparaginase, and an anthracycline (daunorubicin or idarubicin). Only those patients treated with chemotherapy who survived in second remission up to the mean time that patients were transplanted (135 days) were included in the control group (33 of 43 patients who achieved second remission). RESULTS: The actuarial 2-year event-free survival of transplanted patients is 37+/-22% (95% C.I.) compared to 18+/-13% for chemotherapy-treated patients (P=0.017). EFS for allo-transplant recipients was similar to that for auto-transplant recipients. Duration of initial remission was a strong predictor of the outcome of retrieval therapy. Patients whose initial remission was greater than 3 years had better EFS after achieving second remission (five of 11 still in remission, compared to four of 41 patients whose initial remission was less than 3 years). Adjustment in the multivariate analysis for duration of initial remission did not diminish the benefit of transplant over chemotherapy. CONCLUSIONS: While there remains considerable possibility for further improvement in EFS after achieving second remission of childhood ALL, bone marrow transplant is superior to chemotherapy in maintaining second remission.
PMID: 9324340 [PubMed - indexed for MEDLINE]
Ther Drug Monit 1997 Aug;19(4):382-5 Related Articles, Links
Pharmacokinetics of mercaptopurine: plasma drug and red cell metabolite concentrations after an oral dose.
Welch J, Lennard L, Morton GC, Lilleyman JS.
University of Sheffield, Department of Paediatrics, Children's Hospital Sheffield, United Kingdom.
Measurement of red cell 6-mercaptopurine (MP) derived 6-thioguanine nucleotide (TGN) and methylmercaptopurine metabolites (MeMPs) can be used to monitor therapy in children who are administered MP for childhood lymphoblastic leukemia. Red cell TGNs are not influenced by the time of blood sampling in relation to the last MP dose. The purpose of this study was to find out whether the same is true for the MeMPs. Plasma MP and red cell MP metabolite pharmacokinetics were studied in seven children immediately before and for 4 hours after a protocol standardized dose of MP. Duplicate blood samples were taken, one was processed immediately whereas one was left at an ambient temperature for 24 hours. The variation in TGN and MeMP metabolites over the 0- to 4-hour period (10 time points per child) was within the error of the assays used. The coefficients of variation for the TGNs ranged from 2.7% to 7% and for the MeMPs, 4% to 10.7%. There was no difference in the TGN and MeMP concentrations measured when the blood samples were left for 24 hours. If a child takes a MP tablet immediately before a clinic appointment, it has no major influence on MeMP measurements.
PMID: 9263376 [PubMed - indexed for MEDLINE]
Med Pediatr Oncol 1997 Oct;29(4):252-5 Related Articles, Books, LinkOut
Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia: 6-mercaptopurine dosage strategies.
Lennard L, Lewis IJ, Michelagnoli M, Lilleyman JS.
Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, U.K.
Daily 6-mercaptopurine (6MP) forms the backbone of continuing chemotherapy for childhood lymphoblastic leukaemia (ALL). A major metabolic route is catalysed by thiopurine methyltransferase (TPMT). TPMT deficiency occurs in 1 in 300 individuals and results in high concentrations of thioguanine nucleotides (TGNs), cytotoxic 6MP metabolites. A leukaemic child taking 6MP repeatedly developed profound pancytopenias. TPMT deficiency was confirmed. TGN formation was then studied on attenuated 6MP dosages. Four weekly oral doses of 75 mg/m2 6MP produced TGNs of 2348 pmol/8 x 10(8) red cells, nearly double the maximum TGNs recorded in ALL children with TPMT activity taking long term daily 75 mg/m2 6MP. Grossly elevated TGN concentrations were also produced at 10% standard 6MP dosage (7.5 mg/m2 daily), accompanied by unacceptable 6MP toxicity (neutropenia, diarrhoea, vomiting). The child was eventually stabilised on 10% alternate day therapy and after 15 weeks TGNs were 1670 pmol, just above the upper end of the TGN range for ALL children with TPMT activity.
PMID: 9251729 [PubMed - indexed for MEDLINE]
Br J Haematol 1997 Jul;98(1):140-6 Related Articles, Books, LinkOut
A prospective study of minimal residual disease in childhood B-lineage acute lymphoblastic leukaemia: MRD level at the end of induction is a strong predictive factor of relapse.
Jacquy C, Delepaut B, Van Daele S, Vaerman JL, Zenebergh A, Brichard B, Vermylen C, Cornu G, Martiat P.
Haematologic Molecular Biology Unit, University of Louvain Medical School, Brussels, Belgium.
We prospectively investigated minimal residual disease (MRD) in 51 children with B-lineage acute lymphoblastic leukaemia (ALL) treated according to the Fralle 93 protocol. PCR follow-up was performed in children in morphological and cytogenetic complete remission, provided an immunoglobulin (IgH) gene rearrangement could be detected using FR 3/J(H) amplimers. MRD was studied according to our previously described methodology, with a few modifications including the use of a consensus J(H) probe to control for PCR efficiency variations. Out of the initial 51 patients, 34 were assessable for MRD at the end of induction at the time of analysis. MRD levels were as follows: > 1/10(3) in 26%, 1/10(3) to 1/10(4) in 50% and < 1/10(4) or not detectable in 24%. With a median follow-up of 20 months there were five relapses, all of which occurred in the group of patients with MRD > 1/10(3). To date, none of the patients with MRD < or = 1/10(3) (good molecular responder) has relapsed. Classification according to molecular response at the end of induction did not correlate with the conventional risks groups: there were no statistically significant differences between good and bad molecular responders. Of particular interest is the absence of correlation between WBC at diagnosis and MRD level at the end of induction. We conclude that classification of patients into good and bad molecular responders using PCR seems to be a better prognostic indicator than conventional risk factors in childhood B-lineage ALL. Patients with MRD level > 1/10(3) have a particularly poor outcome and should always be considered for alternative therapeutic strategies in the future, whereas in good molecular responders belonging to poor or intermediate risk categories, treatment de-escalation might be contemplated.
PMID: 9233577 [PubMed - indexed for MEDLINE]
Leuk Res 1997 May;21(5):429-34 Related Articles, Books, LinkOut
On the prognostic value of systemic methotrexate clearance in childhood acute lymphocytic leukemia.
Comment in: Leuk Res. 1997 May;21(5):435-7.
Seidel H, Nygaard R, Moe PJ, Jacobsen G, Lindqvist B, Slordal L.
Department of Paediatrics, Norwegian University of Science and Technology, Trondheim, Norway.
The prognostic value of systemic methotrexate clearance (ClMTX) during high-dose therapy was evaluated in a cohort of 42 children with acute lymphocytic leukemia (ALL). As part of an extensive chemotherapy protocol, they had received a total of 293 methotrexate (MTX) infusions in the 6-8 g/m2 dose range. At the termination of the study, when they had all been followed up for 3.5 years or more, 26 of these patients were still in continuous complete remission, whereas 16 had suffered relapse. The intrapatient variability in ClMTX during the eight courses was up to six-fold. In 67% of the patients, the maximum level of ClMTX reached at least twice the minimum value. The coefficients of variation for the intra- and interindividual variability in ClMTX were 9-57% and 26-41%, respectively. The cumulative probability of relapse, estimated by the Kaplan-Meier procedure, was increased for patients with a high ClMTX during the initial treatment course, but the difference was not significant on a 5% level. There was no significant relationship between high individual median ClMTX and subsequent relapse of ALL. However, ClMTX during the initial infusion, the time-dependent mean for ClMTX, and the individual patient's median ClMTX, were significant predictors for event-free survival in a Cox proportional hazards regression analysis. The present study demonstrates gross pharmacokinetic variability and unpredictable values of ClMTX in subsequent courses after standardized administration of MTX to paediatric patients with ALL. In spite of the association between ClMTX and prognosis shown by some of the analyses, estimates of ClMTX rates may not necessarily be related to disease outcome in a way that can be exploited to the benefit of the individual patient.
PMID: 9225071 [PubMed - indexed for MEDLINE]
Arch Dis Child 1997 Apr;76(4):365-6 Related Articles, Links
Profile of non-compliance in lymphoblastic leukaemia.
Lancaster D, Lennard L, Lilleyman JS.
Department of Paediatric Oncology, St Bartholomew's Hospital, London.
A nationwide study of intracellular drug metabolite concentrations in children prescribed 6-mercaptopurine for the treatment of lymphoblastic leukaemia was carried out to assess interpatient variability at a standardised dose. Nine children (2% of the total) had completely undetectable metabolites, indicative of non-compliance. Five were adolescents, but otherwise they had no obvious distinguishing characteristics. Not taking any 6-mercaptopurine at all is uncommon, but the problem cannot be predicted. The total number of children who do not comply cannot be determined from this study, but the nine children described represent only a fraction of these.
PMID: 9166035 [PubMed - indexed for MEDLINE]
J Pediatr Hematol Oncol 1997 Mar-Apr;19(2):102-9 Related Articles, Books, LinkOut
Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO).
Schmiegelow K, Glomstein A, Kristinsson J, Salmi T, Schroder H, Bjork O.
Section of Clinical Hematology and Oncology, Juliane Marie Center, University Hospital, Copenhagen, Denmark.
PURPOSE: To study the risk of non-B-cell acute lymphoblastic leukemia (ALL) relapse in relation to the routines of administration of oral methotrexate (MTX) and 6-mercaptopurine (6MP) and to the erythrocyte (E) levels of the intracellular cytotoxic metabolites, that is, MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN). PATIENTS AND METHODS: E-MTX and E-6TGN levels were measured at least three times (medians, eight and nine) in 294 children with non-B-cell ALL during oral MTX and 6MP therapy. For each patient, we registered (a) the individual circadian schedule of drug administration and (b) the coadministration of food, and (c) calculated a mean (m) of all E-MTX and E-6TGN measurements and (d) the product of mE-MTX and mE-6TGN (mE-MTX*6TGN), due to their synergistic action. RESULTS: A total of 42 patients were on a morning schedule, 219 were on an evening schedule, and 33 had miscellaneous routines. A total of 149 patients took the drugs with meals, 106 took the drugs between meals, and 39 had varying routines. With a median follow-up of 78 months, ALL has recurred in 66 patients. The patients on an evening schedule had a superior outcome [probability of event-free survival (pEFS) = 0.82 +/- 0.03 vs. 0.57 +/- 0.08; p = 0.0002], whereas the coadministration of food did not significantly influence outcome. Patients with a mE-MTX*6TGN < 813 [product of median mE-MTX (4.7 nmol/mmol Hb) and mE-6TGN (173 nmol/mmol Hb)] had an inferior outcome (pEFS = 0.70 +/- 0.04 vs. 0.85 +/- 0.03; p = 0.003), even if only patients on an evening schedule were analyzed. Thus, 109 patients on the MTX/6MP evening schedule with an mE-MTX*6TGN < or = 813 (nmol/mmol Hb)2 had a pEFS of 0.89 +/- 0.03 and a probability of continuous hematopoietic remission of 0.91 +/- 0.03. CONCLUSIONS: An evening schedule should be recommended for oral MTX/6MP maintenance therapy. The value of individual dose adjustments by E-MTX and E-6TGN remains to be determined in prospective randomized trials.
PMID: 9149738 [PubMed - indexed for MEDLINE]
Pediatr Pol 1996 Apr;71(4):301-6 Related Articles, Books, LinkOut
[Vaccination against influenza in children with acute lymphoblastic leukemia]
[Article in Polish]
Jackowska T, Brydak L, Rokicka-Milewska R, Lukowska K, Gosk B, Rudnicka H, Regnery H, Cox N.
Katedra i Klinika Pediatrii, Hematologii i Onkologii Akademii Medycznej w Warszawie.
In November and December 1993, 49 children, ages 4 to 20, suffering from acute lymphoblastic leukemia, were vaccinated against influenza in the Department of Paediatric Haematology and Oncology, Medical Academy in Warsaw. These patients were vaccinated either in the course of maintenance treatment or after treatment. Each dose of Wyeth USA subunit trivalent influenza vaccine contained 15 micrograms of hemagglutinin of strains recommended for that season. The level of antibody production was determined in pre- and post vaccination sera in the group of children with leukemia and the control group. It was determined that in the investigated group, the GMT increased more than four times for hemagglutinins H1N1 and H3N2. A somewhat lower increase was observed in case of hemagglutinin HB. The proportion of subjects protected after vaccination was 35% for hemagglutinin H1N1, 76% for H3N2 and 100% for HB. The response rate was 33% for hemagglutinin H1N1, 47% for H3N2 and 45% for HB. In the control group the proportion of subjects protected and the response rate were very low. The results show the significant immunological efficacy of the vaccine used in the vaccination against influenza in high risk groups.
PMID: 8975216 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1996 Nov;18 Suppl 2:43-6 Related Articles, Books, LinkOut
Which children do benefit from bone marrow transplant? The EBMT Paediatric Diseases Working Party.
Niethammer D, Klingebiel T, Ebell W, Henze G, Paolucci P, Riehm H.
Dept. of Paediatrics, Univ. of Tubingen, Germany.
The development of chemotherapy in childhood ALL has been the leader of the success story of paediatric oncology. At least 2/3 of the children can be cured nowadays at the first attempt of treatment. From the remaining again 1/3 can be treated successfully for the relapse of their disease with conventional therapeutic strategies. This means, however, that there is no chance for cure with chemotherapy alone for 20 to 25% of the children. BMT has been shown for a long time to be an alternative therapy especially in those cases in which conventional chemotherapy fails. In spite of the fact that many children with ALL have been transplanted during recent years there is still no general agreement on the question which children need BMT. However a few statements can be made: The value of ABMT in ALL is probably not better than that of chemotherapy alone. In 1st CR a group of children can be defined, which might benefit from BMT. In 2nd CR the value of chemotherapy depends very much from the duration of 1st remission. Allogeneic BMT is the only chance for cure in very early relapses, superior to chemotherapy in early and late relapses and possibly equal to chemotherapy in very late relapses. The paper tries to summarise our current knowledge about the situation.
Publication Types: Review Review, Tutorial
PMID: 8932798 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1996 Nov;18 Suppl 2:4-7 Related Articles, Books, LinkOut
Bone marrow transplant indications for childhood leukemias: achieving a consensus. The EBMT Pediatric Diseases Working Party.
Dini G, Cornish JM, Gadner H, Souillet G, Vossen JM, Paolucci P, Manfredini L, Miano M, Niethammer D.
G.Gaslini Institute, Genova, Italy.
During the "2nd International Course on Bone Marrow Transplantation in Children" a multiple choice questionnaire on bone marrow transplant indications for children with acute leukemias was distributed with the aim of achieving a consensus. The answers obtained from the twenty representatives of fourteen European countries during the meeting were analyzed and assigned to one of the following groups: I. definitive indication: when more than 75% participants were in favour; II. acceptable indication: when 50% to 74% participants were in favour; III. requires further investigation: when 25% to 49% participants were in favour; IV. no indication: when less than 24% participants were in favour. In acute lymphoblastic leukemia the following circumstances were considered a definitive indication for allogeneic bone marrow transplant (BMT) from a matched sibling donor (MSD): infancy, "high risk" (HR) patients in 1st complete remission (CR1); CR2 patients after an early bone marrow relapse (defined as a relapse occurring up to six months after stopping therapy). Patients experiencing an early meningeal relapse and CR2 patients after a late relapse (defined as a relapse occurring later than six months after stopping therapy) were considered an acceptable indication. Further investigation was required in order to better define the role of BMT for patients experiencing an early isolated testicular relapse. If a MSD is not available, HR patients in CR1 and CR2 patients, after an early bone marrow relapse, were considered a definite indication for a matched unrelated donor (MUD). This latter group was considered an acceptable indication for a haploidentical BMT if a MUD was not available. Further investigation was required to better define the role of autologous bone marrow transplant (ABMT) for patients experiencing an early extramedullary relapse and for HR patients in CR1 all of whom lacked MSD's. In acute myeloblastic leukemia (AML), CR2 patients were considered a definitive indication and CR1 patients were considered an acceptable indication for BMT from a MSD. CR2 patients were considered a definitive indication for ABMT and CR1 patients an acceptable indication in cases lacking a MSD. AML was not considered an indication for MUD BMT.
PMID: 8932789 [PubMed - indexed for MEDLINE]
Br J Clin Pharmacol 1996 Oct;42(4):525-7 Related Articles, Links
Mercaptopurine in childhood leukaemia: the effects of dose escalation on thioguanine nucleotide metabolites.
Lennard L, Welch J, Lilleyman JS.
University of Sheffield Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield.
The current U.K. trial protocol (UKALL XI) for childhood lymphoblastic leukaemia demands mercaptopurine (MP) dose escalation in children who tolerate daily 75 mg/m2 MP (100% dose) without cytopenias. The previous trial (UKALL X) did not. MP metabolism was studied in a group of UKALL XI children (n = 21) who tolerated 100% dosages and who were matched in this respect with a similar group of UKALL X children. Red blood cell MP derived thioguanine nucleotide (TGN) concentrations were measured in both groups under comparable conditions; at 75 mg/m2 MP there was no significant difference. MP dose escalation in the UKALL XI children produced higher TGN concentrations (TGNs at 100% vs 125% dosages, median difference 90 pmol/8 x 10(8) RBCs, 95% CI 25 to 165 pmol, P < 0.02). Assayed at the time of cytopenia induced dose reduction, the UKALL XI children had accumulated significantly higher TGN concentrations than the UKALL X children (median difference 78 pmol/8 x 10(8) RBCs, 95% CI 20 to 144, P < 0.02). These findings indicate that dose escalation in children tolerant of 100% MP dosages produces higher peak TGN concentrations.
PMID: 8904630 [PubMed - indexed for MEDLINE]
J Clin Oncol 1996 Oct;14(10):2812-7 Related Articles, Books, LinkOut
Peripheral blast counts at diagnosis of late isolated bone marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage chemotherapy and outcome. Berlin-Frankfurt-Munster Relapse Study Group.
Buhrer C, Hartmann R, Fengler R, Rath B, Schrappe M, Janka-Schaub G, Henze G.
Department of Pediatric Hematology/Oncology, Children's Hospital, Virchow Medical Center, Humboldt University, Berlin, Germany.
PURPOSE: In newly diagnosed childhood acute lymphoblastic leukemia (ALL), a high tumor burden indicates a poor prognosis, while no such link has been established yet after relapse. The impact of the absolute peripheral blast count (PBC) at the time of relapse on the response to salvage chemotherapy after a late isolated bone marrow (BM) relapse is the subject of this prospective analysis. PATIENTS AND METHODS: Since 1983, 260 children with a first isolated BM relapse of ALL that occurred 6 months or later after elective cessation of front-line therapy were enrolled onto four consecutive multicenter trials of the Berlin-Frankfurt-Munster (BFM) Relapse Study Group. All patients received intensive multiagent induction and consolidation chemotherapy for 6 months, followed by maintenance therapy with methotrexate (MTX) and thioguanine for 2 years. Treatment of subclinical meningeal leukemia consisted of high-dose intravenous MTX and intrathecally administered cytostatic drugs, which was augmented by cranial irradiation since 1988. RESULTS: At the time relapse was diagnosed, PBC varied considerably among patients (median, 1,060/microL; range, 0 to 106,800/microL). Achievement of a second complete remission (CR) was not significantly different in children without detectable circulating blasts at relapse (37 of 38) and those with moderate (1 to 9,999/microL) PBC (165 of 171). In contrast, only 42 of 51 children with high PBC (> or = 10,000/microL) achieved a second CR (P = .0015). At a median follow-up time of 40 months, the 10-year event-free survival (EFS) probability was significantly (P = .0001) higher in children without circulating blasts (.64) than in children with moderate PBC (.32) or high PBC (.10). There was a preponderance of boys in the group without detectable circulating blasts, while the three PBC-defined groups did not differ with respect to frontline treatment, age at initial diagnosis, age at relapse, time off therapy, or salvage treatment protocol. On sequential univariate and multivariate analysis, only duration of first remission > or = 48 months was an additional independent indicator of adverse prognosis, while preventive cranial irradiation improved outcome independently of PBC. CONCLUSION: The absence of blasts on peripheral-blood smears at the time of a first late isolated BM relapse of childhood ALL is associated with a favorable response and prognosis in chemotherapy-treated children, who should be regarded as ineligible for bone marrow transplantation (BMT) unless a second round of chemotherapy has failed to produce a response.
PMID: 8874343 [PubMed - indexed for MEDLINE]
Br J Haematol 1996 Sep;94(3):574-8 Related Articles, Books, LinkOut
Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission.
Oakhill A, Pamphilon DH, Potter MN, Steward CG, Goodman S, Green A, Goulden P, Goulden NJ, Hale G, Waldmann H, Cornish JM.
Royal Hospital for Sick Children, Bristol.
Allogeneic sibling bone marrow transplantation (BMT) is the recommended treatment for relapsed childhood acute lymphoblastic leukaemia (ALL), but appropriate donors are only available in 30% of cases. Unfortunately, BMT from unrelated donors (UD) has been associated with high rates of severe graft-versus-host disease (GvHD) and transplant-related mortality (TRM). In an attempt to improve outcome in UD-BMT we have assessed the impact of T-cell depletion using CAMPATH-1 (anti-CD52) monoclonal antibodies in 50 consecutively referred patients with relapsed ALL in second remission. All were previously treated according to MRC protocols UKALL X and XI, and then given chemotherapy on MRC R1 from relapse until UD-BMT, 19 patients had relapsed on and 31 off therapy. Patients and donors were fully matched at HLA-A, -B, -DR and -DQ loci in 29 cases and mismatched in 21 (four mismatched for more than one antigen). Pre-transplant conditioning comprised CAMPATH-1G, cyclophosphamide and total body irradiation. Bone marrow was T-cell depleted in vitro using CAMPATH-1 antibodies. Additional GvHD prophylaxis consisted of cyclosporin A (42 cases), cyclosporin plus methotrexate (four) or none (four). 47 patients engrafted. The incidence of acute GvHD was very low: two patients with grade II disease in the matched group, four with grade II-IV in the mismatched group. Only four patients have chronic GvHD. The actuarial event-free survival (EFS) at 2 years is 53%, with no significant difference between the matched and mismatched group. Further leukaemic relapse was the most important cause of failure. These results are similar to the most favourable published reports for HLA-matched sibling BMT in relapsed ALL.
PMID: 8790160 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 1996 May-Jun;13(3):257-63 Related Articles, Links
Detection of minimal residual disease in childhood acute lymphoblastic leukemia after termination of therapy.
Wu NH, Lu SG, Zhu P, Peng YY.
Department of Pediatrics, Yanjing Hospital, Beijing, China.
Using IgH and TCR gamma gene rearrangements as gene markers, we detected minimal residual disease (MRD) by means of the polymerase chain reaction (PCR) and restriction analysis. Of 18 children with acute lymphoblastic leukemia (ALL), MRDs were detected in 9 patients after termination of therapy. All 18 patients had been followed for 1.5 to 102 months after detection. Three of the nine MRD-positive patients relapsed within 3 to 6 months; none of the nine MRD-negative patients relapsed. We suggest that MRD negativity at the end of therapy might be an important factor for long-term disease-free survival, because the negative cases had a very low risk of relapse. Because the outcome for MRD-positive cases is more difficult to evaluate, patients with MRD after termination of therapy should be monitored.
PMID: 8735342 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1996 May;17(5):763-8 Related Articles, Books, LinkOut
Relapsed acute lymphoblastic leukemia: similar outcomes for autologous and allogeneic marrow transplantation in selected children.
Parsons SK, Castellino SM, Lehmann LE, Eickhoff CE, Tarbell NJ, Sallan SE, Weinstein HJ, Billett AL.
Division of Hematology@Oncology, Children's Hospital, Boston, MA, USA
The therapy of choice for relapsed childhood acute lymphoblastic leukemia is controversial. We retrospectively compared the outcome of 57 patients who received autologous bone marrow transplantation (BMT) with 17 patients who underwent allogeneic BMT for B cell lineage acute lymphoblastic leukemia after at least one marrow relapse. The allogeneic BMT cohort included only those who would also have been eligible for autologous BMT had they not had a matched sibling donor. Specifically, patients who were not in complete remission, those with T cell positive leukemia, t(9;22) or those with only an extramedullary relapse were excluded from both groups. Conditioning regimens included total body irradiation and chemotherapy. Age, white blood count at diagnosis, and duration of first and longest complete remissions were comparable for the two groups. The median follow-up of the event-free survivors was 4.8 years for those who received an autologous BMT (n = 26) and 4.6 years for those who received an allogeneic BMT (n = 8). The relapse rate was higher in the autologous BMT group and the incidence of non-leukemic deaths higher in the allogeneic BMT group. Event-free survival at 3 years was comparable for the two groups (47% +/- 7 vs 53% +/- 12, autologous vs allogeneic, respectively; P = 0.77). Based upon these findings, we concluded that the outcome for autologous BMT was equivalent to allogeneic BMT for relapsed childhood B cell lineage acute lymphoblastic leukemia in selected clinical situations.
PMID: 8733695 [PubMed - indexed for MEDLINE]
Lancet 1996 Jun 29;347(9018):1783-8 Related Articles, Books, LinkOut
Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group.
Childhood AlL Secretariat, CTSU, Radcliffe Infirmary, Oxford, UK.
BACKGROUND: The effects on long-term outcome in childhood acute lymphoblastic leukaemia (ALL) of the duration and the intensity of maintenance chemotherapy need to be assessed reliably. With this objective the Childhood ALL Collaborative Group coordinated a worldwide overview of all randomised trials that began before 1987. METHODS: Individual patient data were sought for about 3900 children in trials of longer vs shorter maintenance (eg, 3 vs 2 years), 3700 in trials of intensive "reinduction" chemotherapy during maintenance, and 4400 in trials of various other questions, including 1300 in trials of pulses of vincristine and prednisone (VP) during maintenance. Analyses were of survival in first remission, overall survival, and cause-specific mortality. FINDINGS: Deaths during remission were increased by longer maintenance (2.7 percent vs 1.2 percent), VP pulses (4.0 vs 3.2 percent), and intensive reinduction (4.8 percent vs 3.3 percent), but these increases were counterbalanced by reductions in relapses. Total events (relapse or death) were significantly reduced by longer maintenance (23.3 percent vs 27.6 percent), VP pulses (31.2 percent vs 40.4 percent) and intensive reinduction (27.8 percent vs 35.8 percent) (each 2p<0.001). Many of those who relapsed were successfully re-treated, however, and only for intensive reinduction was overall survival significantly improved (18.5 percent vs 22.3 percent; 2p=0.01). INTERPRETATION: Intensive reinduction chemotherapy in these trials produced an absolute improvement of about 4 percent in long-term survival; if the extra deaths in remission had been avoided, this would have been a 5 percent benefit. Further improvements in survival seem more likely to be obtained with intensive treatment than with longer low-level maintenance.
Publication Types: Meta-Analysis
PMID: 8667921 [PubMed - indexed for MEDLINE]
Cancer Chemother Pharmacol 1996;38(1):113-6 Related Articles, Links
6-Mercaptopurine dose escalation and its effect on drug tolerance in childhood lymphoblastic leukaemia.
Welch JC, Lilleyman JS.
University of Sheffield, Department of Paediatrics, The Children's Hospital, UK.
Daily oral 6-mercaptopurine (6MP) is important in the treatment of childhood lymphoblastic leukaemia (ALL), but there is great inter-patient variability in the pattern of evident drug effect (myelosuppression) seen at a standard dose. In an attempt to reduce that variability the current practise in the United Kingdom for the last 4 years has been to escalate the amount prescribed in patients who do not experience cytopenias at 75 mg/m2. We undertook a study to see whether that strategy would increase the total dose of 6MP prescribed in such patients and whether it would alter the pattern of myelosuppression. Over a 6-month period we studied 44 children treated conventionally (without escalation) and compared them with another 44 (matched for sex) who were treated on the same protocol but where doses were increased in monthly 25% steps if 75 mg/m2 was tolerated without cytopenias. We then compared the two groups for the total dose of drug prescribed and the frequency and duration of neutropenia or thrombocytopenia. The median cumulative dose of 6MP received by the conventionally treated children (10,002 mg/m2) was not significantly different from that of the children treated with dose escalation (9,429 mg/m2). In a comparison of the 30 children who actually received inflated doses of 6MP with the 37 from the conventional cohort who would have been eligible to do so, it was again found that the cumulative median doses were similar (10,460 versus 10,916 mg/m2). There was a difference between the two groups in the pattern of myelosuppression -- the escalated group spent significantly more time off 6MP than did the non-escalated group (median 4.5 versus 3 weeks; P<0.005, 95% CI from -1 to -3). These findings imply that the method of dose escalation employed does not allow more 6MP to be prescribed in children tolerant of the standard dose. The chief effect seems to be to generate longer periods off therapy, and this could paradoxically decrease the anti-neoplastic activity of the drug. Alternative ways of prescribing should be explored.
Publication Types: Clinical Trial Controlled Clinical Trial
PMID: 8603445 [PubMed - indexed for MEDLINE]
Cancer Chemother Pharmacol 1996;37(5):409-14 Related Articles, Links
Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate.
Innocenti F, Danesi R, Di Paolo A, Loru B, Favre C, Nardi M, Bocci G, Nardini D, Macchia P, Del Tacca M.
Institute of Medical Pharmacology, University of Pisa, Italy.
Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine (6-MP) and methotrexate (MTX) was investigated in patients as well as in rats and in HL-60 human leukemic cells. Ten children affected by acute lymphoblastic leukemia (ALL) in remission received daily doses of 6-MP given at 25 mg/m2 and i.v. infusion of high-dose MTX at 2 or 5 g/m2 once every other week. When 6-MP was given alone, the mean peak plasma concentration (Cmax) and area under the curve (AUC) of 6-MP were 72.5 ng/ml and 225.3 h ng ml(-1). Concurrent treatment with MTX at 2 or 5 g/m2 resulted in a mean increase of 108% and 121% in the Cmax and of 69% and 93% in the AUC, respectively. In rats treated with an oral dose of 6-MP at 75 mg/m2, MTX given i.p. at 5 g/m2 produced mean increases of 110% and 230% in the Cmax and AUC of 6-MP, respectively. In HL-60 human leukemic cells incubated with 6-MP at 250 ng/ml, the cumulative intracellular concentration of 6-thioguanine and 6-MP nucleotides was not significantly modified by treatment with 20 micrograms/ml of MTX. The present findings indicate that high-dose MTX enhances the bioavailability of 6-MP as evidenced by the observed increases in the plasma Cmax and AUC of 6-MP in humans and animals.
PMID: 8599862 [PubMed - indexed for MEDLINE]
Int J Cancer 1996 Jan 3;65(1):34-8 Related Articles, Books, LinkOut
Childhood cancer incidence in Australia, 1982-1991.
McWhirter WR, Dobson C, Ring I.
Department of Child Health, University of Queensland, Royal Children's Hospital, Brisbane, Australia.
The data of the Australian Paediatric Cancer Registry on childhood cancer incidence in Australia for the 10-year period 1982-1991 are presented. The crude average annual incidence of cancer in children under the age of 15 years was 13.8 per 100,000. The incidence of childhood cancer in Australia is rising. Significant increases were seen in acute non-lymphoblastic leukaemia, astrocytoma and melanoma. The age-standardised incidence of 14.4 per 100,000 is about 34% higher than in the UK. Most types of cancer had a higher incidence in Australia than in the UK, and the difference was significant for acute lymphoblastic leukaemia, astrocytoma and melanoma. Of particular interest is malignant melanoma, whose incidence in Australia is more than 5 times that in the UK, as a result of excessive UV exposure. Australia has a higher incidence of Ewing's tumour than osteosarcoma, nearly twice that of the UK. International comparative studies may help to elucidate the aetiology of these tumours.
PMID: 8543393 [PubMed - indexed for MEDLINE]
Med Pediatr Oncol 1996 Feb;26(2):85-9 Related Articles, Books, LinkOut
Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: pharmacokinetic characteristics.
Berkovitch M, Matsui D, Zipursky A, Blanchette VS, Verjee Z, Giesbrecht E, Saunders EF, Evans WE, Koren G.
Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada.
Treatment with 6-mercaptopurine (6MP) is associated with adverse gastrointestinal (GI) and hepatic effects. Four patients, ages 6.9 +/- 2.6 (mean +/- S.D.) years, with acute lymphocytic leukemia (ALL) on maintenance chemotherapy including 6MP, developed nausea, vomiting, abdominal pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 +/- 1.0 (range 0.5-2) years. Liver biopsy in 1 patient was suggestive of drug-induced intrahepatic cholestatis. Symptoms resolved and liver function returned to normal after discontinuation of 6MP. Pharmacokinetic data of the symptomatic patients were compared with those of 25 ALL patients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabolites of 6MP in red blood cells of the patients with hepatotoxicity, were not significantly different when compared to patients without hepatotoxicity, suggesting similar absorption of 6MP in both groups. Time to achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak levels and standardized concentration versus time curve (AUC) per 1 mg of 6MP per m2 of body surface area were significantly lower in the patients with hepatotoxicity (P = 0.016; P = 0.037, respectively). A significant correlation between peak 6MP levels and standardized AUC (r = 0.729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, leading to hepatotoxicity.
PMID: 8531858 [PubMed - indexed for MEDLINE]
Tijdschr Kindergeneeskd 1993 Feb;61(1):1-7 Related Articles, Books, LinkOut
[The treatment of recurrence in children with acute lymphatic leukemia. Current results and various developments]
[Article in Dutch]
Kaspers GJ, Pieters R, Klumper E, de Waal FC, Veerman AJ.
Afd. Kindergeneeskunde, Academisch Ziekenhuis, Vrije Universiteit, Amsterdam.
The results of current treatment of relapsed childhood acute lymphoblastic leukemia (ALL) are discussed, together with some recent developments which (might) influence such treatment. At present more than 95% of children with ALL will achieve a complete remission (CR), and +/- 70% will remain in CR. Nevertheless, 20-30% of the patients suffer a relapse, which implies a less favorable prognosis. However, after intensive treatment a part of these patients will have a prolonged second complete remission: 30-50% of children with a late relapse and 0-20% of children with an early relapse. It is important to prevent the occurrence of a relapse. The identification at diagnosis of patients at high risk for a relapse, and a subsequent more specific and more intensive treatment of these patients might contribute to that goal. Well-known risk factors are briefly mentioned, factors of which the prognostic significances is therapy-dependent. In addition, the treatment of relapsed ALL needs further improvement. Some alternatives to achieve this goal are discussed, including the role of in vitro cytostatic drug resistance testing.
PMID: 8493696 [PubMed - indexed for MEDLINE]
Am J Pediatr Hematol Oncol 1993 Feb;15(1):80-6 Related Articles, Books, LinkOut
Cellular pharmacology of 6-mercaptopurine in acute lymphoblastic leukemia.
Bostrom B, Erdmann G.
Division of Pediatric Hematology and Oncology, Minneapolis Children's Medical Center, MN.
PURPOSE: The cellular pharmacology of 6-Mercaptopurine (6MP) in acute lymphoblastic leukemia (ALL) is reviewed. DESIGN: Relevant studies on the clinical pharmacology of 6MP were reviewed. RESULTS: 6MP is one of the major drugs used in maintenance therapy of acute lymphoblastic leukemia (ALL). It is also used to treat steroid unresponsive inflammatory bowel disease. 6MP is an inactive prodrug that requires absorption, cellular uptake, and intracellular anabolism to nucleotides for cytotoxic activity. These nucleotides are ultimately incorporated into DNA and RNA, resulting in cell death. Two analogs of 6MP, azathioprine and 6-thioguanine, are also anabolized to the same intracellular metabolites, suggesting they should be therapeutically equivalent to 6MP. 6MP may be anabolized to nonmethylated nucleotides or may undergo methylation by the enzyme thiopurine methyltransferase to S-methylated nucleotides, which are also cytotoxic. CONCLUSION: Recent studies of 6MP pharmacokinetics in children with ALL have suggested that a higher systemic exposure, as measured by a greater area under the plasma concentration time curve or a higher concentration of 6MP metabolites in red blood cells, is associated with a decreased risk of relapse.
Publication Types: Review Review, Tutorial
PMID: 8447563 [PubMed - indexed for MEDLINE]
Med J Aust 1993 Oct 4;159(7):453-5, 458 Related Articles, Books, LinkOut
The experience of a single Australian paediatric oncology unit. 1000 patients 1964-1987.
McCowage GB, Vowels MR, Brown R, O'Gorman-Hughes D, White L, Marshall G.
Department of Haematology and Oncology, Prince of Wales Children's Hospital, Randwick, NSW.
OBJECTIVE: To determine the survival for children with malignant disease diagnosed in the period 1964-1987 and treated in a single paediatric oncology unit. DESIGN: Records of patients treated by the Department of Haematology and Oncology at the Prince of Wales Children's Hospital were reviewed to determine the survival of children with cancer according to decade of diagnosis and diagnostic group. PATIENTS: Patients were eligible for the study if referred for treatment at or soon after diagnosis of malignancy. One thousand patients were treated during the study period. There were 363 with acute lymphoblastic leukaemia (ALL), 126 with tumours of the central nervous system (CNS), 86 with acute non-lymphoblastic leukaemia (ANLL), 81 with lymphoma, 79 with neural crest tumours, 69 with renal tumours, 66 with bone sarcomas, 53 with soft tissue sarcomas, and 77 with various other diagnoses. Age range was one day to 20.75 years. INTERVENTIONS: Treatment included surgery, radiotherapy and chemotherapy in a variety of protocols. RESULTS: Ten-year survival for the 1960s, 1970s and 1980s was 15%, 51% and 64% respectively (P < 0.001), excluding tumours of the CNS. From 1985 onwards, actual survival at five years has been 79%. Survival from Wilms' tumour and Hodgkin's disease remained high throughout the study period, and significant improvement in survival occurred with ALL, non-Hodgkin's lymphoma (NHL) and osteogenic sarcoma. Survival remained poor with neuroblastoma and ANLL. CONCLUSIONS: Significant improvement in outcomes for childhood malignancy has been achieved over the last three decades, with five-year survival currently at 79% (excluding tumours of the CNS). Some diagnostic groups have had only small improvements in outcome and require new strategies.
PMID: 8412916 [PubMed - indexed for MEDLINE]
Cancer Causes Control 1993 Jul;4(4):361-8 Related Articles, Books, LinkOut
Prior medical conditions and the risk of adult leukemia in Shanghai, People's Republic of China.
Zheng W, Linet MS, Shu XO, Pan RP, Gao YT, Fraumeni JF Jr.
Epidemiology and Biostatistics Program, National Cancer Institute, Bethesda, MD.
A population-based case-control interview study of 486 adult leukemia cases and 502 healthy controls was carried out in Shanghai, People's Republic of China during 1987-89 to evaluate the etiologic role of prior medical conditions, medications, and diagnostic X-rays. Risks were examined separately for 236 cases with acute non-lymphocytic leukemia (ANLL), 79 with chronic myeloid leukemia (CML), 81 with acute lymphocytic leukemia (ALL), and 21 with chronic lymphocytic leukemia (CLL). Little difference was found between cases and controls for prior history of diabetes, hypertension, allergic conditions, most medications, and diagnostic X-rays. A few significant associations were observed for appendectomy, tuberculosis, and for several other chronic disorders with specific leukemia cell types, but the odds ratio estimates for most of these ranged from two to three and, with the exception of the two specified above, were based generally on five or fewer exposed controls. In contrast to an association with childhood leukemia in Shanghai, prior use of chloramphenicol was not linked with ANLL or other forms of adult leukemia. Further research is needed to clarify the relation of specific medical conditions and exposures with particular subtypes of leukemia, and to examine reasons for the low incidence of CLL in China and other Asian populations.
PMID: 8347786 [PubMed - indexed for MEDLINE]
Br J Cancer 1993 Jul;68(1):186-90 Related Articles, Books, LinkOut
Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia?
Lennard L, Davies HA, Lilleyman JS.
University of Sheffield Department of Medicine, Royal Hallamshire Hospital, UK.
The cytotoxic activity of 6-mercaptopurine (6-MP) is affected by thiopurine methyltransferase (TPMT), a genetically regulated and variable intracellular enzyme. 6-Thioguanine (6-TG), a closely related thiopurine, is less affected by that enzyme and so it may be a more reliable drug-at least for patients with constitutionally high TPMT activity. We attempted to assess its suitability as an alternative by comparing the pharmacokinetics of both drugs in a small group of children with lymphoblastic leukaemia (ALL). Patients were included who were in their second or subsequent remission, who would otherwise have received 6-MP, and on whom pharmacokinetic data concerning 6-MP metabolism had been collected in a previous remission. Plasma 6-TG concentrations were assayed following an oral dose of 40 mg m-2, and the accumulation and fluctuation of intracellular (erythrocyte, RBC) 6-TG nucleotides (6-TGNs) were measured at regular intervals during daily oral therapy. Seven children were studied. Plasma 6-TG concentrations were low and cleared within 6 h of oral dosing. At 7 days, 6-TGN concentrations ranged from 959 to 2361 pmol 8 x 10(-8) RBCs, in all cases significantly higher (P = 0.002) than those produced by the same patients on 6-MP. After a total therapy time of 35 patient months, a modest rise of alanine aminotransferase was seen on one occasion, otherwise no toxicity apart from myelosuppression was encountered. In the context used, 6-TG appears well tolerated and produces higher concentrations of intracellular cytotoxic metabolites than 6-MP. For children constitutionally 'resistant' to the traditional drug, if not all, it may be a preferable alternative.
Publication Types: Clinical Trial
PMID: 8318412 [PubMed - indexed for MEDLINE]
Med Pediatr Oncol 1994;22(3):187-93 Related Articles, Books, LinkOut
Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with ALL during maintenance therapy with weekly oral methotrexate.
Skoglund KA, Soderhall S, Beck O, Peterson C, Wennberg M, Hayder S, Bjork O.
Department of Pediatric Oncology, Karolinska Hospital, Stockholm, Sweden.
A new high-performance liquid chromatographic assay was used to determine methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OH-MTX), in the plasma (n = 17) and urine (n = 14) of children (age 3-12 years) on maintenance therapy for acute lymphocytic leukemia (n = 14) or non-Hodgkin's lymphoma (n = 3). Each child received oral doses of weekly MTX (4.0-29 mg/m2) and daily 6-mercaptopurine (40-111 mg/m2). Plasma samples were collected daily from two children during the 1-week dose interval. A limited sampling strategy was designed, whereby 2 days of blood sampling were used in the other 15 patients. Morning urine samples were collected daily for 1 week following MTX intake from 14 of the children. MTX was detectable in all plasma and urine samples for the entire dose interval. The main metabolite, 7-OH-MTX, could be detected in plasma and urine from all patients on the first day after dose intake but only in a few patients during the whole dose interval. Interpatient variability of MTX and 7-OH-MTX levels was high at all points during the week. Significant correlation were found between the urinary MTX levels on days 2 and 7 and plasma MTX levels on day 2 after intake. No significant correlation was found between drug levels in plasma or urine and liver function tests in the children showing signs of mild liver injury. This assay provides a tool for further studies on the role of pharmacokinetics for the clinical effects of weekly oral low-dose MTX given alone or in combination with 6-mercaptopurine.
Publication Types: Clinical Trial
PMID: 8272008 [PubMed - indexed for MEDLINE]
Med Pediatr Oncol 1994;23(2):111-5 Related Articles, Books, LinkOut
Liver function studies in children with acute lymphocytic leukemia after cessation of therapy.
Bessho F, Kinumaki H, Yokota S, Hayashi Y, Kobayashi M, Kamoshita S.
Department of Pediatrics, University of Tokyo Hospital, Japan.
We investigated liver function in 27 children with acute lymphocytic leukemia (ALL) after cessation of therapy. Induction therapy consisted of prednisolone+vincristine (VP regimen) alone (16 patients) or with addition of daunorubicin (4 patients) or L-asparaginase (7 patients). Patients treated with VP regimen received short courses of VP regimen every 12 weeks for the first year of maintenance. Twenty-five patients remained in first complete remission and had completed 3-year maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6-MP) 1-7 years prior to this study. Twenty-three patients had received transfusions of packed red blood cells or fresh whole blood (1-11 units; median: 2 units) but none had evidence of either hepatitis B or hepatitis C. Alanine aminotransferase (ALT), which was measured every 3 months during maintenance therapy, had values more than three times the upper limit of the normal range in 25% of the measurements in more than half of the patients. However, by 3 months after the completion of maintenance therapy, ALT had normalized in all patients and remained normal in all but two patients until the time of this study. Serum bilirubin, serum albumin, and prothrombin time were all within normal limits. Fasting and 2-hour postprandial total serum bile acids were high in 5 of 13 patients and in 6 of 13 patients, respectively. The ratio of cholic acids+deoxycholic acids to chenodeoxycholic acids+lithocholic acids was below 1 in all but two patients, whereas this ratio was above 1 in all controls. Our bile acid profile results indicate the necessity of careful long-term follow-up of survivors of ALL treated with hepatotoxic chemotherapy during childhood.
PMID: 8202032 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 1994 May-Jun;11(3):281-92 Related Articles, Books, LinkOut
Recovery of blood T-cell subsets after chemotherapy for childhood acute lymphoblastic leukemia.
Alanko S, Salmi TT, Pelliniemi TT.
Department of Pediatrics, Turku University Central Hospital, Finland.
Recovery of cell-mediated immunity after cessation of chemotherapy for childhood acute lymphoblastic leukemia (ALL) was investigated in 14 children to monitor the duration of immune deficiency. The numbers of blood T cells and their subsets were analyzed at 0, 1, 3, 6, 9 and 12 months after discontinuation of therapy with monoclonal antibodies and flow cytometry. The total T-cell count was low at cessation but normalized at 1 to 3 months, whereas the T-cell subsets CD4+, CD8+, CD4+Leu8-, and CD4+CD45RA+ recovered differently. In children ages 3 to 6 years, the numbers of CD4+ cells and their subsets were normal at cessation, whereas in children ages 7 to 18 years, CD4+ and CD4+Leu8+ cell counts normalized only at 6 months. The numbers of CD8+ cells or activated T cells were not increased and the CD4+/CD8+ ratio was not inverted, unlike recovery after bone marrow transplantation. Although the groups showed a mean reversion to normal values by 6 months, there were individual patients who continued to have subnormal values for 1 year after therapy, some of whom exhibited increased susceptibility to infections.
PMID: 8060812 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 1994 May-Jun;11(3):251-8 Related Articles, Books, LinkOut
6-Mercaptopurine cumulative dose: a critical factor of maintenance therapy in average risk childhood acute lymphoblastic leukemia.
Dibenedetto SP, Guardabasso V, Ragusa R, Di Cataldo A, Miraglia V, D'Amico S, Ippolito AM.
Division of Pediatric Hematology-Oncology, University of Catania, Italy.
A multivariate survival analysis including gender, age, log white blood cell (WBC) count, liver and spleen size at diagnosis, mean log WBC count during maintenance therapy, and the prescribed cumulative doses of 6-mercaptopurine (6-MP), methotrexate (MTX), vincristine (VCR), and prednisone (PDN) during maintenance therapy was performed on 53 children with average-risk acute lymphoblastic leukemia (ALL). The 6-MP cumulative dose prescribed during maintenance therapy resulted in the most important statistically significant independent prognostic factor. Patients who received less than the median cumulative dose of 6-MP (86% of planned protocol dose) fared significantly worse than the other patients, regardless of WBC count at diagnosis, gender, age, and other factors studied. Therefore, 6-MP cumulative dose during maintenance therapy may be the critical factor for effective maintenance therapy in childhood ALL.
PMID: 8060809 [PubMed - indexed for MEDLINE]
Br J Haematol 1994 Jan;86(1):48-54 Related Articles, Books, LinkOut
A second course of treatment for childhood acute lymphoblastic leukaemia: long-term follow-up is needed to assess results.
Chessells JM, Leiper AD, Richards SM.
Department of Haematology and Oncology, Hospitals for Sick Children, London.
We report the results of long-term follow-up of 94 children who completed treatment for acute lymphoblastic leukaemia (ALL) between 1974 and 1986 and subsequently experienced a bone marrow relapse before 1992. 91 children received further induction, intensification and CNS directed therapy; 19 proceeded to BMT or ABMT and the remainder were treated on one of three protocols which increased in intensity. The duration of second remission improved significantly with increasing intensity of treatment and bone marrow transplantation was followed by fewer relapses than chemotherapy. Analysis of factors influencing the duration of second remission showed that only length of first remission was of additional significance; the median duration of second remission being only 19 months in children with a first remission of less than 4 years and 62 months in those with longer first remissions. 29 children electively stopped chemotherapy a second time but only 11 of these remain still in second remission with recurrences occurring for up to 7 years from the the time first relapse. Only three of the 24 long-term survivors had no significant late effects of treatment; these were most marked in children who had received a second course of radiotherapy. We conclude that very long follow-up is necessary to determine whether patients may be successfully re-treated following late bone marrow relapse and that all such treatment is associated with a high incidence of late effects.
PMID: 8011547 [PubMed - indexed for MEDLINE]
Cancer Chemother Pharmacol 1994;34(3):209-15 Related Articles, Books, LinkOut
Methotrexate and 6-mercaptopurine maintenance therapy for childhood acute lymphoblastic leukemia: dose adjustments by white cell counts or by pharmacokinetic parameters?
Schmiegelow K, Schroder H, Schmiegelow M.
Department of Pediatrics, University Hospital, Rigshospitalet, Copenhagen, Denmark.
In a consecutive study of 14 boys and 17 girls with non-B-cell ALL who were > or = 1 year of age at diagnosis, the degree of myelosuppression during the last year of MTX/6MP maintenance therapy was analyzed in relation to the erythrocyte concentration of MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN, the respective major cytotoxic metabolites of MTX and 6MP). For each patient, E-MTX and E-6TGN levels were measured 2-15 (median, 6) and 2-17 (median, 7) times, respectively. From these measurements, arithmetic means of E-MTX and E-6TGN were calculated (mE-MTX and mE-6TGN, respectively). Since MTX and 6MP probably work synergistically, the product of mE-MTX and mE-6TGN was calculated for each patient (mE-MTX x 6TGN). The degree of myelosuppression was registered as the mean WBC determined following cessation of the therapy minus the mean WBC measured during the therapy (mWBCshift). The mean WBCs measured on therapy (mWBC(on)) and off therapy were highly correlated (r = 0.48, P = 0.009). The median mWBCshift was 2.7 x 10(9)/l (range, 1.4-4.8 x 10(9)/l). In a multivariate regression analysis, the best-fit model to predict the mWBCshift included mE-MTX x 6TGN, age at drug withdrawal, and mWBC in the order given [mWBCshift = 4.3 + 0.00089 x (mE-MTX x 6TGN) - 0.097 x age - 0.41 x mWBC(on); global rs = 0.66, P = 0.0002]. Thus, the patients with higher mE-MTX x 6TGN values, the younger patients, and the patients with the lowest WBC during therapy had the most pronounced degree of myelosuppression as measured by mWBCshift. These results indicate that E-MTX and E-6TGN may give a better reflection of the treatment intensity than do the WBCs alone.
PMID: 8004753 [PubMed - indexed for MEDLINE]
Med Pediatr Oncol 1995 Feb;24(2):71-6 Related Articles, Books, LinkOut
Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: a 10-year follow-up study. Italian Association of Pediatric Hematology-Oncology (AIEOP).
Miniero R, Saracco P, Pastore G, Zurlo MG, Terracini B, Rosso P, Masera G.
Department of Pediatrics, University of Turin, Italy.
The outcome of 171 children with ALL who relapsed for the first time after elective cessation of therapy (1-86 mo) and followed over 10 years (median 60 mo; range 1-232 mo) has been evaluated. One hundred and three patients relapsed in the bone marrow (BM), 29 in the testis (T), 21 in the central nervous system (CNS), 14 in the BM plus another site and 4 in other sites. Second remission was achieved in 97% of patients (97% BM, 100% T, 90% CNS, respectively) with reinduction schedules including three or more drugs. All but 4 out of 100 patients who relapsed in the BM received cranial reprophylaxis with intrathecal CT alone or CT plus radiotherapy. Seven patients in second CR underwent allogeneic bone marrow transplantation from an HLA matched sibling. The overall survival was 34% and disease-free survival (DFS) probability at 100 years was 22%. A second relapse was observed in 73% of patients. Forty children are alive in second continuous remission and 24 are alive after a second or subsequent relapse. Patients with isolated T relapse showed a significant better outcome than those with BM or CNS involvement. Most patients (62%) with isolated BM relapse showed a further disease recurrence in BM, and DFS was shorter when relapse occurred within 12 months from off-therapy. Eighty-two patients in second CR stopped the treatment a second time and showed a survival and DFS probabilities, respectively, of 69% and 43%. Thus, children with ALL who relapse after cessation of therapy still have a high risk of further late relapses and should be treated with intensive chemotherapy and CNS reprophylaxis. BMT must be considered for all patients relapsing in the BM within 12 months from off-therapy.
Publication Types: Multicenter Study
PMID: 7990766 [PubMed - indexed for MEDLINE]
Cancer Res 1994 Oct 15;54(20):5387-93 Related Articles, Books, LinkOut
6-Thioguanine-induced growth arrest in 6-mercaptopurine-resistant human leukemia cells.
Morgan CJ, Chawdry RN, Smith AR, Siravo-Sagraves G, Trewyn RW.
Tulane University School of Medicine, Department of Surgery, New Orleans, Louisiana 70112.
The thiopurines 6-thioguanine (6TG) and 6-mercaptopurine (6MP) are cytotoxic to proliferating cells by a mechanism involving incorporation into DNA via the purine salvage pathway, and resistance to these agents can be conferred by lack of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase. However, human and murine hypoxanthine-guanine phosphoribosyltransferase-deficient leukemia cell lines have been shown to respond to 6TG by growth arrest and differentiation by a mechanism apparently not involving incorporation of 6TG into DNA. If so, leukemia cells resistant to 6MP should still respond to 6TG by growth arrest via an undescribed epigenetic mechanism. To test this, polyclonal 6MP-resistant variants were produced from three human leukemia cell lines, HL-60, U937, and CCRF-CEM. Treatment of both sensitive and resistant cells with 6TG induced growth arrest. The effect of 6TG in the 6MP-sensitive HL-60 and U937 cells was associated with significant loss of viability and DNA fragmentation. In contrast, the 6TG-treated 6MP-resistant cells exhibited a slower decline in viability and no DNA fragmentation. To identify the mechanism by which 6TG may induce growth arrest, tRNA was isolated from 6MP-resistant cells cultured for 48 h with 6TG. 6TG was found to be incorporated into tRNAs normally containing queuine in the anticodon wobble position. These studies may provide a basis for the development of new therapeutic regimens for the treatment of leukemia.
PMID: 7923170 [PubMed - indexed for MEDLINE]
Lancet 1994 May 14;343(8907):1188-90 Related Articles, Links
Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia.
Lilleyman JS, Lennard L.
Department of Haematology, Children's Hospital, Sheffield, UK.
Many months' treatment with daily oral mercaptopurine is an important part of therapy for nearly all children with lymphoblastic leukaemia (ALL). Even when prescribed the same dose based on body surface area, patients have widely different intracellular concentrations of drug metabolites. Whether this variation matters in terms of disease control is not yet clear. To find out, we followed up a large group of children with ALL in whom mercaptopurine-derived thioguanine nucleotides in the red cells were measured during treatment with an identical dose of mercaptopurine early in first remission. 172 unselected children (100 boys, 72 girls) were recruited between 1980 and 1992. At median follow-up of 5 years from diagnosis 42 (24%) had relapsed; 30 had erythrocyte thioguanine nucleotide concentrations below the group median (284 pmol per 8 x 10(8) erythrocytes) and 12 had values above the median. The actuarial relapse-free survival at 5 years was 63% in the below-median group and 84% in the above-median group (difference 21% [95% CI 3-39%], p = 0.0018). Multivariate analysis showed that erythrocyte thioguanine nucleotide concentration was independent of other prognostic variables including age, leukaemia immunophenotype, white-blood-cell count at diagnosis, trial protocol, and sex. Whatever the cause, in childhood ALL variable formation of intracellular mercaptopurine metabolites seems to be clinically important. Therapeutic schedules that include long-term daily oral mercaptopurine might be more effective if such metabolites are monitored.
PMID: 7909868 [PubMed - indexed for MEDLINE]
Med Oncol 1994;11(2):75-88 Related Articles, Books, LinkOut
Bone marrow transplantation for acute lymphoblastic leukemia (ALL).
Lazarus HM, Rowe JM.
Department of Medicine, Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University, Ohio 44106.
Advances in the treatment of childhood acute lymphoblastic leukemia (ALL) have been striking while results have been less impressive in adults who develop this disease. Obvious differences in a patient's ability to withstand cytotoxic therapy may account, in part, for these findings, but the biologic behaviour of the disease in the two age groups appears to be different; relapses are more frequent and cures less common in adults. In fact, age alone appears to be the most important prognostic factor in ALL. The demonstration of the efficacy of bone marrow transplantation in advanced disease as well as the marked improvements in supportive care and the development of effective high-dose cytotoxic preparative regimens, especially those which use total body irradiation, however, have paved the way for transplantation in first complete remission. Formerly, most adult ALL patients who underwent bone marrow transplant did so in relapse, or in second or subsequent remission. In most studies 40-50% of first remission adult patients attain long-term disease-free survival after allogeneic and autologous bone marrow transplant. Relapses are considerably higher in the autologous transplant group when compared to the allogeneic group, but the latter population may experience increased morbidity and mortality due to graft-versus-host disease and opportunistic infection. These differences may reflect the beneficial graft-versus-leukemia effect in the allograft as well as infusion of autologous leukemia cells in the autograft but neither transplant subtype appears superior. Compared to more conventional approaches, however, transplantation may offer improved disease-free survival, although patient selection appears to be significantly influence outcome. These many inherent biases must be noted when comparing markedly different approaches, e.g. transplant versus conventional therapy. The challenge of demonstrating which therapy is superior for adult ALL patients can only be addressed in a well-designed, prospective, randomized trial.
Publication Types: Review Review, Tutorial
PMID: 7850267 [PubMed - indexed for MEDLINE]
J Clin Oncol 1995 Feb;13(2):352-8 Related Articles, Books, LinkOut
Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association.
Uderzo C, Valsecchi MG, Bacigalupo A, Meloni G, Messina C, Polchi P, Di Girolamo G, Dini G, Miniero R, Locatelli F, et al.
Clinica Pediatrica Universita di Milano, Ospedale San Gerardo, Monza, Italy.
PURPOSE: To compare the results of allogeneic bone marrow transplantation (AlloBMT) with those obtained with chemotherapy (CHEMO) in children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) after a marrow relapse. The experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association is summarized. PATIENTS AND METHODS: All children who had a relapse in the period 1980 to 1989 in 27 centers in Italy were eligible for the study. Of 287 eligible patients, 230 were treated with CHEMO, most of them (93%) according to a standard multiple-drug relapse protocol. The remaining 57 children underwent AlloBMT. Preparative regimens included total-body irradiation and chemotherapy (n = 51) or chemotherapy alone (n = 6). Statistical analysis was performed with a Cox regression model adjusting for waiting time to transplant and prognostic factors. RESULTS: In the whole series, minimum and median follow-up after second CR were 3 and 6.2 years, respectively; at 8 years from second CR, disease-free survival (DFS) was 20.0% (SE 2.5) and survival was 26.4% (SE 2.9). In the group of patients with an early first relapse, DFS was significantly longer after AlloBMT than after CHEMO (relative risk [RR] = 0.45, P = .002). No significant advantage of AlloBMT over CHEMO was found for patients with a late relapse (> 30 months since diagnosis). Duration of first CR significantly influenced prognosis in the CHEMO group (RR = 0.32, P = .0001 for patients with late first relapse versus patients with early first relapse). CONCLUSION: Results suggest an advantage in DFS of AlloBMT over CHEMO in ALL patients who experienced an early first medullary relapse. Prospective trials are needed to address efficacy of AlloBMT versus CHEMO in patients with late bone marrow relapse.
Publication Types: Clinical Trial Controlled Clinical Trial
PMID: 7844596 [PubMed - indexed for MEDLINE]
Lancet 1995 Jan 21;345(8943):143-8 Related Articles, Books, LinkOut
Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia.
Comment in: Lancet. 1995 Mar 11;345(8950):653.
Chessells JM, Bailey C, Richards SM.
Department of Haematology and Oncology, Institute of Child Health, London, UK.
The UK Medical Research Council trial MRC UKALL X was designed to investigate the benefit of one or two courses of additional intensification therapy in children with acute lymphoblastic leukaemia receiving standard treatment. From 1985 to 1990 1612 children, comprising more than 90% of eligible cases in the UK, were treated with intensive induction therapy, central nervous system directed therapy with cranial irradiation and intrathecal methotrexate, and continuing treatment for 2 years. 1171 children were randomised to receive additional intensification therapy at 5 weeks, 20 weeks, both, or neither. At follow-up of at least 3 years disease-free survival for all children at 5 years was 62% (95% confidence interval [Cl] 60.0-64.4), a significant improvement over the 56% (53.0-59.6) found in the preceding MRC UKALL trial. The 5-year disease-free survival was 71% (65.5-76.1) for children randomised to two blocks of intensification therapy, this being significantly better than the 62% (56.6-68.0), 61% (55.7-67.1), and 57% (50.9-62.7) rates for the groups randomised to one intensification block at 5 weeks, one at 20 weeks, and no intensification, respectively. The benefits of intensification therapy were seen irrespective of clinical factors known to influence outcome such as age, sex, and initial leucocyte count. We conclude that the addition of two courses of intensification therapy has produced a 14% improvement in disease-free survival and an 11% improvement in overall survival for the randomised patients. This additional treatment is of benefit to all children with acute lymphoblastic leukaemia, even those traditionally deemed at lower risk of relapse.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 7823668 [PubMed - indexed for MEDLINE]
Blood Rev 1994 Sep;8(3):161-8 Related Articles, Books, LinkOut
Autologous bone marrow transplantation in acute lymphoblastic leukaemia.
Jackson GH, Taylor PR, Lennard AL, Proctor SJ.
Department of Haematology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
There has been a great deal of interest in the use of high dose chemotherapy and/or radiotherapy, with autologous bone marrow/peripheral blood stem cell rescue, in the treatment of haematological malignancies including acute lymphoblastic leukaemia (ALL). In this review we assess the role of autologous bone marrow transplantation (ABMT) in ALL. The heterogeneity of this disease makes the analysis of treatment results in ALL difficult to interpret. There is some evidence that ABMT may be useful in second complete remission (CR) and increasing interest in ABMT as a therapeutic option in first CR in adults. At the moment there is little evidence that such an approach will have an impact in childhood ALL. ABMT is considerably less toxic than allogeneic bone marrow transplantation and the major cause of 'treatment failure' is disease relapse. There has been considerable effort put into purging autologous bone marrow of malignant stem cells but whether purging is effective remains controversial and not proven. Newer studies involving cytokines post-ABMT to stimulate an artificial 'graft versus leukaemia' effect may prove of value.
Publication Types: Review Review, Tutorial
PMID: 7819818 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1995 Jun;15(6):943-7 Related Articles, Books, LinkOut
Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission: factors predictive of survival, relapse and graft-versus-host disease.
Moussalem M, Esperou Bourdeau H, Devergie A, Baruchel A, Ribaud P, Socie G, Parquet N, Traineau R, Hirsch I, Schaison G, et al.
Bone Marrow Transplant Unit, Saint-Louis Hospital, Paris, France.
Between 1983 and 1993, 42 patients with acute lymphoblastic leukemia (ALL) in second complete remission (CR) underwent an allogeneic HLA-identical bone marrow transplant (BMT; there was one family mismatched graft). The conditioning regimens varied, consisting of cyclophosphamide (CY) and total body irradiation (TBI; n = 10); CY, TBI, Ara C, VP-16 (n = 11); TBI, Ara C, melphalan (n = 20) (TAM) or other (n = 1). Cyclosporine A (CsA) (n = 15) or CsA and methotrexate (MTX) (n = 24) were the main regimens for prophylaxis of graft-versus-host disease (GVHD). Nineteen of 42 patients are alive in CR ranging from 1 to 72 months after BMT with a median follow-up of 36 months. The 4-year actuarial survival rate was 53%. The actuarial relapse rate was 17%. Twenty three patients died: 4 patients of leukemic relapse, 9 of infection, 2 of acute GVHD, 2 of multiorgan failure after chronic GVHD, 2 of a secondary tumour and 4 patients died of other causes. Several pre- and post-transplant characteristics were analyzed to determine predictive factors for survival, relapse and GVHD. The relapse rate was significantly influenced by the type of conditioning regimen with no relapse in the TBI, Ara C, melphalan group. The analysis of long-term sequelae shows that there are no severe complications in this last group. Our results confirm that allogeneic BMT can lead to long-term survival for children with ALL in second CR and suggest an advantage of using the TAM conditioning regimen in the eradication of the leukemic disease.
PMID: 7581095 [PubMed - indexed for MEDLINE]
Br J Cancer 1995 Oct;72(4):1004-6 Related Articles, Links
Intracellular metabolites of mercaptopurine in children with lymphoblastic leukaemia: a possible indicator of non-compliance?
Lennard L, Welch J, Lilleyman JS.
University of Sheffield Department of Medicine and Pharmacology, Royal Hallamshire Hospital, UK.
As part of a programme assessing the pharmacokinetics of oral thiopurines given for lymphoblastic leukaemia, we assayed intracellular metabolites of mercaptopurine in children from all over the United Kingdom who were given a standard dose of the drug. The metabolites we measured, thioguanine nucleotides and methylmercaptopurines, are products of two competing metabolic pathways and would be expected to show an inverse correlation. A total of 327 children from 17 centres in the UK were studied. All were on the same therapeutic schedule of mercaptopurine. All had been on an unattenuated full protocol-directed dose (at least 75 mg m-2) for a minimum of 7 days before assay. There was a very wide variation in the concentration of the two metabolites measured; the thioguanine nucleotides ranged from 0 to 1255 pmol per 8 x 10(8) red cells (median 289, lower quartile 210, upper quartile 377) and the methylmercaptopurine metabolites ranged from 0 to 46.3 nmol per 8 x 10(8) red cells (median 5.18, lower quartile 2.31, upper quartile 11.59). The anticipated negative correlation was not apparent, but the ratio between the two was not randomly distributed. No child had both metabolite concentrations in the upper quartiles, but in 32 (10%) children the concentration of both metabolites was in the lower quartile. Of the 32, only one metabolite was detected in four and none at all in six. The most likely explanation for these findings is that a minority of children with lymphoblastic leukaemia fail to take oral mercaptopurine either totally or intermittently. The extent of the problem is unknown, but we suspect it may be clinically important in at least 10% of patients.
PMID: 7547211 [PubMed - indexed for MEDLINE]
Tohoku J Exp Med 1981 Jul;134(3):273-9 Related Articles, Books, LinkOut
Prophylaxis of bacterial infection by sulfamethoxazole-trimethoprim (SMX-TMP) during chemotherapy in patients with childhood acute leukemia.
Tono-oka T, Nakayama M, Ohkawa M, Nakajima T, Takeda T, Matsumoto S.
A combination of sulfamethoxazole and trimethoprim was given orally to 13 children with acute leukemia on 16 occasions of hospitalization during remission induction chemotherapy for the prophylaxis of bacterial infection. Frequency of episodes of persistent fever in this group of patients was markedly low, namely 0.38 per one hospitalization, whereas that in control group which was given no drug was 0.98. Furthermore, frequency of episodes of definite bacterial infection in the patients given SMX-TMP was 0.25 per one hospitalization. This was significantly low as compared with control patients whose frequency was 0.84. Although, there occurred slight rash and liver dysfunction as the side effects, they were reversible. These results suggest that the prophylactic use of SMX-TMP in children with acute leukemia during chemotherapy is effective and valuable for the protection from bacterial infection.
PMID: 7314104 [PubMed - indexed for MEDLINE]
Cancer Treat Rep 1981;65 Suppl 4:97-100 Related Articles, Books, LinkOut
Optimal current treatment of childhood acute lymphoblastic leukemia.
Simone JV.
The treatment of childhood acute lymphoblastic leukemia (ALL) has been remarkably successful over the past 30 years of the chemotherapy era. A substantial proportion of patients, perhaps 40%-50%, are apparently cured with currently available therapy. However, optimal therapy has not yet been devised because of substantial therapeutic failures in the form of relapse and unacceptable side effects. Remission induction therapy is the most settled aspect of therapy. The addition of asparaginase or an anthracycline to prednisone and vincristine is highly effective. Preventive central nervous system therapy is under revision and study, with a variety of approaches likely to prove equally effective. Continuation (maintenance) therapy is in the most need of revision because a majority of therapeutic failures are due to bone marrow relapse--the failure of systemic therapy to prevent emergence of resistant leukemia cells. The optimal duration of therapy has not been established, the relapse after cessation of therapy lasting 2-3 years currently being 20%-25%. Bone marrow transplantation during remission shows promise as a therapeutic modality. The most promising development, however, is our increasing understanding of biological subpopulations of leukemia cells. This ultimately may help us develop more effective and specific therapy for childhood ALL.
PMID: 7049384 [PubMed - indexed for MEDLINE]
Annu Rev Med 1981;32:207-12 Related Articles, Books, LinkOut
Outlook for acute lymphocytic leukemia in children in 1982.
Simone JV.
The treatment of childhood ALL has been remarkedly successful over the past 30 years of the chemotherapy era. A substantial proportion of patients, perhaps 40--50%, are apparently cured with currently available therapy. However, optimal therapy has not yet been devised because of substantial therapeutic failures in the form of relapse and unacceptable side-effects. Remission induction therapy is the most settled aspect of therapy. The addition of asparaginase or an anthracycline to prednisone and vincristine is highly effective. Preventive central nervous system therapy is under revision and study. It is likely that a variety of approaches will be equally effective. Continuation (maintenance) therapy is in the most need of revision because of a majority of therapeutic failures are due to bone marrow relapse--the failure of systemic therapy to prevent emergence of resistant leukemia cells. The optimal duration of therapy has not been established, the relapse rate after cessation of therapy lasting 2-3 years currently being 20-25%. Bone marrow transplantation during remission shows promise as a therapeutic modality, particularly if autologous techniques are successful. The most promising development, however, is our increasing understanding of biological subpopulations of leukemia cells. This ultimately may help us develop more effective and specific therapy for childhood ALL.
Publication Types: Review
PMID: 7013662 [PubMed - indexed for MEDLINE]
Pediatr Clin North Am 1980 May;27(2):269-91 Related Articles, Books, LinkOut
Acute lymphoblastic leukemia.
Miller DR.
The improved outlook in childhood leukemia can be attributed to more accurate diagnosis, better supportive care, the use of drug combinations to achieve and maintain remission, and prophylactic therapy to prevent central nervous system leukemia. With the best treatment available today, 65 to 70 per cent of children are in complete continuous remission five years after diagnosis. Recent advances in biology, diagnosis, and treatment which have contributed to this progress are reviewed.
Publication Types: Review
PMID: 6992074 [PubMed - indexed for MEDLINE]
Cancer 1980 Apr 15;45(8):2009-16 Related Articles, Books, LinkOut
Testicular relapse in childhood acute lymphoblastic leukemia: association with pretreatment patient characteristics and treatment. A report for Childrens Cancer Study Group.
Nesbit ME Jr, Robison LL, Ortega JA, Sather HN, Donaldson M, Hammond D.
Of 395 male pediatric patients with previously untreated acute lymphoblastic leukemia, 20 (5%) exhibited testicular infiltration prior to or concurrent with their first bone marrow relapse. Fourteen occurred as an isolated relapse and six occurred concomitant with bone marrow and/or central nervous system relapse. Nine of the 20 relapses were in patients who had discontinued therapy after completing three years of continuous complete remission. Factors found to be independently associated with an increased risk of testicular relapse during maintained remission included pretreatment lymphadenopathy, and to a lesser extent, initial hemoglobin level and initial platelet count. Pretreatment splenomegaly and lymphadenopathy appear to imply an increased risk of testicular relapse for those patients who have their maintenance therapy discontinued. Time from testicular relapse to bone marrow relapse or death was significantly shorter for patients with testicular involvement while receiving chemotherapy when compared to patients with testicular relapse after discontinuing therapy. In those patients achieving three years of continuous complete remission, subsequent testicular relapse occurred significantly more often in patients who discontinued therapy than a similar group who continued therapy. In a group of 76 males who received presymptomatic gonadal radiation immediately after achieving an initial marrow remission, protection appears to have been provided against the manifestation of testicular leukemia during maintained remission.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 6989482 [PubMed - indexed for MEDLINE]
Med J Aust 1981 May 16;1(10):523-5 Related Articles, Books, LinkOut
Results of cessation of treatment in childhood acute lymphocytic leukaemia.
Ekert H, Balderas A, Waters KD, Matthews RN.
From 1972 to 1977, 55 of 161 children with acute lymphocytic leukaemia discontinued treatment after being in continuous complete remission for three years. A low total white cell count as diagnosis (less than 10 X 10(9)/L) was significantly associated with cessation of therapy, but there was no significant association with age or sex. Nine patients have relapsed, all but one within 50 weeks of cessation of treatment. Testicular relapse occurred only in one patient. Actuarial complete remission rate with a median duration of follow-up 140 weeks was 76%, and there was no significant sex difference. It is proposed that the relatively good prognosis in boys after cessation of therapy may be related to limited use of steroids during induction chemotherapy.
PMID: 6942206 [PubMed - indexed for MEDLINE]
J Natl Cancer Inst 1983 Apr;70(4):589-92 Related Articles, Books, LinkOut
Incidence of childhood tumors in Shanghai, 1973-77.
Tu J, Li FP.
Data of the Shangai Tumor Registry were analyzed for incidence of cancer in children under 15 years of age, 1973-77. The incidence of all malignant neoplasms combined was 104.7 per million boys and 89.2 per million girls. Leukemia, brain tumors, and lymphomas comprised 70% of all childhood tumors in Shangai. Compared with U.S. whites, Shangai children had higher rates of myeloid leukemia and liver cancer and lower rates of lymphoid cancers and tumors of the kidney, eye, soft tissue, and testis. Effects of migration on tumor rates among Chinese children are largely unknown and merit additional study.
PMID: 6572746 [PubMed - indexed for MEDLINE]
Crit Rev Oncol Hematol 1983;1(2):129-97 Related Articles, Books, LinkOut
Acute lymphoblastic leukemia in children: current status, controversies, and future perspective.
Miller LP, Miller DR.
Disease-free survival (DFS) in childhood ALL is 60%, and survival in good, average, and poor prognostic groups defined by initial WBC and age is 90, 60, and 45%, respectively. Additional immunological, morphological, biochemical, cytokinetic, and cytogenetic factors have been identified, illustrating the heterogeneity of ALL and its derivation from malignant clones at various stages of differentiation and with varying rates of proliferation. Of biologic importance, these factors may refine further the characteristic features of clinically-determined prognostic groups. Multivariate analysis of large prospective trials with homogeneous therapy will be required to determine the independent prognostic importance of these factors. Current treatment strategies in ALL include (1) tailoring therapy and its intensity to prognostic groups; (2) multiple-drug combinations in induction; (3) early use of intrathecal (IT) methotrexate (MTX); (4) CNS prophylaxis with IT MTX alone in good prognosis patients and combined cranial radiation (CXRT), 1800 rads plus IT MTX, in average and poor prognosis patients. Current studies show a CNS relapse rate of 5% in all prognostic groups. Late neuropsychological defects caused by cranial XRT and IT MTX have prompted programs designed to reduce the potential late toxicity of CNS prophylaxis. More pronounced in younger children, these abnormalities include decreased IQ, visual-motor incoordination, poor performance in mathematics, and memory dysfunction. Until 1980, more intensive induction, consolidation, and maintenance therapy had failed to prolong DFS in children with a poor prognosis. In West Germany (Berlin-Frankfurt-Muenster protocol) a 70 to 75% DFS is seen in all patients regardless of initial WBC, suggesting that effective therapy will override prognostic factors. Ultra-high-dose MTX, without cranial radiation, is also showing promise in poor prognosis patients. Other issues include the optimal duration of therapy, the role of testicular biopsies, and prophylactic testicular radiation. Recent studies suggest that prognostic factors lose their significance after 2 years of continuous complete remission and that 2 years of maintenance therapy is adequate. Bilateral open-wedge testicular biopsies have identified occult testicular disease in 8 to 10% of males. A unified approach to children with leukemia/lymphoma, a group with a particularly poor prognosis, utilizing NHL-type therapy may be more effective than conventional ALL therapy.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types: Review
PMID: 6397264 [PubMed - indexed for MEDLINE]
Ann Med Interne (Paris) 1978 Feb;129(2):137-40
[Hyponatremia in acute leukemia]
[Article in French]
Vernant JP, Mouchnino G, Brun B, Reyes F, Kuentz M, Rochant H, Dreyfus B.
PMID: 637470 [PubMed - indexed for MEDLINE]
1: J Pediatr 1978 Jan;92(1):30-5 Related Articles, Books, LinkOut
Influenza immunization in immunosuppressed children.
Gross PA, Lee H, Wolff JA, Hall CB, Minnefore AB, Lazicki ME.
Optimal influenza immunization of individuals with malignancy and other immunodeficient states requires and understanding of responses to currently recommended regimens. Children with acute lymphocytic leukemia and other malignancies between three and 17 years of age were immunized with bivalent influenza vaccine containing A/New Jersey/76 and A/Victoria/75. Folowing a two-dose immunization schedule, only 37% (25468) on cancer chemotherapy seroconverted to a hemagglutination inhibition titer greater than or equal to 20 for A/NJ/76; the seroconversion rate in those not on chemotherapy was 92% (68/74, P less than 0.001). The immune response to the A/Vic/75 antigen was also related to a history of recent chemotherapy. There was no correlation between the immune response and the peripheral white blood cell count except at counts less than or equal to 1,000. The optimum time to immunize children with malignancies is when they have been off chemotherapy for one month and have peripheral white blood counts greater than 1,000.
PMID: 619076 [PubMed - indexed for MEDLINE]
Am J Med 1971 Aug;51(2):269-71
Inappropriate secretion of antidiuretic hormone secondary to vincristine therapy.
Cutting HO.
PMID: 5095530 [PubMed - indexed for MEDLINE]
Vincristine neurotoxicity with hyponatremia.
Slater LM, Wainer RA, Serpick AA.
PMID: 4974027 [PubMed - indexed for MEDLINE]
1: Rinsho Ketsueki 1974 Oct;15(10):1149-55
[Severe hyponatremia in two cases of childhood acute myeloid leukemia--syndrome of inappropriate secretion of antidiuretic hormone secondary to vincristine therapy (author's transl)]
[Article in Japanese]
Tsunematsu Y, Kikuchi K, Koide R.
PMID: 4532692 [PubMed - indexed for MEDLINE]
Can Med Assoc J 1972 Feb 19;106(4):356-7
Hyponatremia in association with vincristine therapy.
Nicholson RG, Feldman W.
PMID: 4501374 [PubMed - indexed for MEDLINE]
Arch Intern Med 1973 Nov;132(5):717-20
Vincristine neurotoxicity and abnormal secretion of antidiuretic hormone.
Robertson GL, Bhoopalam N, Zelkowitz LJ.
PMID: 4356234 [PubMed - indexed for MEDLINE]
Padiatr Padol 1985;20(2):117-26
[Electrolyte changes in acute leukemia in childhood]
[Article in German]
Gadner H, Martins da Cunha AC.
Electrolyte imbalance in leukemia can be due to either organ infiltration and cell death or to a side effect of cytostatic drugs. From the wide variety of these disturbances seen in acute leukemias in childhood, the excess of potassium is most dangerous. Further electrolyte changes, which are however less evident, are hyperphosphataemia, hyperphosphaturia, and hypocalcaemia. The destruction of a large amount of cells during aggressive induction therapy can boost the electrolyte imbalance and therefore lead to renal failure. Such situations are demonstrated in two cases. Following Vincristine and Cyclophosphamide administration, electrolyte changes such as acute or prolonged decrease of sodium in the serum and urinary loss of sodium are seen frequently. Based on the data from 20 patients with acute lymphoblastic leukemias we describe the dynamics of this process. These changes are probably caused by the syndrome of inadequate ADH-secretion. The clinical importance of these findings are discussed and procedures for improving therapy are set out.
PMID: 3857551 [PubMed - indexed for MEDLINE]
Medicine (Baltimore) 1979 Jan;58(1):1-31 Related Articles, Books, LinkOut
Infectious complications of human bone marrow transplantation.
Winston DJ, Gale RP, Meyer DV, Young LS.
Infections are an almost inevitable complication of human bone marrow transplantation and account for the majority of deaths in transplant recipients. Even prior to the initiation of the transplantation procedure, patients may present with infections complicating previously unsuccessful chemotherapy for hematological malignancy or aplastic anemia. Nevertheless, these pre-transplantation infections should not exclude the possibility of bone marrow transplantation if they can be successfully controlled with specific antimicrobial therapy and necessary adjunctive measures. The immediate post-transplantation period prior to engraftment is characterized by severe marrow aplasia that results from high-dose chemotherapy and total-body irradiation. Infections are primarily septicemias and localized processes caused by bacteria and fungi and their incidence increases as the intensity of immunosuppression is escalated. The high mortality associated with bacterial septicemia makes early, empirical antibacterial therapy mandatory. However, the reduction in mortality from bacterial infection resulting from such an aggressive approach may be offset by a higher mortality from invasive fungal infection, especially in patients with prior fungal colonization and undergoing prolonged conditioning therapy. Thus, until more specific and sensitive tests for the diagnosis of invasive fungal infection become available, empirical intravenous amphotericin should be considered in patients who are persistently febrile and deteriorate clinically in the face of appropriate antibacterial therapy. Interstitial pneumonia associated with severe GVHD is the major infectious complication after successful marrow engraftment and is the most significant barrier to long-term survival. Trimethoprim-sulfamethoxazole is effective prophylaxis against interstitial pneumonia due to Pneumocystis carinii, but one half of the patients still develop a pneumonitis either associated with CMV or of unknown etiology. Mortality from interstitial pneumonia is related to prior radiation therapy while survival is associated with a four-fold rise in CMV CF antibody titer. The latter observation supports the need to investigate passive immunization with CMV antibody as a means of preventing some interstitial pneumonias. Despite the progress made in many areas of human bone marrow transplantation, the majority of graft recipients still die of infectious complications. Thus, new approaches to the management of infections in transplant recipients are urgently needed. Better-tolerated oral nonabsorbable antibiotics, laminar-air-flow rooms, granulocyte transfusions, and chemotherapy and immunotherapy for CMV are among the prophylactic and therapeutic measures that must be critically evaluated in well-controlled, prospective studies. Continued assessment of the infectious complications of bone marrow transplantation is a critical aspect of any ongoing transplant program, not just a research goal...
Publication Types: Review
PMID: 368507 [PubMed - indexed for MEDLINE]
Cancer 1987 Jan 1;59(1):19-23 Related Articles, Books, LinkOut
Effect of trimethoprim/sulfamethoxazole prophylaxis on outcome of childhood lymphocytic leukemia. A Pediatric Oncology Group Study.
van Eys J, Berry DM, Crist W, Doering EJ, Fernbach DJ, Pullen J, Shuster J.
The Pediatric Oncology Group (POG) undertook a prospective randomized trial using a single chemotherapy regimen with or without trimethoprim/sulfamethoxazole (TS). In a previous acute lymphocytic leukemia (ALL) study of initial therapy, investigators were free to use TS prophylaxis or not. Analysis of those data seemed to favor TS for duration of continuous complete remission. In the study reported here, of 126 randomized patients with ALL, 63 received TS. There was no effect of TS on disease-free survival after 3 years follow-up. Overall severe toxicity did not differ. However, granulocytopenia was somewhat more severe in the TS group. Hepatic toxicity, measured by enzyme elevation approached significance in the TS group versus controls. Some institutions declined randomization and treated with or without TS as a routine. Outcome and toxicities did not differ from randomized patients. There was no statistically significant effect on severe, life-threatening or fatal infection between the randomized TS versus control groups. Children not receiving TS developed varicella more often, a disease for which one would not expect TS to show a preventative effect. Pneumocystis pneumonias were not reported. The authors conclude that TS prophylaxis did not increase the continuous complete remission rate in children with ALL or decrease the incidence of infection. Toxicity is somewhat higher on TS.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 3539306 [PubMed - indexed for MEDLINE]
Cancer 1986 Sep 1;58(5):1047-54 Related Articles, Books, LinkOut
Pulmonary complications occurring after allogeneic bone marrow transplantation. A study of 130 consecutive transplanted patients.
Cordonnier C, Bernaudin JF, Bierling P, Huet Y, Vernant JP.
This report deals with 81 pulmonary episodes occurring in 130 consecutive patients who underwent allogeneic bone marrow transplantation for hematologic malignancy in the same unit over a 5-year period. These episodes observed in 69/130 patients (53%) were mostly of infectious origin, and were investigated by bronchoalveolar lavage (BAL). The main causes of pneumonia were: cytomegalovirus (CMV) (n = 25), bacterial pneumonia (n = 17), invasive aspergillosis (n = 11) and pulmonary hemorrhage (n = 9). The overall mortality due to or associated with pneumonia was 26/130 (20%). Graft-versus-host disease clearly increased the incidence of infectious pneumonia and the mortality due to or associated with pneumonia. Granulocyte transfusions did not influence the incidence of CMV pneumonitis. The main causes and risk factors for pneumonia are discussed. The role of BAL as a noninvasive procedure is stressed.
PMID: 3524798 [PubMed - indexed for MEDLINE]
Cancer Chemother Pharmacol 1987;19(4):339-42 Related Articles, Books, LinkOut
Methotrexate in neutrophils in children with acute lymphoblastic leukemia.
Schroder H.
Methotrexate (MTX) and 6-mercaptopurine (6-MP) are used for maintenance therapy of acute lymphoblastic leukemia (ALL) of childhood, and both are myelotoxic. Clinically the individual tolerance to the two drugs is variable. In order to study to what extent the MTX accumulation in circulating neutrophils is related to the absolute neutrophil count (ANC), neutrophils were isolated on a discontinuous two-step Percoll gradient in 16 children with ALL in maintenance therapy. The MTX concentration in the neutrophils was determined with a sensitive radioligand binding assay. In all children except one who admitted noncompliance, MTX was found in the neutrophils in concentrations (56-460 pmol/10(9) cells) positively correlated with the weekly dose of MTX (r = 0.51, p less than 0.01). The interindividual variation was large. Children with relatively low neutrophil MTX exhibited the widest intraindividual variation of neutrophil MTX upon reexamination during continued MTX administration with the same dosage schedule. Increases in the weekly dose of MTX resulted in proportional increases in the neutrophil MTX. In half the cases the ANC was less than 1.5 X 10(9)/l. The ANC was not related to the weekly MTX dose or the daily 6-MP dose. In children with ANC greater than 1.5 X 10(9)/l there was a significant inverse correlation between the ANC and the neutrophil MTX (r = -0.71, P less than 0.01), which was not found in the group of children with ANC less than 1.5 X 10(9)/l. These findings may be explained by differences in the kinetics of the granulopoiesis between children with high and children with low neutrophil counts.
PMID: 3474084 [PubMed - indexed for MEDLINE]
Clin Pharmacol Ther 1987 Apr;41(4):384-7 Related Articles, Books, LinkOut
The effect of methotrexate on the bioavailability of oral 6-mercaptopurine.
Balis FM, Holcenberg JS, Zimm S, Tubergen D, Collins JM, Murphy RF, Gilchrist GS, Hammond D, Poplack DG.
Fourteen children (aged 3 to 14 years) with average-risk acute lymphoblastic leukemia were studied after an oral dose of 6-mercaptopurine (6-MP) (75 mg/m2) administered alone and, on the next day, concurrently with oral methotrexate (20 mg/m2). When 6-MP was administered alone, both the peak plasma concentration (15 to 150 ng X ml-1) and the AUC (36 to 340 ng X ml-1 X hr) were highly variable. Concurrent methotrexate resulted in a 31% increase in the AUC (P less than 0.01) and a 26% increase in peak plasma levels (P less than 0.05) of 6-MP. The AUC of methotrexate correlated with the degree of increase in 6-MP plasma concentrations. These findings are consistent with previous in vitro studies demonstrating that methotrexate is an inhibitor of xanthine oxidase, the enzyme that catabolizes 6-MP to the inactive metabolite thiouric acid. Although the increases in 6-MP AUC and peak plasma concentrations resulting from concurrent methotrexate administration were statistically significant, this interaction is probably not clinically significant at standard low oral doses of methotrexate in light of the wide interpatient variability in these pharmacokinetic parameters of 6-MP.
PMID: 3470165 [PubMed - indexed for MEDLINE]
Rinsho Ketsueki 1986 Oct;27(10):1916-21
[Successful vindesine treatment in the patient with blastic crisis of CML complicated with syndrome of inappropriate secretion of ADH secondary to vincristine]
[Article in Japanese]
Nishinarita S, Sasaki I, Hiranuma M, Sugai Y, Yoshizawa T, Sawada S, Amaki I.
PMID: 3469429 [PubMed - indexed for MEDLINE]
Cancer 1986 Jul 15;58(2 Suppl):473-80 Related Articles, Books, LinkOut
The pharmacology of orally administered chemotherapy. A reappraisal.
Poplack DG, Balis FM, Zimm S.
Rational treatment of pediatric malignancies requires a detailed knowledge of the clinical pharmacology of those antineoplastic agents used therapeutically. A number of different agents are administered by the oral route. Recently, the clinical pharmacology of 6-mercaptopurine (6-MP) and methotrexate (MTX), the two agents that are the mainstay of maintenance chemotherapy in acute lymphoblastic leukemia (ALL), were investigated. Studies of oral 6-MP indicate that, contrary to previous information, the bioavailability of this drug is relatively poor after oral administration, and that plasma 6-MP concentrations achieved after uniform oral dosing are highly variable. Similarly, study of the pharmacology of orally administered MTX indicates that there is little correlation between MTX dose and the peak serum level achieved. These findings suggest that some patients may not be exposed to adequate systemic concentrations of 6-MP and/or MTX after oral administration, and raise the possibility that the development of relapse in some patients with ALL may be the result of a pharmacologic failure of oral maintenance therapy. A comprehensive prospective study of the clinical pharmacology of MTX and 6-MP in patients with ALL undergoing maintenance chemotherapy is currently in progress.
PMID: 3459570 [PubMed - indexed for MEDLINE]
Clin Pharmacol Ther 1988 May;43(5):588-91 Related Articles, Books, LinkOut
Bioavailability of low-dose vs high-dose 6-mercaptopurine.
Arndt CA, Balis FM, McCully CL, Jeffries SL, Doherty K, Murphy R, Poplack DG.
Pediatric Branch, National Cancer Institute, Bethesda, MD 20892.
The bioavailability of oral 6-mercaptopurine (6MP) at standard doses is very low, largely as a result of extensive first-pass metabolism by xanthine oxidase. Fewer than one third of patients achieve 6MP plasma concentrations known to be cytocidal in vitro (greater than 1 mumol/L). Studies in vitro have suggested that first-pass metabolism can be saturated at higher doses of 6MP. To determine whether saturation occurs in vivo at clinically used doses and whether bioavailability can be enhanced by increasing the dose, the bioavailability of different doses of 6MP was studied first in rhesus monkeys and then in children with acute lymphoblastic leukemia in remission. In monkeys a higher dose of 6MP resulted in enhanced bioavailability, whereas in patients the mean relative bioavailability at the higher dose was significantly less. However, all patients achieved cytocidal (greater than 1 to 10 mumol/L) plasma concentrations at the higher dose without manifesting significant clinical toxicity. Therefore cytocidal levels of 6MP can be achieved in patients with oral 6MP without the risk of unexpectedly high levels caused by saturation of first-pass metabolism.
PMID: 3365920 [PubMed - indexed for MEDLINE]
Ann Genet 1988;31(1):53-6 Related Articles, Books, LinkOut
Poor prognosis of acute lymphoblastic leukemia with translocation (1;19) in childhood: potential interest of allogeneic bone marrow transplantation.
Vagner-Capodano AM, Michel G, Maraninchi D, Tubiana N, Gouzien M, Perrimond H, Carcassonne Y.
Laboratoire de Genetique, Faculte de Medecine, Marseille, France.
We report a new case of childhood acute lymphoblastic leukemia with translocation (1;19). At the time of diagnosis, the only adverse prognosis factor was the existence of this translocation. Under conventional chemotherapy, the girl experienced early marrow relapse (duration of first remission was 2 months). She received allogeneic bone marrow transplantation during the second remission and is alive in continuous complete remission 20 months after transplant. Several earlier reports have suggested that children with the (1;19) have a poor prognosis; If this poor response to conventional therapy is confirmed, an allogeneic bone marrow transplantation should be considered during the first remission.
Publication Types: Review Review of Reported Cases
PMID: 3281571 [PubMed - indexed for MEDLINE]
An Esp Pediatr 1988 Oct;29 Suppl 34:155-6
[Inappropriate ADH syndrome and other toxic effects in the course of childhood ALL treated with vincristine]
[Article in Spanish]
Indiano JM, Gonzalez A, Oria de Rueda O, Sanchez E.
Universidad del Pais Vasco, Departamento de Pediatria, Hospital de Basurto, Bilbao.
PMID: 3214029 [PubMed - indexed for MEDLINE]
Cancer 1988 Aug 1;62(3):635-44 Related Articles, Books, LinkOut
A population-based case-control study of childhood leukemia in Shanghai.
Shu XO, Gao YT, Brinton LA, Linet MS, Tu JT, Zheng W, Fraumeni JF Jr.
Shanghai Cancer Institute, Epidemiology Department, People's Republic of China.
A population-based case-control interview study of 309 childhood leukemia cases and 618 healthy population control children was conducted in urban Shanghai, China. Like some studies in other countries, excess risks for both acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL) were associated with intrauterine and paternal preconception diagnostic x-ray exposure, and with maternal employment in the chemical and agricultural industries during pregnancy. ANLL was linked to maternal occupational exposure to benzene during pregnancy, whereas both ALL and ANLL were significantly associated with maternal exposure to gasoline and the patient's prior use of chloramphenicol. New findings, previously unsuspected, included an association of ANLL with younger maternal age at menarche (odds ratio [OR] = 4.3; 95% confidence interval (CI) = 1.3-13.9); a protective effect for long-term (greater than 1 year) use of cod liver oil containing vitamins A and D for both ALL (OR = 0.4; 95% CI = 0.2-0.9) and ANLL (OR = 0.3; 95% CI = 0.1-1.0); and excess risks of ANLL among children whose mothers were employed in metal refining and processing (OR = 4.6; 95% CI = 1.3-17.2) and of ALL associated with maternal occupational exposure to pesticides (OR = 3.5; 95% CI = 1.1-11.2). No relationships were found with late maternal age, certain congenital disorders, or familial occurrence, which have been related to childhood leukemia in other studies. In contrast with other reports, an excess of leukemia, primarily ANLL, occurred among second or later-born rather than firstborn children.
PMID: 3164642 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 1986;3(4):319-24 Related Articles, Books, LinkOut
Influence of food intake on bioavailability of oral 6-mercaptopurine in children with acute lymphoblastic leukemia.
Riccardi R, Balis FM, Ferrara P, Lasorella A, Poplack DG, Mastrangelo R.
Division of Pediatric Oncology, Catholic University of Rome, Italy.
Plasma levels of 6-mercaptopurine (6-MP) were measured after oral administration in 17 children with acute lymphoblastic leukemia (ALL). In the fasting state or after a breakfast consisting of 250 ml milk and 50 g biscuits, 6-MP was administered at a dose of 75 mg/m2. In patients studied in a fasting state, the mean time to plasma peak (tmax) level was 1.2 h, whereas in patient studied after breakfast the mean tmax was 2.3 h. This difference is statistically significant (p less than 0.001). Moreover, the 6-MP peak plasma concentration (cmax) and the areas under the plasma concentration time curves (AUC) were significantly reduced when the drug was administered after breakfast. The mean Cmax +/- SD were 0.98 +/- 0.54 microM and 0.63 +/- 0.48 microM, respectively (p less than 0.05). The mean 6-MP AUC +/- SD in patients studied in a fasting state and after breakfast were 143 +/- 69 microM min and 105 +/- 68 microM, respectively (p less than 0.01). These results indicated that 6-MP should be taken in a fasting state to optimize drug absorption in children undergoing chemotherapy for ALL.
PMID: 3153245 [PubMed - indexed for MEDLINE]
Br Med J (Clin Res Ed) 1988 Jan 16;296(6616):162-6 Related Articles, Books, LinkOut
Medical cost of curing childhood acute lymphoblastic leukaemia.
Wheeler K, Leiper AD, Jannoun L, Chessells JM.
Department of Haematology/Oncology, Hospital for Sick Children, London.
Between 1970 and 1979 acute lymphoblastic leukaemia was diagnosed in 378 children at this hospital. The outcome for the 181 survivors was examined six or more years after diagnosis to assess morbidity in an unselected group of long term survivors. One hundred and thirty seven of the survivors were in first remission and probably cured (group I). Forty four (group II) had had one or more relapses, some of whom, who had isolated extramedullary relapses, also have a good chance of cure. In group I 136 patients had prophylactic cranial or craniospinal irradiation, while patients in group II, in addition to having that treatment, received local testicular (17) or craniospinal radiation (seven) for testicular or central nervous system relapse. Eight had additional prophylactic cranial radiotherapy after bone marrow relapse, and six had total body irradiation before bone marrow transplantation. The incidence of clinically important growth and endocrine morbidity was 20% in group I and 68% in group II. The morbidity in patients in group I was mainly attributable to early pubertal maturation. In group II 30 patients had growth failure, of whom 19 had gonadal failure from testicular or total body irradiation, 14 had growth hormone deficiency after doses of cranial irradiation of over 2400 cGy, and 10 had spinal growth impairment after craniospinal irradiation. Two also had early pubertal maturation. Five out of six patients who received total body irradiation had multiple endocrine deficiency. Neuropsychological sequelae of treatment were seen in 40 (42%) of 96 schoolchildren in group I and in 12 (38%) of 32 schoolchildren in group II. Postinfective sequelae of treatment were found in patients in both groups. These results show that the survivors who were in their first remission had a 42% residual morbidity related to treatment compared with an 82% morbidity in the survivors of one or more relapses who had multiple treatments.
PMID: 3122982 [PubMed - indexed for MEDLINE]
Pediatr Med Chir 1988 Mar-Apr;10(2):133-41 Related Articles, Books, LinkOut
[Leukemia in childhood]
[Article in Italian]
Masera G, Adamoli L, Conter V, Piacentini G.
Clinica Pediatrica, Universita di Milano, Ospedale San Gerardo di Monza, Italia.
The prognosis of leukemia in children has changed remarkably in the last 20 years. Today more than 50% of children with Acute Lymphoblastic Leukemia (ALL) and about 30% of children with Acute non Lymphoblastic Leukemia (ANLL) can be cured with chemotherapy. The German Group BFM has obtained a significant improvement of results, both in ALL and ANLL using multidrug intensive treatment schedules. In Italy, thanks to the Italian Pediatrics Association of Hematology and Oncology (AIEOP), results have been improved in the last 10 years; very recently, new protocols with the BFM strategy have been started. Allogenic matched bone marrow transplantation (BMT) is indicated in children with ALL in 2nd complete remission (CR) following a relapse during or shortly after discontinuing treatment and in patients with Chronic Myeloid Leukemia. Chemotherapy results remain very poor in these patients. Allogenic BMT in usually performed also in children with ANLL in 1st CR. Autologous BMT, and allogenic BMT mismatched or from unrelated donors are being used with promising results when matched donors are not available. Most children cured of leukemia can enjoy a normal quality of life. However long term studies are still needed to determine the incidence of late effects, and to evaluate the psychosocial impact of the disease. In this context is becoming more and more important the role of the family doctor.
Publication Types: Review Review, Tutorial
PMID: 3050901 [PubMed - indexed for MEDLINE]
J Infect Dis 1979 Sep;140(3):402-6 Related Articles, Books, LinkOut
Antibody responses to influenza immunization of children with acute lymphoblastic leukemia.
Lange B, Shapiro SA, Waldman MT, Proctor E, Arbeter A.
Antibody responses of two doses of a bivalent influenza vaccine containing A/Victoria/75 (A/Vic/75) and A/New Jersey/76 (A/NJ/76) viral antigens were studied in 22 children receiving maintenance chemotherapy for acute lymphoblastic leukemia (ALL), 16 children no longer receiving therapy for ALL, and 50 sibling controls. Before immunization, the three groups showed no difference in titer of antibody to either antigen. After the first immunization, children off therapy showed significantly higher titers to A/NJ/76 than did either sibling controls of children receiving therapy (P less than 0.01). After the second immunization, children off therapy showed significantly higher antibody titers to both antigens than did children receiving therapy or controls (P less than 0.01 for both A/NJ/76 and A/Vic/75). Antibody titers of children receiving therapy were not significantly different from those of controls. A year later, there were no significant differences in antibody titers among the groups. Thus, children with ALL who are receiving chemotherapy respond normally to two doses of influenza vaccine, whereas children off therapy manifest abnormally high titers of antibody to both influenza virus antigens.
PMID: 291662 [PubMed - indexed for MEDLINE]
Lancet 1987 Feb 21;1(8530):429-32 Related Articles, Books, LinkOut
Which treatment for childhood acute lymphoblastic leukaemia in second remission?
Butturini A, Rivera GK, Bortin MM, Gale RP.
The best therapy for children with acute lymphoblastic leukaemia (ALL) who have an initial bone marrow relapse and subsequently achieve second remission is controversial. Some findings suggest that bone marrow transplantation (BMT) is better than chemotherapy whereas others do not. An analysis of 871 children treated by BMT or chemotherapy showed that outcome was correlated with risk factors at diagnosis and with length of first remission. BMT seemed superior in patients who relapsed within 18 months of first remission while on maintenance chemotherapy. BMT was not demonstrably superior in patients who relapsed more than 18 months after first remission. The choice of treatment in childhood ALL must be based on prognostic variables at diagnosis and on the circumstances of the relapse.
Publication Types: Review
PMID: 2880224 [PubMed - indexed for MEDLINE]
Lancet 1986 May 31;1(8492):1239-41 Related Articles, Books, LinkOut
Bone-marrow transplantation has a limited role in prolonging second marrow remission in childhood lymphoblastic leukaemia.
Chessells JM, Rogers DW, Leiper AD, Blacklock H, Plowman PN, Richards S, Levinsky R, Festenstein H.
Fifty-three children with acute lymphoblastic leukaemia whose first complete remission ended in bone-marrow relapse received similar reinduction and consolidation therapy. Thirteen had an HLA-compatible sibling donor and were eligible to receive a bone-marrow transplant (BMT); five survive, all off treatment in continuing remission. Forty had no donor and received further chemotherapy; sixteen survive, twelve in remission and six off treatment. After 1-5.5 years' follow-up from relapse, there is no significant difference in survival between the groups. The major obstacle to success is marrow relapse which occurred in two eligible patients before BMT could be carried out. The lengths of first and second remissions in both groups were significantly correlated. Morbidity in survivors was substantial. The scope of BMT as retrieval therapy for ALL is limited by the instability of second remissions; this difficulty will not be overcome by increasing the number of potential donors or the use of autologous marrow.
PMID: 2872392 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1989 Nov;4(6):609-12 Related Articles, Books, LinkOut
Allogeneic bone marrow transplantation versus chemotherapy in the treatment of childhood acute lymphoblastic leukemia in second complete remission.
Torres A, Martinez F, Gomez P, Fornes G, Rojas R, Herrera C, Gomez JL, Manzanares R, Garcia JM, Andres P, et al.
Department of Haematology of Cordoba, Sevilla, Spain.
Seventy-six patients between the ages of 2 and 17 years with acute lymphoblastic leukemia (ALL) achieved a second complete remission induced by polychemotherapy. Twenty-one had an HLA-identical donor and underwent allogeneic bone marrow transplantation (BMT) after conditioning with total body irradiation and cyclophosphamide. The remaining 55 patients lacked a suitable donor and received intensive chemotherapy as treatment. Fifteen patients were excluded from the analysis because they relapsed within 3 months after achieving a second complete remission. Three of the 21 BMT patients died of transplant-related complications and seven relapsed between 90 and 480 days after transplantation. Eleven patients are alive and disease free at 5.5-71 months with an actuarial survival of 47.1%; eight patients are on a plateau extending from 22 to 71 months. Thirty-three patients treated with chemotherapy died from relapse and seven are alive and disease free 7.5-99 months from the second remission, with an actuarial survival of 9%. The probability of survival was significantly higher in the BMT group (p less than 0.025). The probability of remaining in complete remission in the BMT group was 58.5% versus 10.9% in the chemotherapy group (p less than 0.005). Our results show that BMT is the best alternative therapy for children affected by ALL who have had a relapse in the marrow.
PMID: 2819281 [PubMed - indexed for MEDLINE]
Am J Pediatr Hematol Oncol 1989 Fall;11(3):324-6 Related Articles, Books, LinkOut
Chronopharmacokinetics of oral methotrexate and 6-mercaptopurine: is there diurnal variation in the disposition of antileukemic therapy?
Balis FM, Jeffries SL, Lange B, Murphy RF, Doherty KM, Arndt CA, Luery N, Poplack DG.
Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
The chronopharmacokinetics of the orally administered antileukemic drugs, 6-mercaptopurine and methotrexate, were examined in 13 children with acute lymphoblastic leukemia (ALL) to establish if there is a pharmacokinetic basis for the lower relapse rate associated with administration of these agents in the evening. Children with ALL in complete remission had plasma drug concentrations monitored for 8 h following an oral dose of either methotrexate or 6-mercaptopurine administered in the morning (8 a.m.) and the evening (8 p.m.). Total drug exposure to oral methotrexate, as measured by the mean area under the plasma concentration-time curve (AUC), was 2.75 microM.h following the morning dose and 2.77 microM.h in the evening. For 6-mercaptopurine, the mean morning AUC (198 ng.h/ml) was higher than that following the evening dose (167 ng.h/ml) (p greater than 0.05); but compared to the wide interpatient variability observed with this drug, this 20% difference is not likely to be clinically significant. These results indicate that the suggested benefit of evening drug administration is not likely to be a result of diurnal variation in drug disposition.
PMID: 2782561 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 1989;6(2):105-12 Related Articles, Books, LinkOut
Oral mercaptopurine in childhood leukemia: influence of food intake on bioavailability.
Lonnerholm G, Kreuger A, Lindstrom B, Myrdal U.
Department of Pediatrics, Uppsala University, Akademiska Sjukhuset, Sweden.
Plasma concentrations of 6-mercaptopurine (6-MP) were determined by gas chromatography-mass spectrometry. Ten children (nine with acute lymphatic leukemia) were studied on 2 consecutive days after oral intake of 6-MP. On one day the drug was administered in the fasting state and on the other (in random order) together with breakfast. The peak plasma concentrations of 6-MP after the dose intake with breakfast in percent of that in the fasting state (meal in % of fasting for each individual) varied between 33 and 181% (mean 111), and the area under the plasma concentration-time curve varied between 47 and 186% (mean 103). Thus, there were considerable variations among patients, but, for the group as a whole, there were no statistically significant differences between the two experimental conditions. This study cannot therefore form the basis for a recommendation as to whether 6-MP should be administered on an empty stomach or together with food.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 2702064 [PubMed - indexed for MEDLINE]
Cancer Chemother Pharmacol 1989;24 Suppl 1:S16-9 Related Articles, Books, LinkOut
Chemotherapy for bone marrow relapse of childhood acute lymphoblastic leukemia.
Henze G, Fengler R, Hartmann R, Dopfer R, Gobel U, Graf N, Jurgens H, Niethammer D, Ritter J, Schellong G, et al.
Kinderklinik, Freie Universitat Berlin.
Results of the BMF study group trials ALL-REZ 83 and 85 for relapsed acute lymphoblastic leukemia (ALL) are presented. For children with late marrow relapse, remission rates of about 90% were seen in both studies. In children treated for early marrow relapse, the remission rate in study ALL-REZ 85 was superior (86% vs 62%). The probability of event-free survival for all patients and for those with early marrow relapse was also statistically significant (P less than 0.05). Children with T-cell ALL had an extremely unfavourable prognosis in both studies.
PMID: 2667787 [PubMed - indexed for MEDLINE]
Annu Rev Med 1989;40:99-112 Related Articles, Books, LinkOut
Autologous bone marrow transplantation.
Santos GW, Yeager AM, Jones RJ.
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Autologous bone marrow transplantation in the acute leukemias and lymphomas offers potentially curative treatment in patients who do not have a histocompatible, allogeneic donor. Results of marrow autografting in the lymphomas are especially encouraging, with disease-free survivals of 50-60% in patients who have failed primary and secondary treatment regimens. In the acute leukemias, one may expect 20-40% relapse-free survival after autologous marrow transplantation. We feel that ex vivo treatment ("purging") is necessary to eradicate occult tumor cells from autologous remission marrow in hematological malignancies, but this remains a controversial issue to some investigators. Preliminary studies of autologous bone marrow transplantation are promising in multiple myeloma and certain childhood tumors, and autografting is currently being explored in the treatment of other solid tumors such as adenocarcinoma of the breast.
Publication Types: Review Review, Tutorial
PMID: 2658765 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1989 Jan;4 Suppl 1:80-5 Related Articles, Books, LinkOut
Acute lymphocytic leukemia of childhood: the problem of relapses.
Rivera GK, Santana V, Mahmoud H, Buchanan G, Crist WM.
Department of Hematology-Oncology, St Jude Children's Research Hospital, University of Tennessee, College of Medicine, Memphis.
Developing improved therapy for the one-third or more of patients who can be expected to relapse after initial treatment for acute lymphoblastic leukemia would be less difficult if one could identify potential failures unequivocally at diagnosis. Subgroups of patients who should be considered candidates for highly experimental therapy include infants (less than 1 year of age), patients with the Philadelphia chromosome and perhaps patients with B-cell leukemia. The most important factor that determines the success of therapy after relapse is the length of the patient's initial remission. We recommend bone marrow transplantation for children whose first remission did not exceed 18 months. For all others, it appears that intensive chemotherapy affords as great a potential for cure as one could expect from transplantation. We favor intensive chemotherapy over transplantation in cases of late bone marrow relapse (greater than 18 months), because of the currently high peritransplantation mortality rate. It is not clear whether either modality will be adequate for patients relapsing on contemporary treatment programs.
Publication Types: Review Review, Tutorial
PMID: 2653524 [PubMed - indexed for MEDLINE]
Zhonghua Yu Fang Yi Xue Za Zhi 1989 Jul;23(4):234-6 Related Articles, Books, LinkOut
[Epidemiological survey of childhood leukemia]
[Article in Chinese]
Kuang XF.
This paper reports epidemiological data of childhood leukemia in the 14 years 1973-1986 in Qidong county, Jiangsu province. Mortality of childhood leukemia was 1.74 per 10 million, taking first place among various malignant tumors of children. The annual mortality distribution of this disease and the age and season at death showed no significant difference, But finer age grouping of death rates revealed remarkable difference. Thus, in 0-4 age-group the mortality was 2.95 per 10 million higher than the remainder. Childhood leukemia mortality by space-Time Clusters analysis showed the significance of difference lobe P greater than 0.05, suggesting that childhood leukemia mortality in space and time clusters were random.
PMID: 2627840 [PubMed - indexed for MEDLINE]
Am J Pediatr Hematol Oncol 1989 Winter;11(4):402-6 Related Articles, Books, LinkOut
Milk could decrease the bioavailability of 6-mercaptopurine.
Rivard GE, Lin KT, Leclerc JM, David M.
Centre de Recherche Pediatrique, Hopital Sainte-Justine, Montreal, Quebec, Canada.
The bioavailability of 6-mercaptopurine (6-MP) administered orally for maintenance therapy of children with acute lymphoblastic leukemia is highly variable. Xanthine oxidase (XO) can transform 6-MP into 6-thioxanthine (6-TX) and 6-thiouric acid (6-TUA), which have no therapeutic value. XO is found in high concentration in cow's milk. Incubation at 37 degrees C for 30 min with commercial preparations of pasteurized cow's milk results in transformation of 30% of a clinically relevant concentration of 6-MP into 6-TUA. Milk boiled for 5 min has no effect on the 6-MP. Addition of gastric juice at ratios likely to be seen in children has negligible inhibitory effect on the 6-MP destroying activity of milk. Conversely, folic acid and allopurinol markedly inhibit this effect at clinically relevant concentrations. These observations may help to optimize modalities of administration of 6-MP.
PMID: 2618973 [PubMed - indexed for MEDLINE]
Med Oncol Tumor Pharmacother 1989;6(4):259-65 Related Articles, Books, LinkOut
Variability of 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute leukemia.
Lafolie P, Bjork O, Hayder S, Ahstrom L, Peterson C.
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
The effects of some environmental and genetic factors on the inter- and intraindividual variations of 6-mercaptopurine (6-MP) pharmacokinetics were studied in children on oral remission maintenance therapy for acute lymphoblastic leukemia or non-Hodgkin's lymphoma. Blood samples were obtained 0-4 h after drug intake. 6-MP concentrations were determined in plasma and in erythrocyte concentrates. The influence of food on the pharmacokinetics was examined in a prospective study of 15 children. Each child was examined four times, twice in the fasted state and twice after intake of a standardized, milky, breakfast. There were pronounced inter- and intraindividual variations. Food intake seemed to reduce these variations but there were no significant changes in peak concentrations and area under the plasma concentration vs time curves (AUC) between the fasted and fed states. Food intake reduced the time to peak concentration both in plasma, from 1.8 h to 1.1 h (P less than 0.01) and in red blood cells, from 1.8 h to 1.3 h (P less than 0.01). Retrospective subdivision of the patients indicated a tendency for different pharmacokinetic patterns according to dose; five out of seven patients receiving greater than 70 mg m-2 had a higher AUC in the fasting state, while five out of eight patients receiving less than 70 mg m-2 had a higher AUC in the fed state. The cytochrome P-450-dependent hydroxylation capacity was evaluated with debrisoquine but no correlation was found to the pharmacokinetics of 6-MP.
PMID: 2615529 [PubMed - indexed for MEDLINE]
Med Pediatr Oncol 1989;17(6):450-4 Related Articles, Books, LinkOut
Disposition of oral methotrexate in children with acute lymphoblastic leukemia and its relation to 6-mercaptopurine pharmacokinetics.
Koren G, Solh H, Klein J, Soldin SJ, Greenberg M.
Division of Hematology-Oncology, Toronto, Ontario, Canada.
We studied the disposition pharmacokinetics of methotrexate (MTX) given orally to 16 children with acute lymphoblastic leukemia (ALL) and its relation to the pharmacokinetics of 6-mercaptopurine (6MP) in the same children. There was an eightfold variability in area-under-concentration time-curve (AUC) of MTX achieved by the same dose. Excellent correlation existed between peak concentrations and AUC0----infinity (r = 0.95, P less than 0.001). Elimination T1/2 was between 1.34 and 5 hours (mean 2.16 +/- 0.23 hr, mean +/- SE). A weak correlation existed between AUC achieved by 1 mg/m2 MTX and patients' age or body weight. Weak but significant correlation existed between AUC achieved by 1 mg/m2 of MTX vs. 6MP (r = 0.54, P less than 0.05). In 13/16 patients peak concentrations were achieved at 60 minutes. There was a significantly larger AUC of 6MP achieved by a standardized dose in longer therapy (greater than 15 mo) vs. short therapy (less than 12 mo) (462 +/- 75 and 246 +/- 58 ng.ml-1.min.mg-1.m2, P less than 0.025). No statistical differences in AUC of MTX were found between short and long therapy. The large interpatient variability in MTX pharmacokinetics supports the possibility that differences in absorption and/or clearance of the drug may affect the clinical response. Because of the excellent correlation between peak and AUC of MTX, and because 3 measurements, at 30, 60, and 90 minutes will almost invariably identify the peak, this measurement can be used to estimate AUC for purpose of correlation with clinical outcome.
PMID: 2586358 [PubMed - indexed for MEDLINE]
Biochem Pharmacol 1988 Jun 15;37(12):2321-7 Related Articles, Links
Purine de novo synthesis as the basis of synergism of methotrexate and 6-mercaptopurine in human malignant lymphoblasts of different lineages.
Bokkerink JP, Bakker MA, Hulscher TW, De Abreu RA, Schretlen ED.
Department of Pediatrics, St Radboud Hospital, University of Nijmegen, The Netherlands.
Methotrexate (MTX) causes an inhibition of purine de novo synthesis (PDNS), resulting in increased intracellular availability of 5-phosphoribosyl-1-pyrophosphate (PRPP) in human malignant lymphoblasts with an active PDNS. Normal bone marrow cells and peripheral blood lymphocytes lack this capacity. The increased levels of PRPP can be used for enhanced incorporation of 6-mercaptopurine (6MP), indicating a potential time-, sequence- and dose-dependent synergism of both drugs. The effects of 0.02 microM and 0.2 microM MTX on the PDNS of MOLT-4 (T-), RAJI (B-) and KM-3 (non-B-non-T-) human malignant lymphoblasts were studied with respect to PRPP levels, aminoimidazolecarboxamide ribonucleosidemonophosphate (AICAR) levels and the incorporation of labeled glycine into purine metabolites. These results were correlated with the activity of the PDNS (labeled glycine incorporation) and the purine salvage pathway (labeled hypoxanthine incorporation) in untreated cells. Inhibition of PDNS by 0.02 microM MTX was complete in KM-3 cells with a moderately active PDNS and salvage pathway. RAJI cells, with a relatively low PDNS and high salvage pathway, demonstrated an incomplete, but increasing inhibition of PDNS, whereas inhibition of PDNS in MOLT-4 cells with both pathways active was minimal and recovered in time. Treatment with 0.2 microM MTX resulted in a complete inhibition of PDNS in all cell lines. After treatment with MTX an enhanced incorporation of labeled hypoxanthine and 6MP was noticed, confirming the potential rescue from MTX cytotoxicity by hypoxanthine and a potential synergism of MTX and 6MP on cytotoxicity. The enhanced incorporation of 6MP was more obvious in RAJI and KM-3 cells in comparison with MOLT-4 cells. These data demonstrate the important role of both the activities of the PDNS and the purine salvage pathway in malignant lymphoblasts of different subclasses with respect to the synergism of MTX and 6MP.
PMID: 2455519 [PubMed - indexed for MEDLINE]
N Engl J Med 1990 Jul 5;323(1):17-21 Related Articles, Books, LinkOut
Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children.
Comment in: N Engl J Med. 1990 Nov 29;323(22):1565-6.
Koren G, Ferrazini G, Sulh H, Langevin AM, Kapelushnik J, Klein J, Giesbrecht E, Soldin S, Greenberg M.
Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, ON, Canada.
BACKGROUND. Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse. METHODS. To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted. RESULTS. There was a significant difference in the mean (+/- SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636 +/- 197 nmol per liter x minutes in those who relapsed, as compared with 2424 +/- 177 nmol per liter x minutes in those who did not (P less than 0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043 +/- 12,812 nmol per liter x minutes) than in those who did not (168,862 +/- 18,830 nmol per liter x minutes) (P less than 0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan-Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter x minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P less than 0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter x minutes had a significantly better prognosis than those with a lower exposure (P less than 0.005). CONCLUSIONS. Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure.
PMID: 2355954 [PubMed - indexed for MEDLINE]
Med J Aust 1990 Apr 16;152(8):416-8 Related Articles, Books, LinkOut
Bone marrow transplantation for childhood acute lymphoblastic leukaemia after marrow relapse.
Vowels MR, Lam-Po-Tang R, Mameghan H, Ford D, Trickett A, White L, Marshall G, Brown R.
Prince of Wales Children's Hospital, Randwick, NSW.
Children with acute lymphoblastic leukaemia in whom relapse in bone marrow occurs have a poor outlook when treated with chemotherapy alone. Twenty-seven patients with childhood acute lymphoblastic leukaemia were treated for marrow relapse with high-dose chemotherapy with or without total body irradiation followed by bone marrow transplantation (BMT). Twenty patients received allogeneic marrow from partially or completely matched histocompatible donors. In this group, nine patients (45%) were free of disease with a median follow-up of 57 months (range, 22 to 126 months) after transplantation, four (20%) died from interstitial pneumonitis and seven (35%) died after a further relapse. Seven patients received autologous marrow collected while they were in remission. In this group, one patient died from infection and six died after a further relapse. We conclude that allogeneic BMT is more effective than autologous transplantation and results in long-term disease-free survival in a significant number of patients. New methods are needed to eradicate residual disease in the patient and to purge marrow ex vivo.
PMID: 2329949 [PubMed - indexed for MEDLINE]
Am J Pediatr Hematol Oncol 1990 Winter;12(4):468-71 Related Articles, Books, LinkOut
Bone marrow transplantation improves survival for acute lymphoblastic leukemia in relapse: a preliminary report.
de Alarcon PA, Trigg ME, Giller RH, Rumelhart SL, Holida MD, Wen BC.
Department of Pediatrics and Radiology, University of Iowa, Iowa City 52242.
Acute lymphoblastic leukemia of childhood is the most common malignant disease in children greater than 1 year of age. Chemotherapy has improved the survival of children with this disorder. More than 95% of children will achieve a remission with chemotherapy. However, 30% of children with acute lymphoblastic leukemia who achieved a remission will have a relapse sometime after successful remission-inducing chemotherapy. Although a second remission can be induced in most of these children, in 10-40% a remission cannot be induced or they relapse shortly thereafter and develop refractory leukemia. We present in this preliminary report the early results of therapy for refractory leukemia with an intensive preparative regimen for bone marrow transplantation including etoposide, cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Transplantation was done in twenty-three patients with refractory leukemia. Projected survival at 917 days after transplantation in these patients is 43.4% +/- 11%. The survival of these patients so far is similar to the survival of children with acute lymphoblastic leukemia transplanted in second remission. All patients treated with this regimen who had transplantation in relapse were free of leukemia 27 days after transplantation. The results of this preliminary report suggest that an intensive preparative regimen can improve the outlook of refractory leukemia and may rescue some patients who otherwise would have died of their disease.
PMID: 2285128 [PubMed - indexed for MEDLINE]
Am J Pediatr Hematol Oncol 1990 Winter;12(4):462-7 Related Articles, Books, LinkOut
Maintenance chemotherapy for childhood acute lymphoblastic leukemia: should dosage be guided by white blood cell counts?
Schmiegelow K, Pulczynska MK.
Department of Pediatrics, University Hospitals, Copenhagen, Denmark.
In a retrospective population-based study of 122 children with non-B-cell acute lymphoblastic leukemia (ALL), we analyzed the relation between risk of relapse and the degree of leukopenia achieved during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). After a median follow-up of 62 months for patients still in remission, 43 patients had relapsed (including 28 bone marrow relapses). Patients with a mean white blood cell count during MT (mWBCMT) of less than or equal to 3.5 x 10(9)/L had a significantly lower risk of hematological relapse (p = 0.007) as well as of any relapse (p = 0.02) compared to patients with higher mWBCMT. The clinical advantage of leukopenia could be demonstrated for all risk groups and was not explained by differences in year of diagnosis, gender, age, and white blood cell count at diagnosis, or the prescribed dose of MTX and 6MP. Although prospective studies are needed to establish the benefit of upward dose adjustments to achieve leukopenia, these results indicate a clinical advantage of keeping WBCs low during MT.
PMID: 2285127 [PubMed - indexed for MEDLINE]
Hematol Oncol Clin North Am 1990 Oct;4(5):997-1008 Related Articles, Books, LinkOut
Role of bone marrow transplantation in childhood lymphoblastic leukemia.
Johnson FL.
Section of Pediatric Hematology/Oncology, University of Chicago Medical Center, Illinois.
Allogeneic bone marrow transplantation is the only therapy introduced in the past 2 decades that has offered a better prognosis for children with ALL who have suffered a marrow relapse within 18 months of starting therapy. Currently, 40 to 50% of such patients are obtaining long remissions and are potentially cured by marrow transplantation. This therapy's effectiveness, however, is diminished by the problems of acute and chronic graft-versus-host disease, infection, and relapse. Further impact of marrow transplantation in the treatment of ALL awaits (1) more effective antileukemic preparative regimens or post-transplant antileukemic strategies, (2) less toxic preparative regimens to decrease the incidence of early and late effects, (3) more effective means of preventing and treating graft-versus-host disease, (4) the ability to safely perform mismatched marrow transplantation, and (5) more effective means of purging leukemic cells from remission bone marrow to expand the role of autologous marrow transplantation.
Publication Types: Review Review Literature
PMID: 2262489 [PubMed - indexed for MEDLINE]
Br J Haematol 1991 Jun;78(2):187-96 Related Articles, Books, LinkOut
Results of Medical Research Council Childhood Leukaemia Trial UKALL VIII (report to the Medical Research Council on behalf of the Working Party on Leukaemia in Childhood).
Eden OB, Lilleyman JS, Richards S, Shaw MP, Peto J.
Royal Hospital for Sick Children, Edinburgh.
During the 1970s, despite apparently similar treatment, the prognosis for children with lymphoblastic leukaemia (ALL) improved more in some countries, notably the United States and West Germany, than in others. To find out why, the first phase of the United Kingdom (UK) Medical Research Council (MRC) childhood ALL trial, UKALL VIII, was designed to see whether similar results to the United States Children's Cancer Study Group (CCSG) could be obtained in the U.K. using an identical protocol (CCG 162). Protocol 162 was one of a series of regimens devised by the American Children's Cancer Study Group in the 1970s and was used specifically for their average risk patients (all children with ALL with an initial white cell count up to 50 x 10(9)/l except those aged 3-6 years with white cell counts under 10 x 10(9)/l). One arm (1A) of their study was adopted by the MRC for all children in the U.K. aged 0-14 years with confirmed ALL. Eight hundred and twenty-nine consecutive patients were entered between 1980 and 1984. The first 199 patients formed a single arm study as per the original protocol 162 (arm 1A), but the subsequent 630 children were randomized to receive or not two doses of daunorubicin on the first 2 d of induction. This randomization was an attempt to answer the important question as to whether event-free survival was influenced by the use of four rather than three induction agents. A second randomization between 2 and 3 years continuing therapy was also introduced at this stage as it had been by the CCSG in their protocol. With a minimum follow up period of more than 5 years, disease-free survival for the whole group is 55%, a considerable improvement on all previous UKALL trials. Results for patients directly comparable with those in CCSG 162 ('average risk' patients) and their American counterparts were similar. Daunorubicin was associated with more early deaths but improved disease-free survival for those achieving remission. More children relapsed who stopped treatment after 2 years than those who continued for 3, but this was balanced by increased treatment mortality in the third year. The fact that for UKALL VIII the results were similar to those of the CCSG suggests that previous MRC protocols were not sufficiently sustained and intensive, particularly during the maintenance phase of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 2064956 [PubMed - indexed for MEDLINE]
Ther Drug Monit 1991 Jan;13(1):37-41 Related Articles, Books, LinkOut
Fat body mass and pharmacokinetics of oral 6-mercaptopurine in children with acute lymphoblastic leukemia.
Zuccaro P, Guandalini S, Pacifici R, Pichini S, Di Martino L, Guiducci M, Giuliano M, Di Tullio MT, Pettoello Mantovani M.
Department of Pediatrics, University of Naples, Italy.
To evaluate the reasons for the wide variability in bioavailability of orally administered 6-mercaptopurine in children with acute lymphoblastic leukemia, we studied several pharmacokinetic parameters of the drug in 18 affected children receiving remission maintenance therapy, and compared them with their anthropometric data and with the results of intestinal function tests. No correlation was found between estimates of small intestinal absorption (the oral lactose tolerance test and 1 h blood xylose test) and 6-mercaptopurine serum levels. Of the anthropometric measurements considered, only the weight/height percentile (an index of the fat body mass) strongly and linearly correlated with the area under the curve of 6-mercaptopurine. The dose of 75 mg of 6-mercaptopurine/m2 of body surface resulted in higher serum concentrations in children below the 75th percentile than in those with a weight/height ratio exceeding the 75th percentile. In conclusion, these data caution about the risk of underdosing 6-mercaptopurine in overweight children when administering it on the basis of body surface area.
PMID: 2057989 [PubMed - indexed for MEDLINE]
Arch Dis Child 1991 Apr;66(4):462-6 Related Articles, Links
Importance of 6-mercaptopurine dose in lymphoblastic leukaemia.
Hale JP, Lilleyman JS.
Department of Haematology, Children's Hospital, Western Bank, Sheffield.
To explore the possibility that higher total dosage of 'maintenance' treatment may have contributed to the recent improvement in outlook of children in the United Kingdom with lymphoblastic leukaemia, details of the amount of 6-mercaptopurine prescribed during the first two years of treatment were studied in an unselected cohort of children diagnosed between 1973 and 1987. Eighty five patients were studied, 30 diagnosed before and 55 after 1980. The group diagnosed after 1980 showed an 18% improvement in relapse free survival at five years. Their median total dose of 6-mercaptopurine had increased by 22%, whereas according to the protocol it should have risen by an average of only 9%. After 1980 boys were prescribed significantly more 6-mercaptopurine than girls, and had fewer dose reductions because of myelosuppression. These findings support the clinical impression that after 1980 an important therapeutic difference resulting from the new United Kingdom acute lymphoblastic leukaemia protocols was an increase in the amount of 6-mercaptopurine that children actually received as a result of changes in prescribing guidelines rather than dose. They also provide further evidence that boys tolerate 6-mercaptopurine better than girls, which may be related to the still unexplained difference in prognosis between the sexes.
PMID: 2031601 [PubMed - indexed for MEDLINE]
Eur J Clin Pharmacol 1991;40(6):599-601 Related Articles, Books, LinkOut
Intraindividual variation in 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute lymphoblastic leukaemia.
Lafolie P, Hayder S, Bjork O, Peterson C.
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Intraindividual variation in 6-mercaptopurine (6-MP) kinetics has been little studied. It has now been examined in 18 children with acute lymphoblastic leukaemia (ALL). On 2 to 4 occasions in each patient drug concentrations in plasma and red cells were followed for 4 h after administration by means of HPLC. The mean individual coefficient of variation (C.V.) in AUC was 57.9% and it was not related to dose or concentration. The variation was the same in plasma and in red cells. It is concluded that regular monitoring of 6-mercaptopurine concentration would identify periods when a patient deviates strongly from the mean range. Both undertreatment and concentration-dependent toxicity could then be corrected.
PMID: 1884741 [PubMed - indexed for MEDLINE]
Blood 1991 Sep 1;78(5):1166-72 Related Articles, Books, LinkOut
Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85). A relapse study of the BFM group.
Henze G, Fengler R, Hartmann R, Kornhuber B, Janka-Schaub G, Niethammer D, Riehm H.
Department of Hematology and Oncology, University Children's Hospital, Berlin, Germany.
Between April 1985 and March 1987 130 children and adolescents up to 18 years of age with first relapse of acute lymphoblastic leukemia (ALL) were registered on the stratified and randomized multicentric trial ALL-REZ BFM 85 designed for patients pretreated with intensive front-line therapies. Stratification criteria were time and site of relapse: bone marrow (BM) relapse on or up to 6 months after stopping front-line therapy (group A), BM relapse beyond 6 months after therapy (group B), and isolated extramedullary relapse at any time (group C). Treatment consisted of alternating courses of polychemotherapy including randomly administered high- or intermediate-dose methotrexate (HDMTX:12 g/m2 as 4-hour infusion; IDMTX: 1 g/m2 as 36-hour infusion). During maintenance therapy the patients received daily oral thioguanine and biweekly intravenous (IV) MTX. The overall second complete remission (CR) rate was 92% (groups A, B, and C: 88%, 92%, and 100%), and the probability of event-free survival (EFS) at 6 years is 0.31 +/- 0.04 (groups A, B, and C: 0.18 +/- 0.05, 0.30 +/- 0.07, and 0.72 +/- 0.11). HDMTX did not prove to be superior to IDMTX, which led to premature stopping of randomization. Risk factor analyses showed early relapse, particularly BM relapse within 18 months, and T-cell phenotype to be independent predictors of poor outcome. The incidence of central nervous system (CNS) relapses following BM relapse was 19%, indicating that reprophylaxis to the CNS with IV/intrathecal (IT) MTX was insufficient. For 17 children who received bone marrow transplantation in second CR from HLA-compatible siblings the EFS was 0.53 +/- 0.12 at 5 years. Their outcome was not influenced by the above-mentioned risk factors. With the proposed treatment regimen long-lasting second remissions can be achieved in about one third of patients even after intensive front-line treatment.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 1878583 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 1991 Apr-Jun;8(2):171-8
Vincristine overdose: experience with 3 patients.
Comment in: Pediatr Hematol Oncol. 1991 Apr-Jun;8(2):ix.
Kosmidis HV, Bouhoutsou DO, Varvoutsi MC, Papadatos J, Stefanidis CG, Vlachos P, Scardoutsou A, Kostakis A.
Department of Oncology, Children's Hospital, A. Kyriakou, Athens, Greece.
Vincristine overdose (7.5 mg/m2) was accidentally administered to 3 children with acute lymphoblastic leukemia. Treatment included double-volume exchange transfusion, phenobarbital administered prophylactically, and folinic acid rescue 18 mg every 3 hours for 16 doses. Vincristine levels were also assayed and showed a dramatic decline in postexchange levels in the 2 patients who survived and an almost unchanged value in the patient who succumbed. Early signs of toxicity in the 2 survivors were peripheral neuropathy (day 4), bone marrow toxicity (day 5), gastrointestinal toxicity (days 6 and 7), and hypertension (days 7 and 8). Marrow aplasia lasted for 4 and 10 days, peripheral neuropathy for 15 and 42 days, gastrointestinal toxicity for 3 and 5 days, and hypertension for 5 and 14 days. The 2 children were discharged on days 13 and 16 and cytostatic therapy was restarted on days 18 and 25. Both are alive without evidence of leukemia. The third patient developed liver and marrow toxicity on day 3 and died on day 9. Postmortem examination showed leukemia infiltration of the liver and spleen.
PMID: 1863543 [PubMed - indexed for MEDLINE]
J Pediatr 1991 Aug;119(2):311-6 Related Articles, Books, LinkOut
Dose-dependent kinetics of orally administered 6-mercaptopurine in children with leukemia.
Kato Y, Matsushita T, Chiba K, Hijiya N, Yokoyama T, Ishizaki T.
Department of Hospital Pharmacy, Clinical Research Institute, National Medical Center, Tokyo, Japan.
To determine whether the pharmacokinetics of 6-mercaptopurine (6-MP) would show dose dependency, we studied three different single oral doses in eight children (aged 3.6 to 15.1 years) with acute leukemia in remission. Marked interindividual differences in maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were observed when children received the 50 mg/m2 dose. This variability decreased when the doses were increased. Six of the eight children showed a disproportionate increase in the AUC with increasing doses; the other two had a proportionate relationship between the AUC and dose. Overall mean (+/- SD) Cmax and AUC values increased disproportionately (88 +/- 123, to 326 +/- 194, to 653 +/- 344 ng/ml for Cmax, and 147 +/- 180, to 451 +/- 177, to 1291 +/- 415 ng/ml per hour for AUC, respectively) when the dose increased from 50 to 87.5 mg/m2 and then to 175 mg/m2. The results suggest that a saturable first-pass metabolism of oral 6-MP occurs with increasing oral doses in some, but not all, children. Whether and to what extent this pharmacokinetic character of oral 6-MP affects the interindividual difference in systemic exposure to the drug in children with leukemia receiving maintenance therapy require further studies.
PMID: 1861221 [PubMed - indexed for MEDLINE]
Blood 1991 Nov 15;78(10):2780-4 Related Articles, Books, LinkOut
Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALL-protocols: results of the German Cooperative Study.
Dopfer R, Henze G, Bender-Gotze C, Ebell W, Ehninger G, Friedrich W, Gadner H, Klingebiel T, Peters C, Riehm H, et al.
Department of Hematology/Oncology, Children's University Hospital, Tubingen, Germany.
Fifty-one children between 26 and 214 months of age (median, 100 months) with acute lymphoblastic leukemia (ALL) were grafted in second remission from HLA-identical sibling donors (except for two patients who were grafted with a marrow with 1 antigen-mismatch). Initial treatment and relapse therapy were similar in all patients according to the BFM- and CoALL-protocols (front line: 38 patients according to BFM-protocols and 13 patients according to CoALL-protocols; relapse: 12 patients in study ALL-REZ-BFM 83, 17 in ALL-REZ-BFM 85, 20 in ALL-REZ-BFM 87, and two in ALL-REZ-BFM 90). The conditioning regimens were different, consisting of cyclophosphamide (CY) total body irradiation (TBI) plus (n = 27), VP-16-TBI (n = 23), and CY-TBI and ARA-C (n = 1). Three patients had a second graft after conditioning with CY-TBI for the first transplantation. The second ablative regimen consisted of CY plus VP-16 in the first patient and CY plus busulfan in the two other patients, one of whom relapsed again. All patients but three had bone marrow (BM), either isolated or combined, relapses. Twenty-nine of the patients are in continuous complete remission (CCR), ranging from 1 to 67 months after transplantation with a median time of 30 months. One patient was lost to follow-up in continuous remission. Nine patients died from treatment-related complications (infections and graft-versus-host disease) and 12 patients suffered a leukemic relapse; three of them received a second graft and two are in CCR. Kaplan-Meier analysis yields an event-free survival (EFS) of 0.52 +/- 0.08. The probability of a 7-year relapse-free interval (RFI) is 0.68 +/- 0.08. EFS for patients with late relapses is 0.47 +/- 0.12 and for patients with early relapses 0.56 +/- 0.1. The RFI for patients with late relapses is 0.65 +/- 0.12 and for patients with early relapses 0.69 +/- 0.11. There is a nonsignificant trend towards superior results for patients grafted after conditioning with VP-16 plus TBI. When all patients who are not in CCR at day +125 (which is the median interval between relapse diagnosis and BM transplantation [BMT]) are excluded from the chemotherapy results, there is no significant difference between the results of BMT and chemotherapy for late relapses. On the other hand, there is a significant advantage between chemotherapy and BMT for early relapses over chemotherapy (P less than or equal to .01).
Publication Types: Clinical Trial Controlled Clinical Trial Multicenter Study
PMID: 1824271 [PubMed - indexed for MEDLINE]
Acta Paediatr Jpn 1991 Aug;33(4):548-57 Related Articles, Books, LinkOut
Allogeneic bone marrow transplantation in childhood leukemia.
Kato S, Yabe M, Yabe H, Kubota C, Hinohara T, Hattori K, Shinohara O.
Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan.
Allogeneic bone marrow transplantation was performed in 94 patients with hematologic malignancies or other various diseases during the period between March 1982 and November 1990 at Tokai University Hospital. Projected disease-free survival rates of HLA genotypically identical marrow recipients were 88.9% for chronic myeloid leukemia transplanted in the first chronic phase (N = 9), 90.9% for acute leukemia in the first complete remission (N = 15), 54.5% for acute leukemia in later remissions (N = 14), 62.5% for solid tumors (N = 8) and 0% for patients transplanted in relapse (N = 7). The rate for HLA-mismatched marrow recipients with leukemia was 27.8% (N = 16). For patients with non-neoplastic diseases it was 100% regardless of HLA-compatibility (N = 26). The quality of life in long-term surviving pediatric marrow recipients has been acceptable. Common abnormalities among survivors are long-lasting hypogonadism due to radiation and subclinical impairment of lung function in the first year post-BMT. About two-thirds of children experienced a transient decrease in growth velocity in the immediate posttransplant period.
Publication Types: Clinical Trial
PMID: 1792915 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 1991 Oct-Dec;8(4):301-12
Prognostic significance of methotrexate and 6-mercaptopurine dosage during maintenance chemotherapy for childhood acute lymphoblastic leukemia.
Erratum in: Pediatr Hematol Oncol 1992 Apr-Jun;9(2):following 198
Schmiegelow K.
Department of Pediatrics, University Hospital, Copenhagen, Denmark.
Tolerance of full-dose methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy for childhood acute lymphoblastic leukemia (ALL) without side effects could reflect insufficient systemic drug exposure, and drug withdrawals due to toxicity might reduce the chance of cure. The present study included 122 children with non-B cell acute lymphoblastic leukemia with a median follow-up of 84 months. Leukopenia and hepatotoxicity were calculated as weighted means of all white cell counts and all serum aminotransferase measurements, respectively, registered for each patient. Forty-five patients relapsed (30 in bone marrow). Patients tolerating an average dose of MTX of more than 75% of the recommended protocol doses and having cumulated drug withdrawals of less than 1% of the period of maintenance therapy had an increased risk of hematological relapse (p = 0.008) as well as of any relapse (p = 0.03) when compared to the remaining patients. Patients with a cumulative withdrawal of MTX or of 6MP for greater than 10% of the maintenance therapy period had an increased risk of hematological relapse (MTX: p = 0.009, 6MP: p less than 0.0001) and of any relapse (MTX: p = 0.16, 6MP: p = 0.0002). Liver toxicity was the main reason for cumulative long-term drug withdrawals. However, patients with a mean aminotransferase level above the upper normal limit (40 IU/l) who were kept on therapy (cumulative withdrawals of neither drug for more than 5% of their maintenance therapy period) had a significantly lower risk of hematological relapse (p = 0.02) as well as of any relapse (p = 0.06) than the remaining children. The concept of treating to toxicity seems warranted for maintenance therapy of childhood lymphoblastic leukemia.
PMID: 1782110 [PubMed - indexed for MEDLINE]
Leukemia 1992;6 Suppl 2:144-7 Related Articles, Books, LinkOut
Controversies in therapy of acute lymphoblastic leukemia.
Gale RP, Butturini A.
Department of Medicine, UCLA School of Medicine 90024-1678.
There are several important controversial in therapy of acute lymphoblastic leukemia including: 1. What is the best initial chemotherapy; 2. Is maintenance chemotherapy effective; 3. How is cure achieved; 4. Are assays of residual leukemia cells useful; 5. Why are some persons currently incurable; 6. What is the best treatment strategy in children; 7. What is the best treatment strategy in adults; and 8. What are new approaches to cure the incurable. Here, we consider these issues. Our conclusion is that more intensive treatment is more effective but that no specific regimen is superior. Further dose escalations are unlikely to increase cures substantially. Maintenance chemotherapy is effective; it may work by controlling the ALL clone so that normal mechanisms regulating B-cell survival operate. Cure of ALL is probably achieved by diverse mechanisms including leukemia eradication in children and leukemia control in adults. Assays of minimal residual leukemia are possible but should not yet be used to direct therapy. There are several reasons why some persons are incurable including treatment resistance and a stem cell origin of leukemia. In most children and adults, chemotherapy is the best strategy followed by allogeneic transplants in those who relapse. Autotransplants are of minimal efficacy. Finally we consider new therapy approaches including immune therapy and regulation of leukemia-related genes.
PMID: 1578918 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 1992 Apr-Jun;9(2):91-7 Related Articles, Books, LinkOut
Relapse in acute lymphoblastic leukemia as a function of white blood cell and absolute neutrophil counts during maintenance chemotherapy.
Lucas K, Gula MJ, Blatt J.
Department of Pediatrics, Children's Hospital, Pittsburgh, Pennsylvania 15213.
Several reports document an inverse correlation between bioavailability of maintenance chemotherapeutic agents and the likelihood of relapse in childhood. White blood cell counts (WBC) and absolute neutrophil counts (ANC) are easily ascertainable parameters which might be expected to reflect plasma levels of chemotherapy. To determine whether WBC and ANC predict outcome of children with acute lymphoblastic leukemia (ALL), we did a multivariate analysis of means of these values during maintenance therapy in patients with ALL treated on a single protocol. Of the 52 patients, 15 (29%) relapsed. For those still disease-free, minimum time of follow-up is 7-8/12 years. During the first year of maintenance therapy, mean WBC (x 10(3)/mm3) in the relapsed and nonrelapsed groups were 4.5 +/- 0.9 and 3.9 +/- 0.7, respectively (p = 0.03); mean ANC (x 10(3)/mm3) were 3.0 +/- 0.9 and 2.5 +/- 0.6 (p = 0.05). However, the range of values was large with considerable overlap between the two groups. There was no obvious difference in distribution of values when confounding prognostic features were adjusted for in the analysis. No significant differences were seen between WBC or ANC during the second year of therapy. Larger numbers of patients will be needed to ascertain whether specific guidelines for dosage modifications can be made on the basis of serial WBC. Future pharmacokinetic studies should look at possible correlations with mean WBC and ANC.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 1524994 [PubMed - indexed for MEDLINE]
Pediatr Blood Cancer. 2004 Jun;42(7):563-73. Related Articles, Links
Long-term cause-specific mortality among five-year survivors of childhood cancer
Cardous-Ubbink MC, Heinen RC, Langeveld NE, Bakker PJ, Voute PA, Caron HN, van Leeuwen FE.
Long-Term Follow-Up Clinic, Department of Paediatric Oncology, Emma Kinderziekenhuis AMC, Academic Medical Center, Amsterdam, The Netherlands. M.C.Ubbink@amc.uva.nl
BACKGROUND: The purpose of our study was to assess long-term cause-specific mortality of 5-year childhood cancer survivors. PROCEDURE: The study population consisted of 1,378 patients who had been treated for childhood cancer in The Netherlands between 1966 and 1996 and survived at least 5 years; follow-up was complete for 99% of survivors. Cause-specific mortality was compared with general population rates to assess relative and absolute excess risks of death (standardized mortality ratio (SMR) and AER). RESULTS: After a median follow-up of 16.1 years, 120 patients had died. The overall SMR was 17-fold (95% CI: 14.3-20.6) increased compared to the general population. Our cohort experienced an excess of 7 deaths per 1,000 person-years. Patients who received combined modality treatment and were treated for at least one recurrence experienced the highest risk of death (SMR = 92.3; AER = 37.0 per 1,000 person-years). The SMR appeared to stabilize at an about 4 to 5-fold increased risk of death after 20 years of follow-up. Only after more than 20 years of follow-up excess mortality due to other causes than the primary cancer exceeded mortality from the primary childhood cancer (2.3 vs. 0.3/1,000 patients/year). The SMR for all causes other than primary cancer was 5.4 in 25-year survivors. The overall risks of death strongly decreased with increasing attained age, with an SMR of 1.6 (n.s.) and an AER of 0.3 per 1,000 person-years for survivors of 30 years or older. CONCLUSIONS: The first primary cancer contributes most to the absolute excess risk of death in 5-year survivors of childhood cancer, but after 25 years childhood cancer mortality is negligible. Relative risk of death due to other causes is still significantly increased after 25 years of follow-up. Copyright 2004 Wiley-Liss, inc.
PMID: 15127410 [PubMed - indexed for MEDLINE]
1: Ann Hematol. 2004;83 Suppl 1:S121-3.
Evolution of BFM trials for childhood ALL.
Schrappe M.
Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany.
Up to 80% of pediatric patients with acute lymphoblastic leukemia (ALL) can be cured if intensive therapy is applied. Severe side effects are encountered in all patients of which, however, only the minority is life-threatening. The leading cause of failure in childhood ALL is still recurrence of disease. To reduce the rate of relapses, but also to limit treatment morbidity, the ALL-BFM group has aimed to improve the risk-adaptation of therapy. The most important addition to clinical factors (e.g. age, WBC, extramedullary involvement), and biological characteristics (such as immunphenotype and cytogenetics), was the recognition of early in vivo treatment response as the strongest predictor for relapse. The determination of leukemic blasts in peripheral blood after exposure to 7 days of prednisone (PRED) and one dose of intrathecal methotrexate (prednisone response) as developed by BFM identified multidrug resistant patients: Such patients had still more than 1,000 blasts per microL at day 8 of therapy (defined as PRED poor responders, 10% of all patients). Prognosis for these was only approximately 35% as compared to approximately 80% in patients with adequate PRED response. Patient characteristics at relapse reveal that most of them were originally comprised in "good risk" patient subgroups: e.g., in trial ALL-BFM 90, 50% of the relapses were noted in patients with c-ALL even though that group had an EFS of 82% (SE 1%). 70% of the recurrences are found among patients with good response to PRED indicating the lack of specificity in the definition of that subgroup. Therefore, the more refined way of determining in vivo response based on the detection of minimal residual disease (MRD) at defined timepoints by identifying clone-specific T-cell receptor- (TCR) or immunglobuline (Ig) gene rearrangements appears to be able to define the patient at high risk to relapse more specifically. In the current ALL-BFM strategy, the high sensitivity of the method is utilized to apply treatment reduction in patients with fast clearance of leukemia. Persistent disease in contrast is an indication for treatment modification and intensification. Logistics and quality controls are demanding but essential for the introduction of this new technology into clinical practice.
PMID: 15124702 [PubMed - indexed for MEDLINE]
Blood Rev 1992 Dec;6(4):193-203 Related Articles, Books, LinkOut
Treatment of childhood acute lymphoblastic leukaemia: present issues and future prospects.
Chessells JM.
Leukaemia Research Fund Centre for Childhood Leukaemia, Institute of Child Health, London, UK.
Modern treatment for acute lymphoblastic leukaemia (ALL) achieves long term survival in two thirds of children, many of whom are truly cured. Recent improvements have occurred as a result of progressive intensification of treatment, particularly during the first 6 months from diagnosis. This article reviews the means of identifying children for whom standard therapy is not appropriate, and the aspects of standard therapy requiring further refinement, in particular central nervous system (CNS) directed treatment and continuing (maintenance) therapy, a concept unique to ALL. Modern methods for identification of minimal residual disease afford the hope that it may become possible to identify both children who have received sufficient treatment and, conversely, those at subsequent risk of relapse. Selection of patients for alternative therapy, for example marrow transplantation in first remission is difficult and this area needs further study. Treatment for the one third of children who relapse remains unsatisfactory and when successful is only achieved with significant morbidity. Most long-term survivors of childhood leukaemia are well and problem-free but a significant number have problems with learning, concentration, growth and development; the risk of second neoplasms remains unclear. Recent years have seen undeniable progress in the treatment of ALL but there is a continuing need to develop effective forms of treatment which have less potential for damaging late effects.
Publication Types: Review Review, Tutorial
PMID: 1486288 [PubMed - indexed for MEDLINE]
Chronobiol Int 1992 Dec;9(6):434-8 Related Articles, Books, LinkOut
Chronopharmacology of methotrexate pharmacokinetics in childhood leukemia.
Koren G, Ferrazzini G, Sohl H, Robieux I, Johnson D, Giesbrecht E.
Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, Ontario, Canada.
Survival has been shown to improve when maintenance therapy for acute lymphocytic leukemia in children is given at night rather during the day. We examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In a crossover study, we determined the pharmacokinetics of intravenous methotrexate at 10:00 and 21:00 h in six children with standard or high-risk leukemia. During the study, children refrained from concomitant drugs (6-mercaptopurine and trimethoprim sulfamethoxazole). There was a significant fall in methotrexate plasma clearance at night (from 5.6 +/- 3 ml/min/kg to 4.7 +/- 2.3 ml/min/kg p < 0.05). Renal clearance of methotrexate tended to decrease at night and unbound renal clearance decreased significantly (from 17.5 +/- 1.7 ml/min/kg to 8.5 +/- 3.6 ml/min/kg p < 0.05). Creatinine clearance did not exhibit diurnal variation, when comparing two 12-h collections, but there was a significant decrease in the nonglomerular clearance of methotrexate (from 14.8 +/- 5.2 to 6 +/- 4 ml/min/kg). Because it is a weak organic acid, the tubular secretion of methotrexate depends on urinary pH. At night urinary pH is more acidic. This may result in more reabsorption and hence reduced renal clearance.
PMID: 1473196 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1992 Sep;10(3):267-72 Related Articles, Books, LinkOut
Pneumocystis carinii pneumonitis following bone marrow transplantation.
Tuan IZ, Dennison D, Weisdorf DJ.
Department of Medicine, University of Minnesota, Minneapolis.
Pneumocystis carinii pneumonitis (PCP) can occur in immunocompromised hosts, especially AIDS and cancer patients. Although recent research has focused on PCP in AIDS patients, few studies have described the clinical presentation of PCP in recipients of bone marrow transplantation (BMT). Between 1976 and 1991, of 1454 BMT patients at the University of Minnesota, PCP was documented in only 19. Eighteen of these had not been receiving PCP prophylaxis. Patients presented with a brief period (2-10 days) of symptoms including dyspnea, cough, and fever in greater than 75% of patients, but had only scant abnormal physical findings. Chest X-rays showed bilateral infiltrates in 58% of all patients, though 15% had no or minimal X-ray findings. Bronchoscopic alveolar lavage confirmed the diagnosis most often, but 13% of lavages were negative and required biopsy for the diagnosis. High dose trimethoprim-sulfamethoxazole was the initial treatment for 84% of the patients though 25% of these patients were later switched to pentamidine due to poor response or hypersensitivity reactions. Despite prompt diagnosis and therapy, overall survival was poor, with only 37% of patients surviving pneumonitis. Patients developing PCP less than 6 months post-BMT had greater mortality (89%) versus only 40% in later onset PCP (p less than 0.0001). Despite this better survival in the late-onset PCP cohort, the development of pneumonitis in these patients underscores the necessity for continued PCP prophylaxis beyond 1 year in some patients. Ongoing immunocompromise and need for prophylaxis should be appreciated in patients with graft-versus-host disease.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 1422481 [PubMed - indexed for MEDLINE]
Haematologica 1992 Jan-Feb;77(1):49-53 Related Articles, Books, LinkOut
High-dose methotrexate administration and acute liver damage in children treated for acute lymphoblastic leukemia. A prospective study.
Locasciulli A, Mura R, Fraschini D, Gornati G, Scovena E, Gervasoni A, Uderzo C, Masera G.
Clinica Pediatrica, Universita di Milano, Ospedale S. Gerardo, Monza, Italy.
BACKGROUND. Methotrexate-induced hepatotoxicity following chronic low-dose administration has been extensively reported. Current protocols now include high-dose methotrexate (HDMTX), but there are few studies providing data on its acute hepatotoxicity in childhood leukemia. METHODS. To evaluate the prevalence of HDMTX-induced acute hepatotoxicity, sixty-eight consecutive children with ALL were prospectively studied from diagnosis to the end of HDMTX courses with biochemical and clinical evaluation performed at regular intervals. RESULTS. Prevalence of HDMTX-induced acute hepatotoxicity was 1.47% (1/68 patients). ALT values did not change in 22% (15/68) and decreased in 76.4% (52/68) after HDMTX infusion. Mean ALT levels calculated in all the patients decreased significantly during HDMTX administration when compared to the values reached during induction (p less than 0.0001). Direct hyperbilirubinemia was present only in the child with HDMTX-related hepatotoxicity. CONCLUSIONS. The use of HDMTX in the treatment of childhood ALL is not associated with major evidence of direct acute hepatotoxic effects, while it may modify the pattern of preexisting liver diseases.
PMID: 1398282 [PubMed - indexed for MEDLINE]
Leuk Res 1992;16(3):275-80 Related Articles, Links
On the biochemical modulation of 6-mercaptopurine by methotrexate in murine WEHI-3b leukemia cells in vitro.
Liliemark J, Pettersson B, Peterson C.
Department of Medicine, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.
The chemicals 6-mercaptopurine (6-MP) and methotrexate (MTX) are the cornerstones in the maintenance treatment of acute lymphoblastic leukemia. The intracellular metabolism of 6-MP to 6-thioguanosine nucleotides (TGN) via 6-thioinosine 5'-monophosphate (TIMP) is crucial for its cytotoxic effect. MTX inhibits purine de novo synthesis and thereby increases the intracellular PRPP being a substrate for the phosphoribosylation of 6-MP to TIMP. Hypoxanthine has been shown to inhibit the uptake of 6-MP over the cell membrane and the phosphoribosylation of 6-MP to TIMP. We have previously shown that the conversion of TIMP to TGN decreases at 6-MP concentrations above 5 microM in vitro. The aim of the present study was therefore to investigate the effect of MTX increasing the PRPP and TIMP concentrations and of hypoxanthine decreasing the TIMP concentration on the formation of TGN from TIMP. Murine myelomonocytic leukemia cells (WEHI-3b) were treated with 6-MP in vitro. The drug concentration was kept constant by continuous addition of 6-MP during the experiment. With this technique, the concentration of TGN begins to decrease already at 6-MP concentrations above 2 microM. The addition of 0.2 microM MTX 6 h before 6-MP strongly inhibited the purine de novo synthesis, decreased the ATP, and increased the PRPP concentration 4-fold. The intracellular concentrations of TIMP and to a lesser extent TXMP also increased. The concentrations of the TGN were, however, basically unaffected by the preincubation with MTX. Simultaneous addition of 20-50 microM hypoxanthine and 6-MP decreased the accumulation of all cellular 6-MP metabolites. It is concluded that the synergistic cytotoxic effect of the combination of 6-MP and MTX is not based on biochemical modulation of the 6-MP metabolism by MTX.
PMID: 1373210 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1992 Mar;9(3):213-5 Related Articles, Books, LinkOut
Dual infection with Pneumocystis carinii and respiratory viruses complicating bone marrow transplantation.
Lehner PJ, Rawal B, Hoyle C, Cohen J.
Department of Medicine, Hammersmith Hospital, Royal Postgraduate Medical School, London, UK.
Pneumonia due to dual infection with Pneumocystis carinii and respiratory viruses is a rare but formidable complication of bone marrow transplantation. We report here two cases of viral infections complicating P. carinii pneumonia in bone marrow transplant recipients who, at the time of infection, were not taking P. carinii prophylaxis. Both patients died following the pneumonia. Potential factors contributing to the dual infection included graft-versus-host disease, high-dose steroids and cyclosporin A. P. carinii prophylaxis should be continued for 12 months, or longer in bone marrow transplant recipients requiring prolonged immunosuppressive therapy. As specific antiviral therapy becomes available for some respiratory viral infections, performing regular viral surveillance cultures and responding with active early treatment may help improve the outcome in these immunocompromised patients.
PMID: 1324758 [PubMed - indexed for MEDLINE]
J Clin Oncol 2003 Apr 1;21(7):1332-9 Related Articles, Links
Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia.
Schmiegelow K, Bjork O, Glomstein A, Gustafsson G, Keiding N, Kristinsson J, Makipernaa A, Rosthoj S, Szumlanski C, Sorensen TM, Weinshilboum R.
Departments of Pediatrics and of Biostatistics, The University Hospital and The University of Copenhagen, Denmark.
Purpose: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). Patients and Methods: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). Results: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P =.002), and high average neutrophil counts during maintenance therapy (P =.0009), with a significant interaction between sex and randomization group (P =.0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P =.001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P <.0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P =.03; boys 19.3 v 18.0 U/mL, P =.04). Conclusion: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.
PMID: 12663723 [PubMed - in process]
Best Pract Res Clin Haematol 2002 Dec;15(4):729-40 Related Articles, Links
New treatment strategies in childhood acute lymphoblastic leukaemia.
Schrappe M, Beier R, Burger B.
Department of Paediatric Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
Today, 80% of paediatric patients with acute lymphoblastic leukaemia (ALL) can be cured. To reduce the rate of relapses, but also to limit treatment morbidity, risk-adapted treatment has been attempted after identifying the most specific prognostic factors. In addition to clinical factors (e.g. age, WBC), the immunophenotype and cytogenetic results, the early in vivo treatment response as determined by cytology had evolved as the most important predictor for relapse. The lack of specificity of most prognostic factors stimulated the search for more relevant parameters. Detection of minimal residual disease (MRD) at defined time points by identifying clone-specific T-cell receptor- (TCR) or immunoglobulin (Ig) gene rearrangements can provide new, highly specific prognostic information which allows definition of new risk groups. The high sensitivity of the method is a prerequisite for applying treatment reduction in patients with fast clearance of leukaemia. Persistent disease is an indication for treatment modification and intensification. Logistics and quality control are demanding but are essential for the introduction of this new technology into clinical practice.
PMID: 12617873 [PubMed - in process]
J Clin Oncol. 2003 Feb 15;21(4):704-9. Related Articles, Links
Importance of minimal residual disease testing during the second year of therapy for children with acute lymphoblastic leukemia.
Comment in: J Clin Oncol. 2003 Dec 1;21(23):4463-4; author reply 4464-5.
Marshall GM, Haber M, Kwan E, Zhu L, Ferrara D, Xue C, Brisco MJ, Sykes PJ, Morley A, Webster B, Dalla Pozza L, Waters K, Norris MD.
Children's Cancer Institute Australia for Medical Research, Sydney Children's Hospital Randwick, Randwick 2031, Sydney, Australia.
PURPOSE: A high level of minimal residual disease (MRD) after induction chemotherapy in children with acute lymphoblastic leukemia (ALL) is an indicator of relative chemotherapy resistance and a risk factor for relapse. However, the significance of MRD in the second year of therapy is unclear. Moreover, it is unknown whether treatment intervention can alter outcome in patients with detectable MRD. PATIENTS AND METHODS: We assessed the prognostic value of MRD testing in bone marrow samples from 85 children at 1, 12, and 24 months from diagnosis using clone-specific polymerase chain reaction primers designed to detect clonal antigen receptor gene rearrangements. These children were part of a multicenter, randomized clinical trial, which, in the second year of treatment, compared a 2-month reinduction-reintensification followed by maintenance chemotherapy with standard maintenance chemotherapy alone. RESULTS: MRD was detected in 69% of patients at 1 month, 25% at 12 months, and 28% at 24 months from diagnosis. By univariate analysis, high levels of MRD at 1 month, or the presence of any detectable MRD at 12 or 24 months from diagnosis, were highly predictive of relapse. Multivariate analysis showed that MRD testing at 1 and 24 months each had independent prognostic significance. Intensified therapy at 12 months from diagnosis did not improve prognosis in those patients who were MRD positive at 12 months from diagnosis. CONCLUSION: Clinical outcome in childhood ALL can be predicted with high accuracy by combining the results of MRD testing at 1 and 24 months from diagnosis.
PMID: 12586809 [PubMed - indexed for MEDLINE]
Leukemia 2003 Jan;17(1):138-48 Related Articles, Links
Flow cytometric follow-up of minimal residual disease in bone marrow gives prognostic information in children with acute lymphoblastic leukemia.
Bjorklund E, Mazur J, Soderhall S, Porwit-MacDonald A.
Department of Pathology, Karolinska Hospital and Institutet, Stockholm, Sweden.
Using flow cytometry (FC) and live gate (LG) analysis we have followed levels of minimal residual disease (MRD) in the bone marrow (BM) of 70 consecutive patients with childhood acute lymphoblastic leukemia (59 B precursor ALL and 11 T-ALL) treated according to the Nordic (NOPHO-92) protocols. Thorough studies of B and T cell antigen expression patterns in normal BM performed during BIOMED 1 Concerted Action on MRD, made it possible to tailor individual protocols of marker combinations for follow-up in 97% of patients. In 12% of LG analyses, the numbers of cells exceeded 10(6) and in 82% exceeded 10(5), giving the sensitivity level of MRD detection 10(-5) and 10(-4), respectively. The median follow-up time was 53 months. Patients with MRD levels >/=0.01% at follow-up time-points during and after first induction, and at the end of treatment had significantly lower disease-free survival by comparison to patients with MRD values <0.01%. Seven of nine patient with recurrence in the BM showed under treatment persisting MRD levels >/=0.01% of BM cells. This was also observed in another two patients with infant leukemia who relapsed. In conclusion, the investigation of levels and the dynamics of MRD by sensitive and quantitative FC can provide a basis for further clinical studies for at least upgrading of therapy.Leukemia (2003) 17, 138-148. doi:10.1038/sj.leu.2402736
PMID: 12529671 [PubMed - in process]
Curr Opin Oncol 2003 Jan;15(1):23-35 Related Articles, Links
Recent advances in pediatric acute lymphoblastic and myeloid leukemia.
Ravindranath Y.
Acute leukemia is the most common form of childhood cancer and is the primary cause of cancer-related mortality in children. In the United approximately 3250 cases are diagnosed annually in children and adolescents younger than 20 years, of whom 2400 have acute lymphoblastic leukemia (ALL). Treatment results in childhood ALL continue to improve, and the expected current cure rates approach 75 to 80% of all children with ALL, including T-ALL and mature B-cell ALL, the two variants that, not too long ago, had a considerably poorer prognosis compared with the common form of BpALL. The most significant new development in the past 2 years has been the development of further evidence for fetal origin of childhood leukemias, and additional evidence to support the notion that postnatal events modulating the events of immune-mediated elimination of these leukemic clones play a major role in the eventual development of clinical disease. Other epidemiologic developments include (1) increased appreciation of the role of drug-metabolizing enzymes, both in determining the predisposition to leukemia and response to therapy; and (2) both clinical observations and gene expression studies seeming to identify a new approach to the evaluation and treatment of children with MLL (11q23) rearrangements. A most remarkable new development in the induction therapy of childhood leukemia and lymphoma in the United States is the use of urate oxidase for prevention of tumor lysis syndrome and the associated uric acid nephropathy. Drug resistance, determined either on leukemic blast cells or by studies of MRD, is being looked at critically in an effort to improve the treatment results further. Consolidation with HDMTX has gained wider popularity with the realization that effective CNS prophylaxis can be achieved with intrathecal therapy plus HDMTX for consolidation. In contrast to ALL, the progress in the therapy of acute myeloid leukemia (AML) lags behind, with cure rates of approximately 40 to 50%. There is no convincing evidence for substitution of daunorubicin with other anthracyclines, nor evidence for using high-dose cytarabine during induction in childhood AML. Rather, a 3 + 10 regimen with total daunorubicin 180 mg/m and cytarabine 100 to 200 mg/ for 10 days appears to yield the best results. The most important component of the postremission chemotherapy continues to be several courses of high-dose cytarabine. The results from the MRC 10, LAME 89/91 studies and the recent BFM 93 trial with high-dose cytarabine and mitoxantrone suggest that there may be some benefit to including this combination in the postremission phase of AML. Despite these improvements in chemotherapy, allogeneic BMT from a matched family donor remains the best option for most patients (excluding Down syndrome, APL, and possibly those with inv16). Newer prognostic markers of interest include FLT3/ITD and minimal residual disease at the end of induction therapy.
PMID: 12490758 [PubMed - in process]
Blood 2002 Oct 1;100(7):2399-402 Related Articles, Links
Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia.
Coustan-Smith E, Sancho J, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, Pui CH, Campana D.
Departments of Hematology-Oncology, Biostatistics, and Pathology, St Jude Children's Research Hospital, and the University of Tennessee, Memphis.
In children with acute lymphoblastic leukemia (ALL), response to treatment is assessed by bone marrow aspiration. We investigated whether minimal residual disease (MRD) can be effectively monitored in peripheral blood. We used flow cytometric techniques capable of detecting 1 leukemic cell among 10 000 or more normal cells to compare MRD measurements in 718 pairs of bone marrow and peripheral blood samples collected from 226 children during treatment for newly diagnosed ALL. MRD was detected in marrow and blood in 72 pairs and in marrow but not in blood in 67 pairs; it was undetectable in the remaining 579 pairs. Remarkably, findings in marrow and blood were completely concordant in the 150 paired samples from patients with T-lineage ALL: for each of the 35 positive marrow samples, the corresponding blood sample was positive. In B-lineage ALL, however, only 37 of 104 positive marrow samples had a corresponding positive blood sample. Notably, peripheral blood MRD in these patients was associated with a very high risk for disease recurrence. The 4-year cumulative incidence of relapse in patients with B-lineage ALL was 80.0% +/- 24.9% for those who had peripheral blood MRD at the end of remission induction therapy but only 13.3% +/- 9.1% for those with MRD confined to the marrow (P =.007). These results indicate that peripheral blood may be used to monitor MRD in patients with T-lineage ALL and that peripheral blood MRD may provide strong prognostic information in patients with B-lineage ALL. (Blood. 2002;100:2399-2402)
PMID: 12239148 [PubMed - in process]
Blood 2002 Sep 15;100(6):1957-64 Related Articles, Links
Racial and ethnic differences in survival of children with acute lymphoblastic leukemia.
Bhatia S, Sather HN, Heerema NA, Trigg ME, Gaynon PS, Robison LL.
Children's Oncology Group, City of Hope National Medical Center, PO Box 60012, Arcadia, CA 91006-6012, USA. sbhatia@coh.org
Black children with acute lymphoblastic leukemia (ALL) have poor outcomes, but limited information is available for children from other racial and ethnic backgrounds, such as Hispanic and Asian. We undertook a retrospective cohort study of children with ALL treated on Children's Cancer Group therapeutic protocols to determine outcomes by racial and ethnic backgrounds of patients treated with contemporary risk-based therapy. In total, 8447 children (white, n = 6703; Hispanic, n = 1071; black, n = 506; and Asian, n = 167) with newly diagnosed ALL between 1983 and 1995 were observed for a median of 6.5 years. Analysis of disease outcome was measured as overall survival (OS) and event-free survival (EFS) and was adjusted for known predictors of outcome including clinical features, disease biology, socioeconomic status, and treatment era (1983-1989 vs 1989-1995). There was a statistically significant difference in survival by ethnicity (P <.001). Five-year EFS rates were: Asian, 75.1% +/- 3.5%; white, 72.8% +/- 0.6%; Hispanic, 65.9% +/- 1.5%; and black, 61.5% +/- 2.2%. Multivariate analysis revealed that when compared with white children, black and Hispanic children had worse outcomes and Asian children had better outcomes after adjusting for known risk factors. The poorer outcomes among black children were most apparent among patients with standard-risk features (relative risk [RR], 2.0; 95% confidence interval [CI], 1.6-2.5), whereas poorer outcomes in Hispanic children (RR, 1.4; 95% CI, 1.2-1.6) were most evident among patients with high-risk features. Asian children had better outcomes than all racial and ethnic groups among high-risk patients, particularly in the recent era (5-year EFS, 90.9% +/- 6.1%). Racial and ethnic differences in OS and EFS persist among children with ALL who receive contemporary risk-based therapy. Future studies should focus on reasons-perhaps compliance or pharmacogenetics-for those differences.
PMID: 12200352 [PubMed - indexed for MEDLINE]
Blood 2002 Jul 1;100(1):52-8 Related Articles, Links
Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia.
Coustan-Smith E, Sancho J, Behm FG, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, Pui CH, Campana D.
Department of Hematology-Oncology, St Jude Children's Research Hospital and the University of Tennessee, Memphis, TN 38105, USA.
Early clearance of leukemic cells is a favorable prognostic indicator in childhood acute lymphoblastic leukemia (ALL). However, identification of residual leukemic cells by their morphologic features is subjective and lacks sensitivity. To improve estimates of leukemia clearance, we applied flow cytometric techniques capable of detecting 1 leukemic cell in 10,000 or more normal cells and prospectively measured residual leukemia in bone marrow samples collected on day 19 of remission-induction chemotherapy from 248 children with newly diagnosed ALL. In 134 samples (54.0%), we identified at least 0.01% leukemic cells (0.01%-< 0.1% in 51 samples [20.6%], 0.1%-< 1% in 36 [14.5%], and > or = 1% in 47 [19.0%]). Among 110 children treated within a single chemotherapy program, the 5-year mean +/- SE cumulative incidence of relapse or failure to achieve remission was 32.2% +/- 6.5% for the 59 patients with 0.01% residual leukemic cells or greater on day 19 and 6.0% +/- 3.4% for the 51 patients with less than 0.01% leukemic cells (P <.001). The prognostic value of day-19 bone marrow status defined by flow cytometry was superior to that defined by morphologic studies and remained significant after adjustment for other clinical and biologic variables. Lack of detectable leukemic cells on day 19 was more closely associated with relapse-free survival than was lack of detectable residual disease at the end of remission induction (day 46). Thus, approximately half of the children with ALL achieve profound clearance of leukemic cells after 2 to 3 weeks of remission-induction chemotherapy, and these patients have an excellent treatment outcome.
PMID: 12070008 [PubMed - indexed for MEDLINE]
Wien Klin Wochenschr 2002 Feb 28;114(4):148-57 Related Articles, Links
Treatment results of childhood acute lymphoblastic leukemia in Austria--a report of 20 years' experience.
Comment in: Wien Klin Wochenschr. 2002 Feb 28;114(4):141-2.
Attarbaschi A, Mann G, Dworzak M, Urban C, Fink FM, Dieckmann K, Riehm H, Gadner H; Austrian Cooperative Study Group.
St. Anna Children's Hospital, Vienna.
Between 1981 and 1999, 890 Austrian children with acute lymphoblastic leukemia (ALL) were treated in 5 consecutive trials using protocols from the Berlin-Frankfurt-Munster (BFM) Group. In the trials BFM-A (Austria) 81 and ALL A 84, treatment stratification was performed using a risk factor, which was calculated from the initial peripheral blast cell count, and size of liver and spleen. In the following studies (BFM-A 86, 90 and 95) early response to a 7-day systemic mono-therapy with prednisone (as measured by the peripheral blast cell count) was used as an overriding stratification factor; in order to reduce the need for cranial radiotherapy, all patients received high-dose methotrexate (5 g/m2) for preventive central nervous system treatment. Event-free survival (EFS) rates increased from study BFM-A 81 (n = 141, probability (p) of EFS: 59% +/- 4%) and study ALL A 84 (n = 127, pEFS: 67% +/- 4%) to 77% +/- 4% in trial BFM-A 86 (n = 142), 79% +/- 3% in trial BFM-A 90 (n = 256), and 84% +/- 3% in trial BFM-A 95 (n = 224). However, the prognosis for high-risk patients has not significantly improved within the last 20 years (pEFS: 50%). Furthermore, conventional risk factors such as leukocyte count and age at time of diagnosis, could not be used to indicate patients in the low and intermediate risk group who might eventually relapse. Thus, in trial BFM-A 2000, detection of minimal residual disease by polymerase chain reaction-based methods after 5 and 12 weeks of therapy was introduced for treatment stratification. Minimal residual disease was prospectively shown to predict relapses more precisely and, as a matter of fact, may allow a more exact definition of which patients are at risk and which patients belong to the subgroup with a good prognosis despite reduced treatment.
PMID: 12060981 [PubMed - indexed for MEDLINE]
Br J Haematol 2002 Jun;117(4):821-7 Related Articles, Books, LinkOut
Evidence that continued remission in patients treated for acute leukaemia is dependent upon autologous natural killer cells.
Lowdell MW, Craston R, Samuel D, Wood ME, O'Neill E, Saha V, Prentice HG.
Department of Haematology, Royal Free Campus, Royal Free and University College Medical School, London NW3 2PF, UK. m.lowdell@rfc.ucl.ac.uk
Although it has been known for more than 40 years that allogeneic immune responses cure leukaemias after bone marrow transplantation, autologous leukaemia-specific immunity remains controversial and its impact upon survival has not been established. Here we have tested 25 patients with de novo acute leukaemias, while in remission at completion of their anti-leukaemia therapy, for evidence of autologous cytolytic immunity to their leukaemic cells taken and cryopreserved at disease presentation. We have measured this degree of cell-mediated cytotoxicity in vitro and termed it "leukaemia cytolytic activity" (LCA). Patients whose disease ultimately relapsed had significantly lower LCA than those who remained in remission beyond 2 years (P < 0.001); the absence of LCA when in remission predicted subsequent relapse within 2 years with a sensitivity of 100% and specificity of 77%. LCA was mediated in vitro by CD56+/CD8alpha+/CD3- natural killer cells. We propose that it is this immune response, rather than the chemotherapy per se, which is responsible for continued remission and that measurement of LCA in patients at completion of therapy may be used as an indicator of risk of subsequent relapse. Patients lacking this response will require further treatment, either with an allogeneic donor transplant or an alternative immunotherapeutic strategy.
PMID: 12060116 [PubMed - in process]
Blood 2002 Apr 15;99(8):2734-9 Related Articles, Books, LinkOut
Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial.
Duval M, Suciu S, Ferster A, Rialland X, Nelken B, Lutz P, Benoit Y, Robert A, Manel AM, Vilmer E, Otten J, Philippe N.
Service d'Hemato-Immunologie, Hopital Robert-Debre, Paris, France. michel.duval@umontreal.ca
Asparaginase is an enzyme used in the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in children. It has minimal bone marrow toxicity. Its major side effects are anaphylaxis, pancreatitis, diabetes, coagulation abnormalities, and thrombosis, especially intracranial. It is derived from 2 different sources: Escherichia coli and Erwinia chrysanthemi. Nonrandomized clinical studies have suggested a similar efficacy of these 2 types of asparaginases and a lower toxicity for Erwinia-asparaginase. The European Organisation for Research and Treatment of Cancer-Children's Leukemia Group (EORTC-CLG) 58881 trial randomized 700 children with acute lymphoblastic leukemia or lymphoblastic lymphoma to either E coli- or Erwinia-asparaginase at the same dosage of 10 000 IU/m(2) twice weekly to compare toxicity and efficacy. Coagulation abnormalities were more frequent in the E coli-asparaginase than in the Erwinia-asparaginase arm of the study (30.2% versus 11.9%, P <.0001). The incidence of other toxicity was not significantly different. In the Erwinia-asparaginase arm, more patients failed to achieve complete remission (4.9% versus 2.0%; P =.038) and the relapse rate was higher, leading to shorter event-free survival (hazard ratio,1.59; 95% CI, 1.23-2.06; P =.0004). The estimate of event-free survival rate (SE) at 6 years was 59.8% (2.6%) versus 73.4% (2.4%). Overall survival rate at 6 years was also lower in the Erwinia-asparaginase arm at 75.1% (2.3%) versus 83.9% (2.0%), P =.002. With the dose scheduling used in this protocol, E coli-asparaginase induced more coagulation abnormalities but was superior to Erwinia-asparaginase for the treatment of childhood lymphoid malignancies.
Publication Types: Clinical Trial Clinical Trial, Phase III Randomized Controlled Trial
PMID: 11929760 [PubMed - indexed for MEDLINE]
Cancer Treat Rev 2001 Dec;27(6):351-63 Related Articles, Books, LinkOut
Continuing therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of methotrexate, 6-mercaptopurine and 6-thioguanine.
Estlin EJ.
Department of Paediatric Oncology, Royal Manchester Children's Hospital, Pendlebury, Manchester M27 4HA, UK. eestlin@mch.srht.nwest.nhs.uk
Across the world, therapy with 6-mercaptopurine (6-MP) and methotrexate (MTX) forms the basis of the continuing therapy of childhood acute lymphoblastic leukaemia (ALL). In this review, the pharmacological determinants of the sensitivity of human leukaemia cell lines and lymphoblasts derived from children with ALL will be discussed. In addition, clinical pharmacological studies of 6-MP and MTX in relation to the continuing therapy with childhood ALL will be reviewed. For 6-MP in vitro, prolonged exposure times to relatively high extracellular drug concentrations are necessary for cytotoxicity, and these concentrations are much higher than those achieved during continuing therapy for childhood ALL. For MTX, plasma concentrations are achieved during continuing therapy that would be cytotoxic to human leukaemia cells during prolonged exposures in vitro. For both MTX and 6-MP, wide inter- and intrapatient variation in plasma pharmacokinetic parameters has been described. For 6-MP and MTX, cellular pharmacological studies have been largely restricted to erythrocytes as a surrogate of the possible effects in leukaemic blasts. Although measures of the pharmacology of 6-MP and MTX in erythrocytes has been related to prognosis in many studies, 6-MP systemic exposure and the dose intensity of 6-MP and MTX actually received by children during this phase of therapy seems to be the most important determinant of efficacy. Further studies will be needed to determine the importance of pharmacokinetic variability during continuing therapy as a determinant of outcome for children with ALL. In this respect, minimal residual disease status during this phase of treatment may prove to be a useful pharmacodynamic endpoint. Copyright 2002, Elsevier Science Ltd. All rights reserved.
Publication Types: Review Review, Tutorial
PMID: 11908928 [PubMed - indexed for MEDLINE]
Blood 2002 Mar 15;99(6):1952-8 Related Articles, Books, LinkOut
Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia.
Dworzak MN, Froschl G, Printz D, Mann G, Potschger U, Muhlegger N, Fritsch G, Gadner H; Austrian Berlin-Frankfurt-Munster Study Group.
Children's Cancer Research Institute, St Anna Kinderspital, Kinderspitalgasse 6, A-1090 Vienna, Austria. dworzak@ccri.univie.ac.at
Detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) predicts outcome. Previous studies were invariably based on relative quantification and did not investigate sample-inherent parameters that influence test accuracy, which makes comparisons and clinical conclusions cumbersome. Hence, we conducted a prospective, population-based MRD study in 108 sequentially recruited children with ALL uniformly treated with the ALL-Berlin-Frankfurt-Munster (ALL-BFM) 95 protocol in Austria (median follow-up of 40 months). Using sensitive, limited antibody panel flow cytometry applicable to 97% of patients, we investigated 329 bone marrow samples from 4 treatment time points. MRD was quantified by blast percentages among nucleated cells (NCs) and by absolute counts (per microliter). Covariables such as NC count, normal B cells, and an estimate of the test sensitivity were also recorded. Presence and distinct levels of MRD correlated with a high probability of early relapse at each of the time points studied. Sequential monitoring at day 33 and week 12 was most useful for predicting outcome independently from clinical risk groups: patients with persistent disease (> or =1 blast/microL) had a 100% probability of relapse, compared to 6% in all others. Absolute MRD quantification was more appropriate than relative, due to considerable variations in total NC counts between samples. Regeneration of normal immature B cells after periods of rest from treatment limited the test sensitivity. In conclusion, MRD detection by flow cytometry is a strong and independent outcome indicator in childhood ALL. Standardization regarding absolute quantification on the basis of NCs and assessment during periods of continuous treatment promise to increase the accuracy, simplicity, and cost efficiency of the approach.
PMID: 11877265 [PubMed - in process]
Zhonghua Xue Ye Xue Za Zhi 2000 Jan;21(1):27-9 Related Articles, Links
[Detection of minimal residual disease in childhood hematological malignancies and its clinical significance]
[Article in Chinese]
Tang S, Lu S, Zhang X, et Al.
No. 301 Hospital, Beijing 100853, China.
OBJECTIVE: Expoloring the detection of minimal residual malignant cells in bone marrow from children with hematological malignancies to predict the prognosis. METHODS: Seventy-five patients with acute lymphoblastic leukemia (ALL), stage IV non-Hodgkin's lymphoma or stage IV neuroblastoma were studied. Complete remission was maintained for over 3 months before the detection. Minimal residual disease was detected by polymerase chain reaction (PCR) for IgH and TcRgamma rearrangements in lymphoid tumors by reverse transcriptase-polymerase chain reaction (RT-PCR) for neuroblastoma patients. RESULTS: Thirty five patients were positive for minimal residual disease, and 21 of them (60%) relapsed 3 similar 40 months later, while only 7 (17%) negative patients relapsed (chi(2) = 12.59, P < 0.01). CONCLUSION: Minimal residual disease detection in bone marrow by PCR might predict prognosis in some childhood hematological malignancies.
PMID: 11876957 [PubMed - in process]
J Clin Oncol 2002 Feb 15;20(4):1094-104 Related Articles, Books, LinkOut
Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia.
Mortuza FY, Papaioannou M, Moreira IM, Coyle LA, Gameiro P, Gandini D, Prentice HG, Goldstone A, Hoffbrand AV, Foroni L.
Department of Hematology, Royal Free and University College School of Medicine, London, United Kingdom.
PURPOSE: Investigation of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) using molecular markers has proven superior to other standard criteria (age, sex, and WBC) in distinguishing patients at high, intermediate, and low risk of relapse. The aim of our study was to determine whether MRD investigation is valuable in predicting outcome in Philadelphia-negative adult patients with ALL. PATIENTS AND METHODS: MRD was assessed in 85 adult patients with B-lineage ALL by semiquantitative immunoglobulin H gene analysis on bone marrow samples collected during four time bands in the first 24 months of treatment. Fifty patients received chemotherapy only and 35 patients received allogeneic (n = 19) or autologous (n = 16) bone marrow transplantation (BMT) in first clinical remission. The relationship between MRD status and clinical outcome was investigated and compared with age, sex, immunophenotype, and presenting WBC count. RESULTS: Fisher's exact test established a statistically significant concordance between MRD results and clinical outcome at all times. Disease-free survival (DFS) rates for MRD-positive and -negative patients and log-rank testing established that MRD positivity was associated with increased relapse rates at all times (P <.05) but was most significant at 3 to 5 months after induction and beyond. MRD status after allogeneic BMT rather than before was found to be an important predictor of outcome in 19 adult patients with ALL tested. In patients receiving autologous BMT (n = 16), the MRD status before BMT was more significant (P =.005). CONCLUSION: The association of MRD test results and DFS was independent of and greater than other standard predictors of outcome and is therefore important in determining treatment for individual patients.
PMID: 11844835 [PubMed - indexed for MEDLINE]
Br J Haematol 2002 Feb;116(2):266-72 Related Articles, Books, LinkOut
ETV6 (TEL)-AML1 pre-B acute lymphoblastic leukaemia cells are associated with a distinct antigen-presenting phenotype.
Alessandri AJ, Reid GS, Bader SA, Massing BG, Sorensen PH, Schultz KR.
Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, University of British Columbia and British Columbia's Children's Hospital, Vancouver, BC, Canada.
The recently recognized translocation t(12;21)(p13;q22), which results in the ETV6-AML1 fusion product, is the most common genetic rearrangement found in childhood pre-B acute lymphoblastic leukaemia (ALL). It has been associated with a more favourable prognosis and a distinct immunophenotype in terms of myeloid and B cell-associated antigen expression. Using flow cytometry, we investigated whether the unique ETV6-AML1 phenotype extended to molecules associated with antigen presentation by analysing 50 diagnostic bone marrow samples from paediatric pre-B ALL patients. Reverse transcription polymerase chain reaction for the ETV6-AML1 fusion transcript was positive in 14 patients. ETV6-AML1-positive samples were characterized by a significantly higher expression of the co-stimulatory molecule CD40 (P < 0.0001), as well as a significantly higher class II HLA-DR mean channel fluorescence (P = 0.001). In contrast, CD86 expression was significantly lower on fusion-positive samples (P = 0.010) while there was no difference in expression of CD80 or major histocompatibility complex class I between ETV6-AML1-positive and -negative samples. This is the first observation in acute leukaemia that the distinct immunophenotype associated with specific translocations includes the expression of molecules associated with antigen presentation. In the case of ETV6-AML1 pre-B ALL, this characteristic immunophenotype may have implications for the immunogenicity of the leukaemic cells.
PMID: 11841426 [PubMed - indexed for MEDLINE]
Leukemia 2002 Feb;16(2):209-12 Related Articles, Links
Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine.
Dervieux T, Hancock M, Evans W, Pui CH, Relling MV.
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (40 mg/m(2)) dose combined with daily mercaptopurine (75 mg/m(2)). A total of 141 erythrocyte TGN concentrations were measured with erythrocyte methotrexate polyglutamates (MTX-PG) concentrations in 87 patients. Average TGN concentrations ranged from 137 to 958 pmol/8 x 10(8) cells (median 389), average total MTX-PG concentrations (MTX- PG(1-7)) from 0.60 to 97.7 pmol/10(9)cells (median 29), and average long chain polyglutamate concentrations (MTX-PG(5-7)) from 0 to 8.35 pmol/10(9) cells (median 2.43). Higher TGN concentrations correlated with higher MTX-PG(5-7) concentrations (P = 0.002). These data support the practice of administering methotrexate with mercaptopurine during continuation therapy of acute lymphoblastic leukemia.
PMID: 11840287 [PubMed - indexed for MEDLINE]
Ugeskr Laeger 2002 Jan 21;164(4):488-92 Related Articles, Books, LinkOut
[Trimethoprim-sulfamethoxazole as antibacterial prophylaxis during induction therapy of children with acute lymphatic leukemia]
[Article in Danish]
Agger KE, Schroder H, Rosthoj S, Carlsen NT, Schmiegelow K.
Arhus Universitetshospital, Skejby Sygehus, borneonkologisk afdeling, DK-8200 Arhus N.
INTRODUCTION: Children with acute lymphoblastic leukaemia (ALL) are treated with intensive chemotherapy, which results in profound immunosuppression. Treatment with trimethoprim/sulphamethoxazole (TMP-SMX) is therefore used in some departments as prophylaxis against infections with both bacteria and Pneumocystis carinii. The use of TMP/SMX for prophylaxis during the induction therapy is not uniform in the four departments of paediatric oncology in Denmark. This gave us the opportunity to describe the effect of TMP/SMX on bacterial infections in children with ALL during the induction therapy. MATERIAL AND METHODS: Between 1 January 1992 and 31 December 1997, 210 children were diagnosed with ALL in Denmark. From a retrospective review of the medical charts, the number of children with fever (> 38 degrees C), the number of febrile days, days of antibiotic treatment, and the number of positive blood cultures were registered for each febrile episode. RESULTS: One hundred and fourteen children received TMP/SMX prophylaxis (10-30 mg/SMX/kg/day) and 76 did not. Children who received TMP/SMX prophylaxis had significantly fewer episodes of fever (66/114 (58%) vs. 60/76 (79%), p < 0.01) and significantly fewer children who received the prophylaxis had positive blood cultures before the start of antibiotic treatment compared with children who did not receive prophylaxis (23/114 (20%) vs 37/76 (49%), p < 0.001)). Nineteen different species were isolated from the blood stream before the start of antibiotic treatment. In the non-prophylaxis group there were a preponderance of isolates with Staph. aureus, Str. pneumoniae, E. coli, and P. aeruginosa. There was no difference in the mortality between the two groups (p = 0.44). There were no cases of P. carinii pneumonia in the period of induction therapy. DISCUSSION: TMP/SMX prophylaxis during induction therapy for childhood ALL seems to reduce the risk of bacteraemias and febrile illness.
PMID: 11838420 [PubMed - indexed for MEDLINE]
Pediatr Int 2001 Dec;43(6):673-7 Related Articles, Books, LinkOut
Comparative pharmacokinetics of oral 6-mercaptopurine and intravenous 6-mercaptopurine riboside in children.
Mawatari H, Unei K, Nishimura S, Sakura N, Ueda K.
Department of Pediatrics, Hiroshima University School of Medicine, Kasumi 1-2-3, Minami-ku, Hiroshima, 734-8551, Japan. mawatari@triton.ocn.ne.jp
BACKGROUND: The poor absorption of orally administered 6-mercaptopurine (6MP) causes a wide variation in its cytotoxic efficacy. An i.v. dosage form would eliminate this problem. Our objective was to compare the pharmacokinetics of 6MP administered orally with those of an i.v. dosage form 6-mercaptopurine riboside (6MPR), in children with acute lymphoblastic leukemia or malignant lymphoma. METHODS: A total of 10 children were treated with oral 6MP, 50 mg/m(2) per day, while five children were treated with 6MPR, 50 mg/m(2) per day, administered by rapid i.v. injection. The plasma concentrations of 6MP and of 6MPR were measured on day 0, while the concentrations of 6-thioguanine nucleotides (6TGN) in red blood cells (RBC) were measured on day 2. The area under the plasma concentration-time curve (AUC1-5) was calculated from 1 to 5 h after drug administration. RESULTS: With the intravenously administered 6MPR, the AUC1-5 ranged from 124 to 186 (1.5-fold range, median 145) microM min; only two samples were obtained for the RBC concentration of 6TGN, and were 121 and 273 pmol per 25 mg hemoglobin. With the orally administered 6MP, the AUC1-5 ranged from 23 to 65 microM min (2.8-fold range, median 56); the RBC concentration of 6TGN ranged from 18 to 152 pmol per 25 mg hemoglobin (median 75). CONCLUSION: The i.v. administration of 6MPR showed less interindividual variation in the AUC1-5 coupled with a higher RBC level of 6TGN as compared with those by oral 6MP. We conclude that the i.v. administration of 6MPR achieves stable blood levels of active drug in children undergoing cancer chemotherapy.
PMID: 11737747 [PubMed - indexed for MEDLINE]
Haematologica 2001 Dec;86(12):1245-53 Related Articles, Books, LinkOut
Fluorescence in situ hybridization study of TEL/AML1 fusion and other abnormalities involving TEL and AML1 genes. Correlation with cytogenetic findings and prognostic value in children with acute lymphocytic leukemia.
Martinez-Ramirez A, Urioste M, Contra T, Cantalejo A, Tavares A, Portero JA, Lopez-Ibor B, Bernacer M, Soto C, Cigudosa JC, Benitez J.
Dpto. de Genetica Humana, Programa de Patologia Molecular, Centro Nacional de Investigaciones Oncologicas (CNIO), Ctra. Majadahonda-Pozuelo, Km. 2, 28220 Majadahonda, Madrid, Spain. angmartinez@cnio.es
BACKGROUND AND OBJECTIVES. The TEL/AML1 fusion is the most common genetic abnormality found in childhood acute lymphoblastic leukemias (ALL). Although it is very difficult to identify by conventional cytogenetic techniques it can be readily detected using fluorescence in situ hybridization (FISH). We carried out cytogenetic and FISH studies on 42 children with ALL in order to know the frequency of this translocation in our population, the incidence of TEL and/or AML1 gene alterations, and their correlation with clinical evolution and prognosis. In addition, we performed reverse transcription polymerase chain reaction (RT-PCR) in some cases, confirming the feasibility of FISH techniques in the detection of this translocation. DESIGN AND METHODS. Bone marrow samples were obtained from 42 childhood ALL patients. The copy number of AML1 and TEL genes were studied using fluorescent in situ hybridization with a dual color DNA probe specific for the AML1 and TEL genes. RESULTS. We found a frequency of TEL/AML1 fusion of 17% in our sample. Double TEL/AML1 fusion, lack of TEL signal and extra AML1 signals were frequent additional FISH abnormalities. Duplication of a chromosomal complement, deletion of chromosome 12p arm, and polysomies of chromosome 21 are plausible explanations for these additional FISH findings. However, a relatively high proportion of our cases (9.5%) presented specific amplification of AML1. A statistically significant difference in prognosis was found between patients with and without these additional AML1 or TEL FISH alterations (p<0.02), which could be related to the presence of specific karyotypes. INTERPRETATIONS AND CONCLUSIONS. The frequency of TEL/AML1 fusion is similar to that found in other populations (17%). We found that FISH analysis of AML and TEL is related to the evolution of the disease. The absence of alterations in these genes revealed by FISH could be indicative of bad prognosis, while the presence of alterations is related to a good evolution. Our results suggest that interphase FISH analysis to search for alterations in AML and TEL genes could be extremely useful for complementing cytogenetic studies and for providing additional information about the possible outcome of the disease in patients with ALL.
PMID: 11726315 [PubMed - in process]
Br J Haematol 2001 Oct;115(1):34-45 Related Articles, Links
Early response to chemotherapy as a prognostic factor in childhood acute lymphoblastic leukaemia: a methodological review.
Donadieu J, Hill C.
Service de Biostatistique et d'epidemiologie, Institut Gustave Roussy, Villejuif, France. jean.donadieu@trs.ap-hop-paris.fr
Published studies of the prognostic value of the early response to induction treatment in childhood acute lymphoblastic leukaemia (ALL) were analysed. Three criteria were used to judge the early treatment response: persistence of peripheral blasts (PPB) or of bone marrow blasts (PBMB) during induction therapy and minimal residual disease (MRD) after completion of induction therapy. Studies with more than 50 patients, published between 1980 and 2000, were reviewed. Among 13 659 distinct articles published on ALL, we identified only 43 applicable studies. Within- and between-laboratory variations were evaluated in only one study. Treatment modalities differed among, and sometimes within, studies. The cut-off points used in the statistical analyses were never discussed, and in many studies appeared to be selected after multiple tests. The proportion of missing data was > 30% in almost all studies of MRD, as a result of technical difficulties and not missing samples. PPB and PBMB were associated with shorter survival in, respectively, 13 out of 14 and 15 out of 16 studies. Detection of MRD was associated with poor outcome in 12 of the 13 studies. Because none of the parameters used to measure the early response to induction therapy for childhood ALL have been properly assessed as prognostic factors, we conclude that they should be considered only as candidate prognostic indicators pending more thorough studies.
Publication Types: Meta-Analysis
PMID: 11722407 [PubMed - indexed for MEDLINE]
Cas Lek Cesk 2001 Aug 30;140(17):519-24 Related Articles, Books
[Fluorescent in situ hybridization (FISH) in the diagnosis of acute childhood lymphatic leukemia (ALL)]
[Article in Czech]
Zemanova Z, Michalova K, Brezinova J, Sindelarova L, Kurkova S, Smisek P, Zuna J, Trka J, Stary J.
III. interni klinika 1. LF UK a VFN, Praha. zuze@vfn.cz
Classical cytogenetic analysis plays an important role in the diagnosis, classification, therapy monitoring and prognosis of patients with leukemia. Many recurrent cytogenetic abnormalities with major prognostic values have been described in childhood ALL. Hyperdiploidy and/or t(12;21) are associated with good prognosis, whereas t(9;22) and/or rearrangements of MLL gene correlate with poor outcome and therefore early detection of these abnormalities is very important. FISH can overcome some limitations of conventional cytogenetic and molecular-genetic analyses and due to high sensitivity specific chromosomal aberrations in mitoses and/or interphase nuclei can be detected. In the Center of Oncocytogenetics of the 3rd Medical Department for assessment of hyperdiploidy and structural rearrangements we use double-color FISH with centromeric and/or locus-specific probes and complex aberrations are ascertained by whole chromosome painting probes and multicolor FISH. Among 275 children with ALL examined during the last 8 years by different FISH methods we found seven patients with translocation t(9;22) and 14 patients with MLL rearrangements in bone marrow cells. Since 1988 we focus on detection of hyperdiploidy and/or t(12;21). High hyperdiploidy was found in 35 children, 10 of them had further complex rearrangements. Translocation t(12;21) was proved in 37 patients and complex rearrangements were found in 22 of them. FISH, cytogenetic and molecular-genetic analyses become obligatory for the first diagnostic examination as well as for monitoring of treatment effect in children with ALL.
Publication Types: Review Review, Tutorial
PMID: 11702476 [PubMed - indexed for MEDLINE]
Leukemia 2001 Nov;15(11):1706-12 Related Articles, Books, LinkOut
Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine.
Dervieux T, Medard Y, Verpillat P, Guigonis V, Duval M, Lescoeur B, Suciu S, Vilmer E, Jacqz-Aigrain E.
Service de Pharmacologie Pediatrique et Pharmacogenetique, Hjpital Robert Debre, Paris, France.
6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P= 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P< 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides.
Publication Types: Clinical Trial
PMID: 11681411 [PubMed - indexed for MEDLINE]
Best Pract Res Clin Haematol 2001 Sep;14(3):593-607 Related Articles, Books, LinkOut
Acute lymphoblastic leukaemia.
Harrison CJ.
Leukaemia Research Fund/UK Cancer Cytogenetics Group Karyotype Database in Acute Lymphoblastic Leukaemia, Department of Haematology, Royal Free and University College School of Medicine, Rowland Hill Street, London, NW3 2PF, UK.
In acute lymphoblastic leukaemia (ALL) the karyotype provides important prognostic information which is beginning to have an impact on treatment. The most significant structural chromosomal changes include: the poor-risk abnormalities; t(9;22)(q34;q11), giving rise to the BCR/ABL fusion and rearrangements of the MLL gene; abnormalities previously designated as poor-risk; t(1;19)(q23;p13), producing the E2A/PBX1 and rearrangements of MYC with the immunoglobulin genes; and the probable good risk translocation t(12;21)(p13;q22), which results in the ETV6/AML1 fusion. These abnormalities occur most frequently in B-lineage leukaemias, while rearrangements of the T cell receptor genes are associated with T-lineage ALL. Abnormalities of the short arm of chromosome 9, in particular homozygous deletions involving the tumour suppressor gene (TSG) p16(INK4A), are associated with a poor outcome. Numerical chromosomal abnormalities are of particular importance in relation to prognosis. High hyperdiploidy (51-65 chromosomes) is associated with a good risk, whereas the outlook for patients with near haploidy (23-29 chromosomes) is extremely poor. In view of the introduction of risk-adjusted therapy into the UK childhood ALL treatment trials, an interphase FISH screening programme has been developed to reveal chromosomal abnormalities with prognostic significance in childhood ALL. Novel techniques in molecular cytogenetics are identifying new, cryptic abnormalities in small groups of patients which may lead to further improvements in future treatment protocols. Copyright 2001 Harcourt Publishers Ltd.
Publication Types: Review Review, Tutorial
PMID: 11640871 [PubMed - indexed for MEDLINE]
Chin Med J (Engl) 1999 Jul;112(7):615-9 Related Articles, Books, LinkOut
Very long survival in pediatric cancer between 1944 and 1993.
Zhao G, Boysen CD, Brown EF, Hassanein KM, Holmes FF, Holmes GE.
Henan Institute of Medical Sciences, Henan Medical University, Henan 450052, China.
OBJECTIVE: To identify factors associated with very long survival among all cancer cases diagnosed at age 19 years or younger registered by the Cancer Data Service at the University of Kansas Medical Center in Kansas City, Kansas, U.S.A. in the 40-year period between 1944 and 1983, with follow-up to 1993. METHODS: There were 2720 pediatric patients with 2750 cancers who were studied. Forty-four types of cancer were grouped into 11 diagnostic categories. Diagnosis years spanned four eras: 1944-1953, 1954-1963, 1964-1973, and 1974-1983. Cases were compared using specific characteristics and were divided into short-term and long-term survivors with the division generously set at seven years. The proportions of the long-term survivors were compared by specific characteristics. RESULTS: Among the diagnostic categories, leukemias were the most common (29.8%), followed by CNS tumors (15.2%), and Hodgkin's disease (9.0%). Male to female ratio was 4:3; average age at diagnosis was 8.83 +/- 6.08 years. Long-term survivors totaled 1148 (41.7%). Prognosis was better in cases diagnosed in earlier stages and in later eras. Proportion of long-term survivors increased from 18.7% in era I to 52.6% in era IV. Improvement of survival was statistically significant in most diagnostic categories. CONCLUSIONS: This study shows continuing improvement of survival during four consecutive eras for childhood and adolescent cancer. Early diagnosis was associated with better survival. Unstaged cases decreased over time reflecting progress in diagnostic techniques. Many patients died before seven years after diagnosis. Those who survived more than seven years had excellent survival. Pediatricians can expect to participate in the care of these patients long after the original dianosis and treatment.
PMID: 11601255 [PubMed - indexed for MEDLINE]
Br J Haematol 2001 Sep;114(4):786-93 Related Articles, Books, LinkOut
Interphase fluorescence in situ hybridization and spectral karyotyping reveals hidden genetic aberrations in children with acute lymphoblastic leukaemia and a normal banded karyotype.
Nordgren A, Schoumans J, Soderhall S, Nordenskjold M, Blennow E.
Department of Molecular Medicine, L8-02 Karolinska Hospital, SE-171 76 Stockholm, Sweden. ann.nordgren@cmm.ki.se
Twenty-two cases of childhood acute lymphoblastic leukaemia (ALL) with normal G- or Q-banded karyotypes were studied by interphase fluorescence in situ hybridization (FISH) and spectral karyotyping. Probes detecting MLL, BCR/ABL and TEL/AML1 rearrangements were used for the interphase studies, along with centromere-specific probes from chromosomes 17 and X. In 10 patients (45%), previously undetected aberrations were demonstrable. Specific gene rearrangements and structural changes were found in six cases and numerical changes in five. Five of these aberrations have previously been reported to have an impact on prognosis. Three cases were massively hyperdiploid and, in one, the prognostically important BCR/ABL fusion was detected. In addition, a near-haploid karyotype with 27 chromosomes was found in one patient and TEL/AML1 rearrangements were detected in two cases. This study indicates that about half of childhood ALL cases with apparently normal karyotypes harbour genetic aberrations that may be detected using interphase FISH and spectral karyotyping.
PMID: 11564064 [PubMed - indexed for MEDLINE]
Am J Hematol 2001 Oct;68(2):91-8 Related Articles, Books, LinkOut
TEL/AML1 rearrangement and the prognostic significance in childhood acute lymphoblastic leukemia in Hong Kong.
Tsang KS, Li CK, Chik KW, Shing MM, Tsoi WC, Ng MH, Lau TT, Leung Y, Yuen PM.
Hematology and Bone Marrow Transplantation Division, Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
The TEL/AML1 rearrangement has been implicated as an independent good prognostic factor in pediatric acute lymphoblastic leukemia (ALL). We examined TEL/AML1 using nested reverse-transcription polymerase chain reaction (RT-PCR) and correlated TEL/AML1 with cytogenetics and immunophenotypes in 75 consecutively analyzed Chinese children with ALL in Hong Kong. TEL/AML1 was detected in 17.9% (12/67) B-lineage ALL at diagnosis but not in 8 T-ALL children or in 34 adults with ALL. E2A/PBX1, MLL/AF4, and BCR/ABL were not found in TEL/AML1+ patients. Coexpression of cross-lineage antigens was associated with TEL/AML1 gene fusion (p = 0.032), with CD13 in 80% (4/5) TEL/AML1+ cohort. Chromosomal abnormalities were demonstrated in 50% of the TEL/AML1+ ALL; however, a cryptic t(12;21) was not detected in these cases. Hyperdiploidy of 47-48 chromosomes was encountered in 25%. Deletion of 12p resulting in the loss of the normal allele of TEL and nonspecific del(6q) were noted in 8% (1/12) and 25% (3/12) of the TEL/AML1+ children, respectively. Rapid clearance of TEL/AML1 was noted in 50% of the patients on completion of the induction therapy; however, 16.7% (2/12) TEL/AML1+ ALL relapsed at a mean of 48.6 months from diagnosis (25 months off-therapy). The incidence of relapses of TEL/AML1+ ALL was comparable to that at diagnosis in B-lineage ALL (14.3% [2/14] vs. 17.9% [12/67], p > 0.05). The relapse rate in TEL/AML1+ ALL was similar to that of TEL/AML1- ALL (16.7% [2/12] vs. 20.6% [13/63], p > 0.05). The duration of first complete remission in TEL/AML1+ ALL was significantly longer as compared to TEL/AML1- ALL (mean [range] in month: 48.6 [47.2 - 50] vs 14.6 [2.9 - 42.3], p < 0.0001). Irrespective of TEL/AML1 rearrangement, the probabilities of the five-year overall survival and the event-free survival of patients were comparable (overall survival: 100% vs. 72.3%, p = 0.166 and event-free survival: 60% vs. 56.2%, p = 0.343). Our data would not suggest a less aggressive treatment regimen for TEL/AML1+ ALL. Copyright 2001 Wiley-Liss, Inc.
PMID: 11559948 [PubMed - indexed for MEDLINE]
Aust Health Rev 2001;24(2):135-42 Related Articles, Books
Treatment for childhood acute lymphoblastic leukaemia: the fathers' perspective.
McGrath P.
Centre for Palliative Care Research & Education, Royal Brisbane Hospital, QLD.
Research on parental adaptation to a child's chronic illness is still scant, and this is particularly so in relation to the experience of treatment for paediatric Acute Lymphoblastic Leukaemia (ALL). The work that does exist on parental reactions tends to conflate maternal responses with paternal responses, as fathers are usually seen as having a secondary role. Consequently, little is known about how fathers cope with treatment for childhood ALL. The present discussion seeks to make a contribution to this area by presenting findings on the paternal experience of treatment for paediatric ALL from a longitudinal study conducted at Royal Children's Hospital in Brisbane, Queensland. The findings from this research clearly indicate the emotional pain that fathers face in their struggle to accept the diagnosis of a serious, life-threatening illness such as ALL in their child. The findings challenge the notion of the make stereotype by showing that the shock of diagnosis, the emotional pain of coping with the illness, the expression of pain through tears, the desire to be with the child, the struggle to cope with the medical interventions, and concerns about other family members are not gender specific, but are rather issues common to both parents.
PMID: 11496455 [PubMed - indexed for MEDLINE]
Arch Pediatr 2001 Jul;8(7):734-43 Related Articles, Books, LinkOut
[Immunization for children treated for solid tumors: what are the guidelines?]
[Article in French]
Marec-Berard P, Floret D, Schell M, Mialou V, Frappaz D, Philip T, Bergeron C.
Departement d'oncologie pediatrique, centre Leon-Berard, 28, rue Laennec, 69373 Lyon, 08, France. marec@lyon.fnclcc.fr
There is no agreement on immunization of children treated with chemotherapy (CT) for solid tumors. Based on a review of the literature, we have attempted to establish guidelines on this subject. Except for hepatitis B vaccine, there is no argument to support the use of vaccine during CT. After a standard CT, a 3-month washout period appears to be necessary before starting an immunization program for a child not previously vaccinated, or to proceed with the recommended booster injections for diphteria anatoxin, tetanus vaccine, poliomyelitis inactivated vaccine, pertussis vaccine, and haemophilus influenza type b vaccine if the child is less than 5 years old. For mumps, measles, and rubella live vaccines, a longer post-CT washout of 6 months is suggested for the initial immunization, or for a revaccination of a child proved to be negative for all three serologies. Following high-dose CT a minimal 12-months term and a normalization of the blood lymphocytes count is necessary before planning booster injections once having checked for antidiphteria, tetanic, polio, measles, mumps, rubella and +/- haemophilus antibody titles. We don't find any reason to recommend a systematic varicella immunization in pediatric oncology. Pneumococcal vaccine is recommended in case of asplenia. Any other vaccination (BCG, influenza, yellow fever) must be evaluated individually.
PMID: 11484458 [PubMed - indexed for MEDLINE]
Bull Acad Natl Med 2001;185(1):149-60; discussion 160-2 Related Articles, Books, LinkOut
[Prognosis of acute lymphoblastic leukemia in children. Results of the French protocol FRALLE 93]
[Article in French]
Schaison G, Auclerc MF, Baruchel A, Leblanc T, Leverger G.
Service de Pediatrie a Orientation Hematologique-Hopital Saint-Louis, 1 avenue Claude Vellefaux-75475 Paris.
1,120 children were included in protocol FRALLE 93 from june 1993 to september 1998. Disease Free Survival for the all protocol is 78% +/- 3 and overall survival 83% +/- 3. Various clinical and laboratory features at the time of diagnosis have been correlated with prognosis. They provide a potential mean to stratify patients into treatment subgroups according their relative risk of treatment failure. The identification of these prognostic factors has been an essential element in the design of current therapeutic trials. Prognostic characteristics of childhood ALL include: age, white blood cell count, tumor burden, cytogenetics (chromosome count and chromosomal translocation), immunophenotype and early response to treatment. Molecular biology has been the revolution of the last two decades permitting the cloning of the genes involved in the leukemic process. Finally the new molecular techniques allow a sensitive diagnostic approach to minimal residual disease (MRD). The better detection of MRD must allow a more rational basis for therapeutic intensification for a subset of poor responder patients. A decrease in therapy of very good responders can also be envisaged.
Publication Types: Review Review, Tutorial
PMID: 11474564 [PubMed - indexed for MEDLINE]
Med Pediatr Oncol 2001 Jul;37(1):20-3 Related Articles, Books, LinkOut
Pneumocystis carinii pneumonia during maintenance treatment of childhood acute lymphoblastic leukemia.
Poulsen A, Demeny AK, Bang Plum C, Gjerum Nielsen K, Schmiegelow K.
Section of Pediatric Hematology and Oncology, Pediatric Clinic II, The Juliane Marie Center, The Copenhagen University Hospital, Rigshospitalet, Denmark.
BACKGROUND: Pneumocystis carinii pneumonia (PCP) is a wellknown risk among patients with deficient T-cell function such as children treated for acute lymphoblastic leukemia (ALL). The purpose of this study was to estimate the risk for PCP during maintenance treatment (MT) to identify patients at risk who could benefit from prophylaxis. PROCEDURE: We registered all episodes of PCP during MT in 71 children diagnosed between January 1992 and June 1997 with non-B-cell ALL at The Copenhagen University Hospital. Sulphametoxazole and trimetroprim (SMX/TMP) prophylaxis against PCP was given during induction and consolidation therapy but stopped prior to MT with oral methotrexate/6-mercaptopurine. Patients with standard (SR), intermediate (IR), and high risk (HR) ALL started MT at 3, 8, and 15 months from diagnosis, respectively. RESULTS: The HR group had a cumulated risk of 70% for developing PCP, whereas the risk for PCP in children with IR and the SR was 11 and 8%, respectively (P < 0.0001). All but one of these 13 cases of PCP occurred within 8 months after cessation of SMX-TMP prophylaxis. CONCLUSIONS: The higher incidence of PCP among HR compared to non-HR patients following cessation of SMX/TMP prophylaxis probably reflects the significantly longer T-cell suppressive consolidation therapy in this group. The very low incidence of PCP during the later part of MT emphasizes that methotrexate/6-mercaptopurine MT have more impact on B-cell than on T-cell function. TMP/SMX prophylaxis should be recommended for all children treated for ALL. Copyright 2001 Wiley-Liss, Inc.
PMID: 11466718 [PubMed - indexed for MEDLINE]
J Clin Oncol 2001 Jul 1;19(13):3188-93 Related Articles, Books, LinkOut
Relapse of TEL-AML1--positive acute lymphoblastic leukemia in childhood: a matched-pair analysis.
Seeger K, Stackelberg AV, Taube T, Buchwald D, Korner G, Suttorp M, Dorffel W, Tausch W, Henze G.
Department of Pediatric Oncology/Hematology, Charite Medical Center, Humboldt-University, Berlin, Germany. karl.seeger@charite.de
PURPOSE: The aim of this study was to investigate whether, in relapsed childhood acute lymphoblastic leukemia (ALL), the frequent genetic feature of TEL-AML1 fusion resulting from the cryptic chromosomal translocation t(12;21)(p13;q22) is an independent risk factor. PATIENTS AND METHODS: A matched-pair analysis was performed within a homogeneous group of children with first relapse of BCR-ABL-negative B-cell precursor (BPC) ALL treated according to relapse trials ALL-Rezidiv (REZ) of the Berlin-Frankfurt-Munster Study Group. A total of 249 patients were eligible for this study: 53 (21%) were positive for TEL-AML1, and 196 (79%) were negative. Positive patients were matched for established most-significant prognostic determinants at relapse, time point, and site of relapse, as well as age and peripheral blast cell count at relapse. RESULTS: Fifty pairs matching the aforementioned criteria could be determined. The probabilities with SE of event-free survival and survival at 5 years for matched TEL-AML1 positives and negatives are 0.63 +/- 0.10 versus 0.38 +/- 0.10 (P =.09) and 0.82 +/- 0.09 versus 0.42 +/- 0.19 (P =.10), respectively. These results were confirmed by multivariate analysis, revealing an independent prognostic significance of time point and site of relapse (both P <.001) but not of TEL-AML1 expression (P =.09). CONCLUSION: TEL-AML1 expression does not constitute an independent risk factor in relapsed childhood BCP-ALL after matching for relevant prognostic parameters. It undoubtedly characterizes genetically an ALL entity associated with established favorable prognostic parameters. High-risk therapeutic procedures such as allogeneic SCT should be considered restrictively.
Publication Types: Multicenter Study
PMID: 11432885 [PubMed - indexed for MEDLINE]
J Clin Oncol. 2001 Jul 1;19(13):3173-81. Related Articles, Links
Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries.
Comment in: J Clin Oncol. 2001 Jul 1;19(13):3161-2.
Moller TR, Garwicz S, Barlow L, Falck Winther J, Glattre E, Olafsdottir G, Olsen JH, Perfekt R, Ritvanen A, Sankila R, Tulinius H; Association of the Nordic Cancer Registries; Nordic Society for Pediatric Hematology and Oncology.
Department of Cancer Epidemiology, University Hospital, Lund, Sweden. torgil.moller@cancerepid.lu.se
PURPOSE: To assess the risk of death in patients who survive more than 5 years after diagnosis of childhood cancer and to evaluate causes of death in fatal cases. PATIENTS AND METHODS: This was a population-based study in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) using data of the nationwide cancer registries and the cause-of-death registries. The study cohort included 13,711 patients who were diagnosed with cancer before the age of 20 years between 1960 and 1989 and who survived at least 5 years from diagnosis. By December 31, 1995, 1,422 patients had died, and death certificates were assessed in 1,402. Standardized mortality ratios (SMRs) for validated causes of death were calculated based on 156,046 patient-years at risk. RESULTS: The overall SMR was 10.8 (95% confidence interval [CI], 10.3 to 11.5), mainly due to high excess mortality from the primary cancer. SMR for second cancer was 4.9 (95% CI, 3.9 to 5.9) and was 3.1 (95% CI, 2.8 to 3.5) for noncancer death. The pattern of causes of death varied markedly between different groups of primary cancer diagnoses and was highly dependent on time passed since diagnosis. Overall late mortality was significantly lower in patients treated during the most recent period of time, 1980 to 1989, compared with those treated from 1960 to 1979 (hazard ratio, 0.61; 95% CI, 0.54 to 0.70), and there was no increase in rates of death due to cancer treatment. CONCLUSION: Long-term survivors of childhood cancer had an increased mortality rate, mainly dying from primary cancers. However, modern treatments have reduced late cancer mortality without increasing the rate of therapy-related deaths.
PMID: 11432883 [PubMed - indexed for MEDLINE]
J Clin Oncol. 2001 Jul 1;19(13):3163-72. Related Articles, Links
Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study.
Comment in: J Clin Oncol. 2001 Jul 1;19(13):3161-2.
Mertens AC, Yasui Y, Neglia JP, Potter JD, Nesbit ME Jr, Ruccione K, Smithson WA, Robison LL.
Department of Pediatrics, University of Minnesota Medical School and Cancer Center, Minneapolis, USA. mertens@epi.umn.edu
PURPOSE: Survivors of childhood and adolescent cancer are at risk for long-term effects of disease and treatment. The Childhood Cancer Survivor Study assessed overall and cause-specific mortality in a retrospective cohort of 20,227 5-year survivors. PATIENTS AND METHODS: Eligible subjects were individuals diagnosed with cancer (from 1970 to 1986) before the age of 21 who had survived 5 years from diagnosis. Underlying cause of death was obtained from death certificates and other sources and coded and categorized as recurrent disease, sequelae of cancer treatment, or non-cancer-related. Age and sex standardized mortality ratios (SMRs) were calculated using United States population mortality data. RESULTS: The cohort, including 208,947 person-years of follow-up, demonstrated a 10.8-fold excess in overall mortality (95% confidence interval, 10.3 to 11.3). Risk of death was statistically significantly higher in females (SMR = 18.2), individuals diagnosed with cancer before the age of 5 years (SMR = 14.0), and those with an initial diagnosis of leukemia (SMR = 15.5) or CNS tumor (SMR = 15.7). Recurrence of the original cancer was the leading cause of death among 5-year survivors, accounting for 67% of deaths. Statistically significant excess mortality rates were seen due to subsequent malignancies (SMR = 19.4), along with cardiac (SMR = 8.2), pulmonary (SMR = 9.2), and other causes (SMR = 3.3). Treatment-related associations were present for subsequent cancer mortality (radiation, alkylating agents, epipodophyllotoxins), cardiac mortality (chest irradiation, bleomycin), and other deaths (radiation, anthracyclines). No excess mortality was observed for external causes (SMR = 0.8). CONCLUSION: While recurrent disease remains a major contributor to late mortality in 5-year survivors of childhood cancer, significant excesses in mortality risk associated with treatment-related complications exist up to 25 years after the initial cancer diagnosis.
PMID: 11432882 [PubMed - indexed for MEDLINE]
J Pediatr Oncol Nurs 2001 May-Jun;18(3):111-23 Related Articles, Books, LinkOut
Childhood leukemia: Understanding the significance of chromosomal abnormalities.
Robinson DL.
St. Louis Children's Hospital, 2426 Christopher Winds Lane, St. Louis, MO 63129, USA. dlr3005@bjc.org
The survival for children with acute lymphoblastic leukemia (ALL) has increased from 3% to greater than 70% in the last 30 years, with some patients achieving 95% survival. These advances have been made not only because therapy has improved, but also because there is a much greater understanding of the diversity of ALL. The identification of clinical and biological prognostic factors associated with ALL has resulted in the formation of subsets of patients classified into risk groups. Although age, initial white blood cell count, and central nervous system or testicular disease are all important prognostic factors, cytogenetic abnormalities have now emerged as the single most important prognostic factor for children with ALL. There are specific cytogenetic findings in the leukemic blast cells of these children that influence their prognosis. Some of these findings are positive factors and some adverse. Treatment protocols for ALL today are now determined by these specific chromosomal abnormalities. Copyright 2001 by Association of Pediatric Oncology Nurses
Publication Types: Review Review, Tutorial
PMID: 11373717 [PubMed - indexed for MEDLINE]
Arch Dis Child 2001 Jun;84(6):496-500 Related Articles, Books, LinkOut
Response to influenza immunisation during treatment for cancer.
Chisholm JC, Devine T, Charlett A, Pinkerton CR, Zambon M.
Children's Unit, Royal Marsden Hospital, Down's Rd, Sutton, Surrey SM2 5PT, UK. julia.chisholm@gosh-tr.nthames.nhs.uk
AIMS: To assess the annual risk of influenza infection in children with cancer and the immunogenicity of a trivalent split virus influenza vaccine in these children. METHODS: Eighty four children with cancer were tested for susceptibility to the circulating strains of influenza virus in autumn 1995 and 1996. Non-immunised children were reassessed the following spring for serological evidence of natural infection. Forty two patients received two doses of influenza vaccine. These children were receiving continuing chemotherapy for acute lymphoblastic leukaemia or were within six months of completing chemotherapy. RESULTS: Among the 84 children tested for influenza virus susceptibility only 8% of patients were fully protected (antibody titres >/= 40) against all three of the prevalent influenza virus strains; 33% were susceptible to all three viruses. Evidence of acquired natural infection was seen in 30% of unimmunised patients. Among immunised susceptible patients, 66% made some protective response to the vaccine and 55% showed protective antibody titres to all three viral strains following vaccination. Older age was associated with increased response to the H1N1 and H3N2 vaccine components, but total white cell count or neutrophil count at immunisation, type of cancer, or length of time on treatment for acute lymphoblastic leukaemia did not affect response. CONCLUSIONS: Most children with cancer studied were at risk of influenza infection. A significant response to immunisation was seen, supporting annual influenza vaccination for children being treated for cancer.
PMID: 11369567 [PubMed - indexed for MEDLINE]
Haematologica 2000 Nov;85(11 Suppl):47-53 Related Articles, Books, LinkOut
Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies.
Uderzo C, Dini G, Locatelli F, Miniero R, Tamaro P.
Centro TMO, Clinica Pediatrica, Ospedale S. Gerardo di Monza, Universita di Milano Bicocca, via Donizetti 106, 20052 Monza, Milano, Italy. ctmomonza@libero.it
BACKGROUND AND OBJECTIVES: Treatment of recurrent childhood acute lymphoblastic leukemia (ALL) has been controversial in the last decade. Conventional intensive chemotherapy (CHEMO) can cure up to 30% of children who have relapsed after ALL: similar results have been obtained with autologous bone marrow transplantation (ABMT), but allogeneic bone marrow transplantation (AlloBMT) seems to be the best therapeutic option. In this review the authors point out the contribution of current strategy in the setting of children with ALL who experience a first relapse and should be offered optimal treatment in order to obtain the best disease-free survival (DFS). The principal objective of this issue is to reach a possible consensus on the more controversial points regarding factors considered strong predictors of the outcome of the relapsed patients, second-line chemotherapy, optimal timing and type of transplantation. EVIDENCE AND INFORMATION SOURCE: Data published in the literature over the last decade concerning early and late relapse in childhood ALL suggest that improvements in cure rates may be achieved by intensification of the relapse treatment both with chemotherapy and with different types of transplantation. An accurate search for Medline data has been performed in order to understand the risk-benefit ratio of aggressive therapy adopted in this setting. STATE OF ART: Modern first-line treatment protocols for childhood ALL have contributed to curing an ever larger number of patients but this strategy could be responsible for creating a more resistant leukemic clone at the time of systemic or extramedullary relapse. This hypothesis emerges from a number of single or multicenter experiences; thus clinical and biological features in relapsed patients are being studied carefully in order to understand which risk-directed second-line therapy should be best adopted. The BFM group classified ALL relapses as "very early", "early", or "late" according to the time from diagnosis to first relapse (i.e. < 18, > 18 and < 30 or more than 30 months) and has shown that about 2/3 of the small fraction of children with late extramedullary relapses or late non T-marrow relapses or early combined non T-relapses can be rescued by chemotherapy; in contrast ALL early relapses or T-immunophenotype ALL relapses can be rescue only by AlloBMT. Since 1990 the AIEOP group adopted BFM-like first-line treatment and experienced similar situations for relapsed patients so that, even in absence of a real common relapse protocol, they went in the same direction as the BFM group as far as hematopoietic stem cell transplantation (HSCT) procedures and decision were concerned. A recent AIEOP study on the destiny of 192 consecutive patients with ALL in 2nd complete remission and not having an HLA suitable sibling donor is presented in this issue. The value of different HSCT procedures is addressed and the protection against a new relapse seems to be real, although, of course, the risk-benefit ratio should always be evaluated. PERSPECTIVES: Very few prospective studies on the treatment of childhood ALL relapse have been set up in the last decade because of many difficulties regarding common second-line therapies, some reluctance versus HSCT in consideration of the transplant-related mortality and the so-called late effects. Additional modifications of allogeneic family and unrelated donor HSCT strategies and the promising results both of cord HSCT and auto-grafting methods including in vitro purging or post-transplant immunotherapy, are making transplantation procedures for ALL relapsed patients more appropriate and increasing confidence in their use. The possibility of performing common prospective international studies should be encouraged over the next years in order to elucidate an area of great research as is that of the treatment of childhood ALL relapse.
Publication Types: Review Review, Tutorial
PMID: 11268324 [PubMed - indexed for MEDLINE]
Neoplasma 2000;47(6):382-9 Related Articles, Books, LinkOut
Correlation of clinical picture (event free survival and overall survival) in childhood acute leukemia patients with immunophenotype and chromosomal abnormalities.
Babusikova O, Sejnova D, Kirschnerova G, Kirsnerova Z, Cap J.
Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovak Republic. exonobab@savba.sk
In a group of 102 children with different immunological subtypes of acute leukemia, both lymphoblastic and nonlymphoblastic, the clinical parameters - event free survival and overall survival were correlated with numerical and structural chromosomal abnormalities. In a group of 80 ALL patients genetic abnormalities were observed in 40 patients, from those 19 of numerical type, 17 of structural type and 4 with both, numerical and structural anomalies. From the whole ALL group observed 23 patients (28.75%) died. In 10 died patients genetic abnormalities were found and in 6 cases less mature T-phenotype ALL has been documented. It seems, therefore, that immature T-phenotype with pathological karyotypes of all types of genetic anomalies presents the most risk group of patients of which all children died. ALL patients, as a whole, with pathological karyotype have shown significantly lower event free survival rate, comparing to the group of ALL patients with normal karyotype. Overall survival rate was also lower in the first group, but statistically not significant. In T-ALL patients, in both groups, with and without pathological karyotype, event free survival rate and overall survival rate were also lower in the first group, but statistically not significant. In B-ALL patients with pathological karyotypes vs. normal ones overall survival rate was lower in the first group, but statistically not significant. There was no difference in overall survival rate in these patients between pathological and normal karyotypes. In ANNL group of patients pathological karyotype was observed in 14 of them, with numerical anomalies in 6 patients, structural in 4 patients and both of them - numerical + structural in 4 children. From the whole ANLL group observed 11 (50%) patients died during the follow-up period (9 in relapse and 2 of treatment complications). From 11 died patients in 81.8% pathological karyotype was present. The prevalence of pathological karyotypes was observed in less mature M0-M2 ANLL subtype (71.4%). ANLL patients with pathological karyotype have shown significantly lower event free survival rate (in one of the two statistical log-rank analyses), comparing to the group of ANLL patients with normal karyotype. Overall survival rate was also lower in the first group, but statistically not significant. The presence/absence of CD34 marker expression in blast cells of our group of acute leukemia patients did not show any difference in event free survival and overall survival rates.
PMID: 11263863 [PubMed - indexed for MEDLINE]
Nouv Presse Med 1979 Jun 9;8(26):2181-5
[Inappropriate secretion of antiduiuretic hormone during acute leukaemia treated with vincristine. Two cases (author's transl)]
[Article in French]
Philip T, Souillet G, Gharib C, Geelen G, Allevard AM, Hartemann E, David M.
One the basis of two special typical cases, the authors detail the symptoms and signs and consider the physiopathology of inappropriate secretion of antidiuretic hormone related to vincristine. Urinary ADH was measured in both cases. ADH levels could be studied on ten consecutive occasions during the course of one of the cases (obs. n 1). Eleven similar cases have been found in the literature. ADH was measured in only three of them. Methods of treatment are considered, with particular emphasis on the role of demeclocycline.
PMID: 112579 [PubMed - indexed for MEDLINE]
Leukemia 2001 Jan;15(1):74-9 Related Articles, Books, LinkOut
6-mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia.
Schmiegelow K, Bretton-Meyer U.
The Laboratory for Pediatric Oncology, The Pediatric Clinic II, The Juliane Marie Centre, The National University Hospital, Rigshospitalet, Copenhagen, Denmark.
Through inhibition of purine de novo synthesis and enhancement of 6-mercaptopurine (6MP) bioavailability high-dose methotrexate (HDM) may increase the incorporation into DNA of 6-thioguanine nucleotides (6TGN), the cytoxic metabolites of 6MP. Thus, coadministration of 6MP could increase myelotoxicity following HDM. Twenty-one children with standard risk (SR) and 25 with intermediate risk (IR) acute lymphoblastic leukemia (ALL) were studied. During consolidation therapy they received either three courses of HDM at 2 week intervals without concurrent oral 6MP (SR-ALL) or four courses of HDM given at 2 week intervals with 25 mg/m2 of oral 6MP daily (IR-ALL). During the first year of maintenance with oral 6MP (75 mg/m2/day) and oral MTX (20 mg/m2/week) they all received five courses of HDM at 8 week intervals. In all cases, HDM consisted of 5,000 mg of MTX/m2 given over 24 h with intraspinal MTX and leucovorin rescue. Erythrocyte levels of 6TGN (E-6TGN) and methotrexate (E-MTX) were, on average, measured every second week during maintenance therapy. When SR consolidation (6MP: 0 mg), IR consolidation (6MP: 25 mg/m2), and SR/IR maintenance therapy (6MP: 75 mg/m2) were compared, white cell and absolute neutrophil count (ANC) nadir, lymphocyte count nadir, thrombocyte count nadir, and hemoglobin nadir after HDM decreased significantly with increasing doses of oral 6MP. Three percent of the HDM courses given without oral 6MP (SR consolidation) were followed by an ANC nadir <0.5 x 10(9)/l compared to 50% of the HDM courses given during SR/IR maintenance therapy. Similarly, only 13% of the HDM courses given as SR-ALL consolidation induced a thrombocyte count nadir <100 x 10(9)/l compared to 58% of the HDM courses given during maintenance therapy. The best-fit model to predict the ANC nadir following HDM during maintenance therapy included the dose of 6MP prior to HDM (beta = -0.017, P= 0.001), the average ANC level during maintenance therapy (beta = 0.82, P = 0.004), and E-6TGN (beta = -0.0029, P= 0.02). The best-fit model to predict the thrombocyte nadir following HDM during maintenance therapy included only mPLATE (beta = 0.0057, P = 0.046). In conclusion, the study indicates that reductions of the dose of concurrently given oral 6MP could be one way of reducing the risk of significant myelotoxicity following HDM during maintenance therapy of childhood ALL.
Publication Types: Clinical Trial
PMID: 11243403 [PubMed - indexed for MEDLINE]
Genes Chromosomes Cancer 2001 Apr;30(4):383-92 Related Articles, Books, LinkOut
Reassessment of childhood B-lineage lymphoblastic leukemia karyotypes using spectral analysis.
Elghezal H, Le Guyader G, Radford-Weiss I, Perot C, Van Den Akker J, Eydoux P, Vekemans M, Romana SP.
Service de Cytogenetique, Hopital Necker-Enfants Malades, Paris, France.
We studied a stratified cohort of 51 childhood B-lineage acute lymphoblastic leukemias (B-ALLs) to evaluate the efficiency of spectral karyotyping (SKY) in the detection of chromosome aberrations previously diagnosed using chromosome banding and/or reverse transcriptase polymerase chain reaction. Despite the small number of cases analyzed, several important features emerge from the study: (a) The result of banding analysis was revised in two-thirds of the cases. Eighty-three chromosome anomalies previously undetected or not characterized using chromosome banding were identified by spectral karyotyping, even in patients with apparently normal karyotypes. (b) All hyperdiploidy cases showed one or more extra copies of chromosomes X, 14, and 21. (c) Two hidden rearrangements, a t(7;12)(?p12;p13), and a new translocation, a t(9;12)(q31;p13), both involving the TEL gene, were characterized. (d) Some cryptic rearrangements, such as the der(21) t(12;21) translocation, remained undetected. (e) No new recurrent chromosome anomalies were discovered with this technique. In conclusion, the present study confirms the efficiency of the SKY technique in resolving and characterizing many complex chromosome anomalies seen in childhood B-ALLs, but it raises questions about the ability of this technique to detect cryptic rearrangements, such as the t(12;21) translocation. Copyright 2001 Wiley-Liss, Inc.
PMID: 11241791 [PubMed - indexed for MEDLINE]
Rinsho Ketsueki 2000 Nov;41(11):1231-7
[Severe hemolysis and SIADH-like symptoms induced by vincristine in an ALL patient with liver cirrhosis]
[Article in Japanese]
Nishihori Y, Yamauchi N, Kuribayashi K, Sato Y, Morii K, Hirayama Y, Sakamaki S, Honma H, Suzuki N, Kudo T, Niitsu Y.
Department of Internal Medicine (Section 4), Sapporo Medical University School of Medicine.
An 11-year-old boy was diagnosed as having acute lymphoblastic leukemia (ALL, L1) in 1987 and underwent treatment with an ALL high-risk protocol (prednisolone, vincristine (VCR), daunorubicin, 1-asparaginase), which resulted in complete remission. In 1990 he developed chronic hepatitis C and received interferon therapy. In December 1994, ALL recurred, and the patient was treated with VCR. He subsequently developed severe hemolysis (Hb 12.5 g/dl-->6.8 g/dl) with increases of indirect bilirubin, AST, and LDH. Furthermore, symptoms resembling a syndrome of inappropriate secretion of ADH (SIADH) and DIC developed. Upon incubation of the patient's red blood cells with VCR in vitro, extreme deformity of the cells was observed. These findings suggested that splenomegaly, due to liver cirrhosis which had developed rapidly from chronic hepatitis C while the patient was in an immunosuppressed state induced by anticancer drugs, had trapped the deformed red blood cells and resulted in severe hemolysis. The patient died on the 165th day after admission due to liver failure.
PMID: 11193445 [PubMed - indexed for MEDLINE]
J Trop Pediatr 2000 Dec;46(6):338-43 Related Articles, Books, LinkOut
Age, sex, haemoglobin level, and white cell count at diagnosis are important prognostic factors in children with acute lymphoblastic leukemia treated with BFM-type protocol.
Ng SM, Lin HP, Ariffin WA, Zainab AK, Lam SK, Chan LL.
Department of Paediatrics, University Hospital, Kuala Lumpur, Malaysia. ngszemay@hotmail.com
The presenting features and treatment outcome for 575 Malaysian children (< or = 12 years of age) with newly diagnosed acute lymphoblastic leukemia (ALL), admitted to the University Hospital, Kuala Lumpur, Malaysia between 1 January 1980 and 30 May 1995 were evaluated to determine their prognostic significance. Two-year overall survival was achieved in 67 per cent of all patients and 55 per cent of patients were relapse-free at 2 years. All except 10 patients, with identified French-American-British L3 morphology were treated with the modified Berlin-Frankfurt-Munster 78 treatment protocol. Univariate analyses of failure rate conferred age, sex, white cell count and hemoglobin level as potentially significant prognostic factors. All four presenting features retained their prognostic strength in a multivariate analysis. Race, platelet count, morphological subtype, liver/spleen size, lymphadenopathy, central nervous system and mediastinal mass involvement did not show any significant effect on treatment outcome. The 2-year survival rate was significantly different with regard to age, white cell count and hemoglobin level. However, sex was not significantly related to overall survival. These prognostic factors may have implications on future stratification of risk-adjusted initial treatment in the management of childhood ALL. Our analysis of Malaysian children is similar to what could be predicted based on previous studies in other populations.
PMID: 11191144 [PubMed - indexed for MEDLINE]
Leukemia 2000 Dec;14(12):2307-20 Related Articles, Books, LinkOut
Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980-1997. Medical Research Council Childhood Leukaemia Working Party.
Eden OB, Harrison G, Richards S, Lilleyman JS, Bailey CC, Chessells JM, Hann IM, Hill FG, Gibson BE.
Academic Unit of Paediatric Oncology, Christie and Royal Manchester Children's Hospital NHS Trusts, Oxford, UK.
Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics.
Publication Types: Clinical Trial Meta-Analysis Randomized Controlled Trial
PMID: 11187922 [PubMed - indexed for MEDLINE]
Leukemia 2000 Dec;14(12):2223-33 Related Articles, Books, LinkOut
Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995.
Gaynon PS, Trigg ME, Heerema NA, Sensel MG, Sather HN, Hammond GD, Bleyer WA.
Department of Pediatric Hematology-Oncology, Children's Hospital, Los Angeles, CA, USA.
Since 1968, the Children's Cancer Group (CCG) has treated more than 16,000 children with acute lymphoblastic leukemia (ALL). Herein, we report improvements obtained in CCG trials during two successive series of studies (1983-1988 and 1989-1995). Overall, 10-year EFS was 62% +/- 10% for the 1983-1988 series and 72% +/- 1% for the 1988-1995 series (P< 0.0001). Five-year cumulative rates of isolated CNS relapses were 5.9% and 4.4%. Therapy based on the Berlin-Frankfurt-Munster 76/79 study improved outcomes for intermediate and higher risk patients in the first series. For intermediate risk patients, delayed intensification (DI) was most crucial for improved outcome and cranial irradiation was safely replaced with maintenance intrathecal methotrexate, providing patients received intensified systemic therapy. In the second series, randomized trials showed better outcome with one vs no DI phase for lower risk patients, with two vs one DI phase for intermediate risk patients, and with the CCG 'augmented regimen' for higher risk patients with a slow day 7 marrow response. Cranial irradiation was safely replaced with additional intrathecal methotrexate for higher risk patients with a rapid day 7 marrow response. In a subsequent study, substitution of dexamethasone in place of prednisone in induction and maintenance improved outcome for standard risk patients. All patients received dexamethasone in DI. These successful treatment strategies form the basis for our current ALL trials.
Publication Types: Clinical Trial Meta-Analysis Randomized Controlled Trial
PMID: 11187913 [PubMed - indexed for MEDLINE]
Br J Haematol 2001 Feb;112(2):293-9 Related Articles, Books, LinkOut
Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI).
Hargrave DR, Hann II, Richards SM, Hill FG, Lilleyman JS, Kinsey S, Bailey CC, Chessells JM, Mitchell C, Eden OB; Medical Research Council Working Party for Childhood Leukaemia.
Department of Paediatric Oncology, The Royal Marsden Hospital, Sutton, UK. d.hargrave@icr.ac.uk
In the last 20 years, the survival rate for children with acute lymphoblastic leukaemia (ALL) has markedly improved, largely owing to a decrease in relapses. However, children still die from complications of treatment and these are potentially preventable. We have analysed data from three large consecutive national protocols for ALL from 1980 to 1997 [Medical Research Council United Kingdom ALL (MRC UKALL) trials VIII, X and XI] to compare the incidence and causes of treatment-related deaths (TRD). The percentage of TRD has fallen from 9% to 2% (UKALL VIII to XI), largely as a result of a decrease in fatal infections. Deaths during induction have fallen from 3% to 1%, the main causes of death being bacterial, followed by fungal infection, while other causes, chiefly haemorrhage, have not declined. Remission deaths also decreased from 6% to 1%, particularly those deaths due to measles and pneumocystis carinii. More guidelines for surveillance and treatment of infections have been included within progressively more intensive protocols. Risk factor analysis showed increased TRD in patients with Down's syndrome, high leucocyte count and older age in UKALL XI. In contrast, the introduction of blocks of intensification was not associated with an increased death rate. While improved supportive care has reduced the incidence of TRD, there is still scope for further reduction by prompt treatment of suspected infection. Maintenance of herd immunity remains of vital importance in avoiding deaths from measles.
PMID: 11167821 [PubMed - indexed for MEDLINE]
Br J Haematol 2000 Dec;111(4):1080-6 Related Articles, Books, LinkOut
Minimal residual disease studies are beneficial in the follow-up of TEL/AML1 patients with B-precursor acute lymphoblastic leukaemia.
de Haas V, Oosten L, Dee R, Verhagen OJ, Kroes W, van den Berg H, van der Schoot CE.
Emma Kinderziekenhuis/AMC, University of Amsterdam, The Netherlands.
The t(12;21)(p13;q22) translocation has been identified as the most common chromosomal abnormality in childhood acute lymphoblastic leukaemia (ALL). Initially, several investigators reported an excellent prognosis in paediatric leukaemias with this translocation, but other studies showed a 20% incidence in relapsed ALL. We performed an extensive analysis of 90 ALL patients. In 17 (19%) cases a TEL/AML1 fusion was found. However, this group was not representative as it included a high number of relapsed patients compared with the normal incidence in B-precursor ALL [54 in continuous complete remission (CCR) and 36 relapsed patients] and only a slightly better prognosis for TEL/AML1-positive patients was found (not significant) (four relapses in 17 TEL/AML1-positive patients vs. 32 relapses in 73 TEL/AML1-negative patients). Comparison of known prognostic factors (age, sex, ploidy, white blood cell count and immunophenotype) between relapsed TEL/AML1-positive and TEL/AML1-positive patients in CCR did not reveal differences, except that the white blood cell count was significantly higher in the relapsed group (P = 0.001). Time between diagnosis and relapse was not different for the relapsed TEL/AML1-positive group vs. the relapsed TEL/AML1-negative group. In 11 TEL/AML1-positive patients, the minimal residual disease (MRD) level at the end of induction therapy was quantified in a limiting dilution assay using IGH or TCRD junctional regions as polymerase chain reaction (PCR) targets. In all four relapsed patients, the level of MRD at the end of induction therapy was high (range 0.24-1.2%), whereas in all seven CCR patients, the MRD level was extremely low (0.02 to < 0.001%). In agreement with previous studies in which MRD levels at the end of induction therapy were found to be the strongest risk factor independent of other risk factors, in the present study we show that the MRD level remains a risk factor independent of the presence of a TEL/AML1 fusion gene.
PMID: 11167743 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 2000 Dec;17(8):615-22 Related Articles, Links
High-dose methotrexate in childhood all.
Moe PJ, Holen A.
Children Hospital, Regionsykehuset i Trondheim, Trondheim, Norway.
An event-free survival is currently achieved in 70-80% of children diagnosed with acute lymphocytic leukemia (ALL). A decline in the long-term sequalae from therapy is a challenge at present. Due to the high incidence of central nervous system (CNS) relapse in ALL patients, cranial irradiation was introduced as a prophylactic measure in the beginning of the 1970s. Cranial irradiation, however, may cause secondary malignancies in the CNS. In recent years neurotoxicities have been demonstrated to follow cranial irradiation in a large proportion of ALL patients. Because of these deleterious effects, most ALL protocols are limited to the combination intrathecal and intravenous methotrexate as the standard for CNS prophylaxis. In the 1970s, an intermediate dose was administered, while from the 1980s a high dose of methotrexate was combined with intrathecal methotrexate. The regular methotrexate dose of later years has been in the range of 5-8 g/m2. The intravenous methotrexate dose has actually varied from 2 to 33.6 g/m2. The highest dose, 33.6 g/m2, has been without intrathecal instillation. In a study from Norway, high-dose methotrexate (6-8 g/m2) was used, and only two (2.2%) of 89 ALL cases showed CNS relapse, both of reversible kind. In the United Kingdom, a randomized controlled study was started in 1990. Results published so far are based on a segment of cases characterized by standard risk and white blood cell count below 50 x 10(9); a 4% reduction in CNS relapse was found for high-dose methotrexate in comparison to those treated only with long-term intrathecal methotrexate. The use of methotrexate unalterably warrants some precautions. Rescue therapy with folinic acid is usually started 36 h after initiating the methotrexate infusion. Steps are also taken to secure adequate intake of fluids and alkalinization of the urine. Provided irradiation is avoided, neurotoxicities rarely occur. For regular high-dose methotrexate adverse effects mostly involve mucositis and myelosuppresion.
Publication Types: Review Review, Tutorial
PMID: 11127393 [PubMed - indexed for MEDLINE]
Cancer Genet Cytogenet 2000 Oct 15;122(2):73-8 Related Articles, Books, LinkOut
TEL/AML-1 fusion gene. its frequency and prognostic significance in childhood acute lymphoblastic leukemia.
Jamil A, Theil KS, Kahwash S, Ruymann FB, Klopfenstein KJ.
Department of Pediatrics, Division of Hematology/Oncology, Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA. jamila@pediatrics.ohio-state.edu
TEL gene rearrangement due to the 12;21 chromosome translocation is believed to be the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL). A study was conducted to investigate the frequency and prognostic significance of TEL/AML-1 fusion gene resulting from a cryptic t(12;21)(p13;q22). Bone marrow samples from 86 patients diagnosed over the past 5 years at Columbus Children's Hospital were analyzed by fluorescence in situ hybridization (FISH) technique for TEL/AML-1 fusion gene, using LSI((R)) DNA probes. The positive cases were analyzed for clinical outcome. Patients in this study received treatment according to Children's Cancer Group (CCG) protocols. Fifteen of the 86 cases (17%) were positive for the fusion gene. All were B-cell lineage and except for one, all were CD10 positive. TEL/AML-1 was not found in any T-cell ALL. The mean overall survival (OS) following diagnosis for the TEL/AML-1-positive group was significantly longer than for the TEL/AML-1-negative group by log-rank = 7.84, P = 0.005. Similarly, the event-free survival (EFS) after remission for the positive group (median 94.5 months) was longer than the negative group (median 57 months) by log-rank = 7.19, P = 0.007. This study confirms that the TEL/AML-1 fusion gene may be the most common genetic event in childhood ALL, occurring in 17% of the patients. It appears restricted to the B-cell lineage. In this study, the presence of a TEL/AML-1 fusion gene was statistically significant in predicting both OS and EFS, indicating a favorable clinical outcome for these patients. Screening for TEL/AML-1 should become routine at diagnosis and a useful biological variable for risk stratification in future clinical trials.
PMID: 11106814 [PubMed - indexed for MEDLINE]
Ann Oncol 2000 Aug;11(8):999-1006 Related Articles, Books, LinkOut
Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party.
Harrison G, Richards S, Lawson S, Darbyshire P, Pinkerton R, Stevens R, Oakhill A, Eden OB.
Clinical Trial Service Unit, Radcliffe Infirmary, Oxford, UK.
BACKGROUND: Although reinduction rates are good for children with relapsed acute lymphoblastic leukaemia there is no consensus on whether bone marrow transplantation (BMT) is the most effective treatment to prolong second remission. PATIENTS AND METHODS: Analyses comparing the outcome of related donor allogeneic BMT (related allograft) with chemotherapy are unreliable because of selection biases. To avoid these biases, the MRC UKALL R1 trial was analysed by HLA-matched donor availability. RESULTS: No significant difference in outcome was found between the donor and no donor groups. The donor group had a non-significant eight-year event-free survival (EFS) advantage of 8%, (95% confidence interval -9%-24%) over the no donor group. Patients with a first remission less than two years appeared to benefit most from having a donor, although the effect was only marginally significantly different from patients with longer first remission. Analysis by treatment received gave similar results, with BMT patients having a 5% (P = 0.8) eight-year EFS advantage over patients who received chemotherapy. CONCLUSIONS: Related allograft was not found to be significantly better than chemotherapy, but there was the possibility of a moderate EFS benefit with related allograft. especially in patients with a short first remission.
Publication Types: Clinical Trial Multicenter Study
PMID: 11038037 [PubMed - indexed for MEDLINE]
Rinsho Ketsueki 2000 Jul;41(7):576-84 Related Articles, Books, LinkOut
[Prognostic significance of chromosome analysis in childhood acute lymphoblastic leukemia. Children's Cancer and Leukemia Study Group (CCLSG)]
[Article in Japanese]
Hyakuna N, Kaneko Y, Katano N, Iwai T, Nagata T, Sakashita K, Takeda O, Tanaka A, Azuma H, Sekine I, Fujimoto T.
We analyzed the prognostic significance of chromosomal findings in children with acute lymphoblastic leukemia (ALL), treated according to the Children's Cancer and Leukemia Study Group protocols between 1987 and 1993. Patients were classified into 5 groups according to chromosome number. The patients with a hyperdiploid(> 50) karyotype(13%) had the best prognosis [4-year event-free survival (EFS): 83 +/- 6%], while those with a pseudodiploid karyotype (24%) had the worst prognosis(4-year EFS: 52 +/- 6%) (log-rank, p = 0.03). However, multivariate analysis revealed that the ploidy classification had no prognostic significance in terms of EFS. When patients were classified according to chromosome abnormalities, those with any type of translocation had a worse outcome (4-year EFS: 33 +/- 9%) than those with hyperdiploidy(> 50), normal diploidy, and other abnormalities(log-rank, p < 0.0001). Multivariate analysis revealed that chromosome abnormalities were an independent prognostic factor (relative risk 3.98; p < 0.0001). Patients with t(1; 19) had an EFS similar to that of patients with chromosome abnormalities other than translocations or normal diploidy. We conclude that chromosomal findings have prognostic significance, although some chromosome abnormalities lost their statistical significance after modern intensified chemotherapy. Childhood ALL should be further stratified according to chromosome classification.
Publication Types: Clinical Trial Multicenter Study
PMID: 11020981 [PubMed - indexed for MEDLINE]
Blood 2000 Oct 1;96(7):2412-8 Related Articles, Books, LinkOut
Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI.
Wheeler KA, Richards SM, Bailey CC, Gibson B, Hann IM, Hill FG, Chessells JM.
John Radcliffe Hospital, Headington, Oxford, England. kate.wheeler@paediatrics.oxford.ac.uk
The role of bone marrow transplantation (BMT) in first remission of children with high-risk acute lymphoblastic leukemia (ALL) remains unclear. There were 3676 patients (aged 1 to 15 years) entered into the United Kingdom (UK) Medical Research Council (MRC) trials UKALL X and XI from 1985 to 1997. Of these patients, 473 patients (13%) were classified as very high (VH) risk and were eligible for a transplantation from a matched histocompatible sibling donor (MSD). We tissue-typed 286 patients; 99 patients had a matched related donor, and 76 patients received transplantations. Additionally, 25 children received transplantations from a matched unrelated donor (MUD) despite trial guidelines for MSD transplantations only. The median time to transplantation was 5 months (range, 2 to 19 months), and the median follow-up was 8 years. The 10-year event-free survival (EFS) adjusted for the time to transplantation, diagnostic white blood cell (WBC) count, Ph chromosome status, and ploidy was 6. 0% higher (95% confidence interval (CI), -10.5% to 22.5%) for 101 patients who received a first-remission transplantation (MSD and MUD) than for the 351 patients treated with chemotherapy (transplantation, 45.3%, vs chemotherapy, 39.3%). The transplantation group had fewer relapses (31%) compared to relapses in the chemotherapy group (55%); however, the transplantation group had more remission deaths (18%) compared to remission deaths in the chemotherapy group (3%). In contrast the adjusted 10-year EFS was 10. 7% higher (95% CI, -2.6% to 24.0%) for patients without a human leukocyte antigen (HLA)-matched donor than for those patients with a donor (no donor, 50.4%, vs donor, 39.7%). In conclusion, for the majority of children with VH-risk ALL, the first-remission transplantation has not improved EFS.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 11001892 [PubMed - indexed for MEDLINE]
Ther Drug Monit 2000 Aug;22(4):375-82 Related Articles, Books, LinkOut
Variable correlation between 6-mercaptopurine metabolites in erythrocytes and hematologic toxicity: implications for drug monitoring in children with acute lymphoblastic leukemia.
Innocenti F, Danesi R, Favre C, Nardi M, Menconi MC, Di Paolo A, Bocci G, Fogli S, Barbara C, Barachini S, Casazza G, Macchia P, Del Tacca M.
Department of Oncology, University of Pisa, Italy.
Nineteen pediatric patients affected by acute lymphoblastic leukemia (ALL) were examined weekly with respect to 6-mercaptopurine nucleotide (6-MPN) and 6-thioguanine nucleotide (6-TGN) levels in erythrocytes during the course of maintenance treatment with 6-MP 50 mg/m2 per d and results were related to various parameters of bone marrow function to assess, in the same individual, the level of reliability of 6-MP metabolites in predicting a later change in peripheral blood cell counts. Median values for 6-MPN and 6-TGN were 57 and 200 pmol/8 x 10(8) erythrocytes, respectively, as measured by reversed-phase high-performance liquid chromatography (HPLC). 6-TGN levels in erythrocytes were inversely related with white blood cell count (r = -0.463, p < 0.0001, n = 361), absolute neutrophil count (r = -0.386, p < 0.0001, n = 347), erythrocyte (r = -0.354, p < 0.0001, n = 287), and platelet counts (r = -0.24, p < 0.0001, n = 319) in the majority of patients (n = 10-12), while no correlation was found for 6-MPN. In the remaining children, no evidence of correlation was demonstrated between 6-TGN levels and myelotoxicity. The results confirm the role of 6-TGN as the reference cytotoxic metabolite for evaluating the exposure to 6-MP and identifying treatment compliance in ALL children but indicate the limits of a follow-up based solely on metabolite levels and suggest that a more correct approach remains the double monitoring of 6-TGN and blood cell count with differential.
PMID: 10942174 [PubMed - indexed for MEDLINE]
Eur J Haematol 2000 Jul;65(1):40-51 Related Articles, Books, LinkOut
Cytogenetic and FISH studies of a single center consecutive series of 152 childhood acute lymphoblastic leukemias.
Andreasson P, Hoglund M, Bekassy AN, Garwicz S, Heldrup J, Mitelman F, Johansson B.
Department of Clinical Genetics, Lund University Hospital, Sweden. Patrik.Andreasson@klingen.lu.se
Between 1977 and 1996, cytogenetic investigations were performed on 182 childhood (< or = 16 yr) acute lymphoblastic leukemias (ALL), constituting 94% (182 of 194) of all ALL patients diagnosed and treated at the Departments of Pediatrics, Lund and Malmo University Hospitals, Sweden, during these two decades. The cytogenetic analyses were successful in 152 cases (84%). The failure rate was higher for the ALL investigated before 1987 (30% vs. 4%, p < 0.0001), and also the incidence of cytogenetically normal cases was higher during 1977-86 (43% vs. 25%, p < 0.05). Clonal chromosomal abnormalities were found in 103 (68%) ALL. Structural rearrangements were detected, by chromosome banding alone, in 76 cases (50%). Fluorescence in situ hybridization (FISH) was used to identify cases with t(12;21), 11q23 rearrangements, and 9p deletions, using probes for ETV6/CBFA2, MLL, and CDKN2A/B, in 72 cases from which cells in fixative and/or unstained metaphase preparations were available. In total, the most common structural rearrangements were del(9p) (17%), t(12;21) (15%), del(6q) (8%), and MLL rearrangements (4%). Six (32%) of nineteen cytogenetically normal ALL analyzed by FISH harbored cryptic abnormalities; three displayed t(12;21) and four had del(9p), one of which also carried a t(12;21). Five (45%) of the t(12;21)-positive ALL showed +der(21)t(12;21) or ider(21)(q10)t(12;21), resulting in the formation of double fusion genes. Among the more rare aberrations, eight structural rearrangements were identified as novel recurrent ALL-associated abnormalities, and nine cases harbored rearrangements previously not reported. Sixteen cases displayed karyotypically unrelated clones at different investigations. Seven ALL (5%) showed simple chromosomal changes, unrelated to the aberrations detected at diagnosis, during morphologic and clinical remission, and in all but one instance the patients remained in remission, with the abnormal clone disappearing in subsequent investigations. This indicates that the emergence of novel clonal chromosomal aberrations during remission in childhood ALL is rather common and does not by necessity predict a forthcoming relapse.
PMID: 10914938 [PubMed - indexed for MEDLINE]
Pediatr Hematol Oncol 1996 Sep-Oct;13(5):433-41 Related Articles, Books, LinkOut
Myelotoxicity, pharmacokinetics, and relapse rate with methotrexate/6-mercaptopurine maintenance therapy of childhood acute lymphoblastic leukemia.
Comment in: Pediatr Hematol Oncol. 1996 Sep-Oct;13(5):vii-x.
Schmiegelow K, Ifversen M.
Section of Pediatric Hematology and Oncology, Juliane Marie Centre, National University Hospital, Copenhagen, Denmark.
White blood cell and absolute neutrophil counts (WBC, ANC), aminotransferase (AT) levels, methotrexate (MTX) and 6-mercaptopurine (6MP) doses, metabolites in erythrocytes (E-MTX and E-6TGN), and the prognostic significance of these parameters were studied in 58 children receiving MTX/6MP maintenance therapy for acute lymphoblastic leukemia diagnosed from July 1986 to December 1991. At the end of follow-up July 1995, 13 patients had relapsed (pEFS = 0.77). Weighted means of AT, WBC, and ANC during and after maintenance therapy (mAT, mWBCON, mWBCOFF, mANCON, mANCOFF), E-MTX (mE-MTX), and E-6TGN (mE-6TGN) were calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX*6TGN), as MTX and 6MP probably act synergistically. Beyond higher MTX and 6MP doses to patients with high mWBCON, neither mWBCON, (median 3.5 x 10(9)/L), mANCON, nor mAT was correlated with the dose of MTX and 6MP, mE-MTX, mE-6TGN, or risk of relapse. Patients with mE-MTX*6TGN above or below 828 (nmol/mmol Hb)2 (median value) had pEFS values of 0.84 and 0.70, respectively (P = .16). All 5 patients who relapsed during therapy had mE-MTX*6TGN < 828 (nmol/mmol Hb)2 (P = .03). mWBCOFF and the degree of myelosuppression (= mWBCSHIFT = mWBCOFF - mWBCON; median: 2.5 x 10(9)/L) were related to age (rs = -0.50, P = .001 and rs = -0.40, P = .006, respectively). All eight relapses off therapy occurred in patients with mWBCSHIFT < 2.5 x 10(9)/L (P = .02). WBC levels during MTX/6MP therapy may underestimate the degree of MTX/6MP treatment intensity, especially in order children. Pharmacokinetic monitoring could be useful for optimizing MTX/6MP maintenance therapy.
PMID: 10897815 [PubMed - indexed for MEDLINE]
J Formos Med Assoc 2000 Apr;99(4):281-9 Related Articles, Books, LinkOut
Cytogenetic pattern of childhood leukemia in Taiwan.
Yang CP, Wu JH, Hung IJ, Jaing TH.
Department of Medicine, Chang-Gung Children's Hospital, Taoyuan, Taiwan.
BACKGROUND: Cytogenetic analyses of leukemic cells can be used to define specific subgroups of leukemia with different prognoses and, thereby, indicate appropriate treatment for individual cases. In this study, we investigated the cytogenetic pattern of childhood leukemia in Taiwanese patients. METHODS: A modified trypsin method of Seabright was used for G-banding of metaphase cells. RESULTS: From October 1996 to January 1999, 111 children with a diagnosis of leukemia were enrolled in the study. Of these, 73 patients had a diagnosis of acute lymphoblastic leukemia (ALL) and 63 of these patients had successful karyotyping of their leukemic cells. Among them, 20 (30.3%) had a normal karyotype, five had hypodiploidy (all had 45 chromosomes), five had low hyperdiploidy (47-50 chromosomes), 16 (24.2%) had high hyperdiploidy (> 50 chromosomes), and 20 had pseudodiploidy. Chromosomal translocation was identified in 24 (36.4%) of the ALL patients, 17 of whom had recurrent translocations including 10 with CD10+ B-precursor ALL [4 with t(9;22), 5 with t(1;19), and 1 infant with t(8;14)(q24;q11)], one neonate with CD10- early pre-B ALL with t(4;11), three B-cell cases with t(8;14), and three T-cell cases [2 with t(11;19)(q23;p13), and 1 (11;14)(p13;q11)]. One B-precursor patient had dic (9;12). Karyotypes of the 30 patients with acute myeloid leukemia (AML) included eight with t(8;21); seven with the French-American-British-M2 subtype (FAB-M2) and one with M1. All four of the patients with M3 had t(15;17), one patient with M4 had inv(16) and 7q-, one with M4Eo (M4 with eosinophilia) had t(7;16)(q21;q22), one with M0 had t(4;11)(q21;q23), and the remaining 11 had a normal karyotype. Three of the five adult-type chronic myeloid leukemia patients had standard Philadelphia chromosome, and the other two had a variant-form of Philadelphia chromosome. Both of the patients with juvenile myelomonocytic leukemia and one patient with myelodysplastic syndrome had a normal karyotype. CONCLUSIONS: Most findings were similar to previous reports. Although the high proportion of FAB-M2 patients (7/8) with t(8;21) and the consequently higher frequency (26.7%) of this translocation in the 30 AML cases in this study might have significance, a larger series of cases is needed to establish this finding.
PMID: 10870310 [PubMed - indexed for MEDLINE]
Leukemia 2000 May;14(5):783-5 Related Articles, Links
New definition of remission in childhood acute lymphoblastic leukemia.
Pui CH, Campana D.
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
The extent of clearance of leukemic cells from the blood or bone marrow during the early phase of therapy is an independent prognostic factor in acute lymphoblastic leukemia (ALL). Several methods are available to measure the minimal residual disease (MRD) remaining after initial intensive chemotherapy. The most promising are flow cytometric detection of aberrant immunophenotypes and polymerase chain reaction analysis of clonal antigen-receptor gene rearrangements. When applied together, these techniques enable one to monitor MRD in virtually all cases of ALL. Patients who achieve an 'immunologic' or 'molecular' remission (ie leukemic involvement of <0.01% of nucleated bone marrow cells at the end of remission induction therapy) are predicted to have a better clinical outcome than patients whose remission is defined solely by morphologic criteria. In studies to date, patients with MRD at a level of 10(-2) or more at the end of induction have fared almost as poorly as those with > or =5% blast cells in the bone marrow (ie induction failures). Sequential monitoring of MRD can improve the clinical utility of risk assessment still further. Additional studies are needed to determine the critical levels of MRD at various times of treatment and whether therapeutic intervention based on MRD findings can improve clinical outcome.
Publication Types: Review Review, Tutorial
PMID: 10803506 [PubMed - indexed for MEDLINE]
Leukemia 2000 Apr;14(4):688-95 Related Articles, Books, LinkOut
Regeneration pattern of precursor-B-cells in bone marrow of acute lymphoblastic leukemia patients depends on the type of preceding chemotherapy.
van Lochem EG, Wiegers YM, van den Beemd R, Hahlen K, van Dongen JJ, Hooijkaas H.
Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, The Netherlands.
Immunofluorescence stainings for the CD10 antigen and terminal deoxynucleotidyl transferase (TdT) can be used for the detection of leukemic blasts in CD10+ precursor-B-acute lymphoblastic leukemia (precursor-B-ALL) patients, but can also provide insight into the regeneration of normal precursor-B-cells in bone marrow (BM). Over a period of 15 years, we studied the regeneration of CD10+, TdT+, and CD10+/TdT+ cells in BM of children with (CD10+) precursor-B-ALL during and after treatment according to three different treatment protocols of the Dutch Childhood Leukemia Study Group (DCLSG) which differed both in medication and time schedule. This study included a total of 634 BM samples from 46 patients who remained in continuous complete remission (CCR) after treatment according to DCLSG protocols VI (1984-1988; n = 8), VII (1988-1991; n = 10) and VIII (1991-1997; n = 28). After the cytomorphologically defined state of complete remission with CD10+ and CD10+/TdT+ frequencies generally below 1% of total BM cells, a 10-fold increase in precursor-B-cells was observed in protocol VII and protocol VIII, but not in protocol VI. At first sight this precursor-B-cell regeneration during treatment resembled the massive regeneration of the precursor-B-cell compartment after maintenance treatment, and appeared to be related to the post-induction or post-central nervous system (CNS) therapy stops in protocols VII and VIII. However, careful evaluation of the distribution between the 'more mature' (CD10+/TdT-) and the 'immature' (CD10+/TdT+) precursor-B-cells revealed major differences between the post-induction/post-re-induction precursor-B-cell regeneration (low 'mature/immature' ratio: generally <1.0), the post-CNS treatment regeneration (moderate 'mature/immature' ratio: 1.2-2.8), and the post-maintenance regeneration (high 'mature/ immature' ratio: 5.7-7.6). We conclude that a therapy stop of approximately 2 weeks is already sufficient to induce significant precursor-B-cell regeneration even from aplastic BM after induction treatment. Moreover, differences in precursor-B-cell regeneration patterns are related to the intensity of the preceding treatment block, with lower 'mature/immature' ratios after the highly intensive treatment blocks. This information is essential for a correct interpretation of flow cytometric immunophenotyping results of BM samples during follow-up of leukemia patients. Particularly in precursor-B-ALL patients, regeneration of normal precursor-B-cells should not be mistaken for a relapse.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 10764156 [PubMed - indexed for MEDLINE]
Br J Haematol 2000 Mar;108(3):531-43 Related Articles, Books, LinkOut
The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study.
Lawson SE, Harrison G, Richards S, Oakhill A, Stevens R, Eden OB, Darbyshire PJ.
Department of Haematology, Birmingham Children's Hospital, Birmingham, UK. isaac.lawson@btinternet.com
We have examined the toxicity and overall outcome of the Medical Research Council UKALL R1 protocol for 256 patients with relapsed childhood acute lymphoblastic leukaemia (ALL). Second remission was achieved in over 95% of patients. Two patients died during induction and seven patients died of resistant disease. The overall actuarial event-free survival (EFS) at 5 years for all patients experiencing a first relapse was 46% (95% CI 40-52). Duration of first remission, site of relapse, age at diagnosis and sex emerged as factors of prognostic significance. Five-year EFS was only 7% for children relapsing in the bone marrow within 2 years of diagnosis, but was 77% for those relapsing without bone marrow involvement > 2.5 years from diagnosis. All analyses in this report are by treatment received. For those receiving chemotherapy alone, the 5-year EFS was 48%; for autologous bone marrow transplantation (BMT), the 5-year EFS was 47%; for unrelated donor BMT, it was 52%; and for related donor BMT, the 5-year EFS was 45%. The groups, however, were not comparable with respect to risk factor profile, and therefore direct comparison of EFS is misleading. Adjustment for time to transplant and prognostic factors was used to reduce the effects of biases between treatment groups, but did not suggest benefit for any particular treatment. There was failure of our planned randomization scheme in this trial with only 9% of those eligible being randomized, which highlights the difficulties in running randomized trials especially in patients who have relapsed from a previous trial. The optimal treatment for relapsed ALL therefore remains uncertain. Alternative approaches are clearly needed for those with early bone marrow relapse if outcome is to improve.
Publication Types: Clinical Trial Controlled Clinical Trial
PMID: 10759711 [PubMed - indexed for MEDLINE]
J Clin Oncol 2000 Apr;18(7):1508-16 Related Articles, Books, LinkOut
Six months of maintenance chemotherapy after intensified treatment for acute lymphoblastic leukemia of childhood.
Toyoda Y, Manabe A, Tsuchida M, Hanada R, Ikuta K, Okimoto Y, Ohara A, Ohkawa Y, Mori T, Ishimoto K, Sato T, Kaneko T, Maeda M, Koike K, Shitara T, Hoshi Y, Hosoya R, Tsunematsu Y, Bessho F, Nakazawa S, Saito T.
Department of Oncology, Kanagawa Children's Medical Center, and Department of Pediatrics, Yokohama City University School of Medicine, Yokohama, Japan.
PURPOSE: We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy. PATIENTS AND METHODS: Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92-13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis. RESULTS: The mean (+/- SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% +/- 3.4% and 81.5% +/- 2.2%, respectively, at 5. 5 years after diagnosis. EFS rates by risk category were similar (60. 2% +/- 6.0% for standard risk, 57.7% +/- 5.6% for high risk, and 62. 5% +/- 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% +/- 2.7%, 80.0% +/- 4.1%, and 72.1% +/- 4.5%, respectively, P <.0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% +/- 7. 9% (standard risk), 42.6% +/- 8.1% (high risk), and 9.6% +/- 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important. CONCLUSION: Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.
Publication Types: Clinical Trial
PMID: 10735899 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 2000 Mar;25(6):599-603 Related Articles, Books, LinkOut
Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission - long-term follow-up.
Comment in: Bone Marrow Transplant. 2000 Nov;26(10):1136-7.
Vaidya SJ, Atra A, Bahl S, Pinkerton CR, Calvagna V, Horton C, Milan S, Shepherd V, Brain C, Treleaven J, Powles R, Tait D, Meller ST.
Paediatric Oncology, The Royal Marsden NHS Trust, Sutton, UK.
From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.
Publication Types: Clinical Trial
PMID: 10734293 [PubMed - indexed for MEDLINE]
J Clin Oncol 2000 Feb;18(4):813-23 Related Articles, Links
Racial differences in the survival of childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.
Comment in: J Clin Oncol. 2000 Jun;18(11):2349-51.
Pollock BH, DeBaun MR, Camitta BM, Shuster JJ, Ravindranath Y, Pullen DJ, Land VJ, Mahoney DH Jr, Lauer SJ, Murphy SB.
University of Florida, and Pediatric Oncology Group Statistical Office, Gainesville, FL, USA. brad@pog.ufl.edu
PURPOSE: We conducted a historic cohort study to test the hypothesis that, after adjustment for biologic factors, African-American (AA) children and Spanish surname (SS) children with newly diagnosed B-precursor acute lymphoblastic leukemia had lower survival than did comparable white children. PATIENTS AND METHODS: From 1981 to 1994, 4,061 white, 518 AA, and 507 SS children aged 1 to 20 years were treated on three successive Pediatric Oncology Group multicenter randomized clinical trials. RESULTS: AA and SS patients were more likely to have adverse prognostic features at diagnosis and lower survival than were white patients. The 5-year cumulative survival rates were (probability +/- SE) 81.9% +/- 0.6%, 68.6% +/- 2.1%, and 74.9% +/- 2.0% for white, AA, and SS children, respectively. Adjusting for age, leukocyte count, sex, era of treatment, and leukemia blast cell ploidy, we found that AA children had a 42% excess mortality rate compared with white children (proportional hazards ratio [PHR] = 1.42; 95% confidence interval [CI], 1.12 to 1. 80), and SS children had a 33% excess mortality rate compared with white children (PHR = 1.33; 95% CI, 1.19 to 1.49). CONCLUSION: Clinical presentation, tumor biology, and deviations from prescribed therapy did not explain the differences in survival and event-free survival that we observed, although differences seem to be diminishing over time with improvements in therapy. The disparity in outcome for AA and SS children is most likely related to variations in chemotherapeutic response to therapy and not to compliance. Further improvements in outcome may require individualized dosing based on specific pharmacogenetic profiles, especially for AA and SS children.
Publication Types: Clinical Trial Multicenter Study Randomized Controlled Trial
PMID: 10673523 [PubMed - indexed for MEDLINE]
Gan To Kagaku Ryoho 2000 Jan;27(1):99-102
[Syndrome of inappropriate secretion of antidiuretic hormone in a patient with myeloid antigen positive acute lymphoblastic leukemia after systemic chemotherapy including vincristine]
[Article in Japanese]
Yoshida M, Ogawa K, Sakamoto H, Motomura S, Ishigatsubo Y.
Dept. of Collagen Disease and Hematology, Fujisawa City Hospital.
We report a case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after the patient had received several anti-cancer drugs, including vincristine (VCR), in a patient with myeloid antigen positive acute lymphoblastic leukemia (My(+)-ALL). A 53-year-old woman presented at the hospital complaining of high-grade fever and general lassitude. Further examination revealed that she had My(+)-ALL. On admission, she was treated with anti-cancer drugs, including VCR. On day 24, after the first administration of VCR, a conscious disturbance suddenly occurred and she was diagnosed with SIADH. A plain head CT scan showed a low density lesion through the gray matter to the white matter in the bilateral occipital lobe, as well as diffuse swelling of the cerebrum. This was not seen on the follow up CT scan, and we concluded that it had been a transient abnormal finding due to SIADH. She achieved complete remission after induction chemotherapy and 3 added courses of consolidation chemotherapy. VCR was also administered 4 times in the second consolidation chemotherapy, but hyponatremia did not occur. This case suggests that a head CT scan is a useful procedure for the diagnosis and monitoring of SIADH, and that VCR may still be used in a patient who has suffered from VCR-induced SIADH.
PMID: 10660739 [PubMed - indexed for MEDLINE]
Br J Cancer 2000 Jan;82(1):234-40 Related Articles, Books, LinkOut
Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia.
Neglia JP, Linet MS, Shu XO, Severson RK, Potter JD, Mertens AC, Wen W, Kersey JH, Robison LL.
Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, USA.
To investigate if decreased exposure to common childhood infections is associated with risk of childhood acute lymphoblastic leukaemia (ALL) we conducted a case-control study of 1842 newly diagnosed and immunophenotypically defined cases of ALL under age 15, and 1986 matched controls in the US. Data regarding day care, sibship size and common childhood infections were obtained through parental interviews. Data were analysed stratified by leukaemia lineage and separately for 'common' childhood ALL (age 2-5 years, CD19, CD10-positive). Neither attendance at day care nor time at day care was associated with risk of ALL overall or 'common' ALL. Ear infections during infancy were less common among cases, with odds ratios of 0.86, 0.83, 0.71 and 0.69 for 1, 2-4, 5+ episodes, and continuous infections respectively (trend P = 0.026). No effect of sibship size or birth interval was seen. With one exception (ear infections), these data do not support the hypothesis that a decrease in the occurrence of common childhood infection increases risk of ALL.
PMID: 10638995 [PubMed - indexed for MEDLINE]
J Exp Clin Cancer Res 1999 Sep;18(3):417-24 Related Articles, Books, LinkOut
Delayed cytotoxicity of 6-mercaptopurine is compatible with mitotic death caused by DNA damage due to incorporation of 6-thioguanine into DNA as 6-thioguanine nucleotide.
Inamochi H, Higashigawa M, Shimono Y, Nagata T, Cao DC, Mao XY, M'soka T, Hori H, Kawasaki H, Sakurai M.
Dept. of Pediatrics, Mie University School of Medicine, Tsu-city, Japan.
Many protocol studies have shown that low dose 6-mercaptopurine (6MP) in maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL) can be utilized to cure the disease. Mitotic or reproductive cell death has been recognized after G2 arrest when cells are treated with antitumor agents. The precise mechanism of mode of action of 6MP still remains unclear. We found delayed cytotoxic effect of 6MP in P388 murine leukemic cells. Morphological study showed that 6MP induced delayed death was characterized by an enlargement of cell size and multinucleated nuclei. Agarose gel electrophoresis of fragmented DNA from cells treated with 6MP showed the typical ladder pattern. These findings were compatible with mitotic death. Our results make us hypothesize that the delayed cytotoxicity of 6MP is one of the drug induced mitotic deaths caused by DNA damage due to incorporation of 6-thioguanine (6TG) into DNA as thioguanine nucleotide (TGN). Mitotic death may be a mechanism for killing the cycling cells from residual leukemic cells in G0 or long G1 phases in the treatment of childhood ALL.
PMID: 10606189 [PubMed - indexed for MEDLINE]
J Pediatr Hematol Oncol 1999 Nov-Dec;21(6):501-8
Infections in children with cancer: a continued need for the comprehensive physical examination.
Auletta JJ, O'Riordan MA, Nieder ML.
Department of Pediatrics, CWRU School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio 44106, USA.
Few studies have addressed the influence of profound myelosuppressive therapy in contemporary protocols on infectious morbidity in pediatric oncology patients. This study evaluates the types of infections and the methods used to diagnose infection in patients enrolled in current Children's Cancer Group (CCG) protocols. Data were collected on patients enrolled in CCG protocols from January 1, 1992, through December 31, 1995. Of the 155 protocol patients, 102 were completely evaluated and had data collected through August 1, 1996. Patients were divided into two diagnosis groups: leukemia/lymphoma (N = 51) and solid tumor (N = 51). Eighty-five (83%) patients had documented infections and 17 (17%) did not. Overall, 96 (94%) patients had in-dwelling central venous catheters. Twelve categories of infection were identified. Data were analyzed for age, gender, diagnosis, neutropenia, organism, and disease state (primary active, recurrent active, primary remission, and secondary remission). Statistical comparisons were made only on rates, whereas descriptive comparisons were given for numbers of infections and organisms. The infection rates for patients with active disease were 1.01 and 1.15 per 100 patient days (primary versus recurrent) and 0.59 and 0.38 per 100 patient days for patients with disease in remission (primary versus secondary). Diagnosis-group infection rates were 0.66 and 0.68 per 100 patient days for patients with solid tumors and leukemia/lymphoma, respectively. Three hundred thirty infections, including 19 polymicrobial infections, were recorded. The three most common types of infection were otitis media, septicemia, and urinary tract infection. More infections were associated with an age at diagnosis of less than 3 years, a leukemia/lymphoma diagnosis in remission, and an absolute neutrophil count >500 cells/microL. One hundred ninety-four organisms were isolated from 330 infections. Gram-positive organisms (n = 74) such as coagulase-negative Staphylococci (n = 38) predominated over gram-negative organisms (n = 63) for all infectious categories. Specifically, gram-positive organisms (n = 39) were isolated more often from blood cultures than were gram-negative organisms (n = 27). The overall mortality for patients was 36%. Seven of the 37 (19%) patient deaths were attributed to infection. These patients predominantly were girls with neutropenia and leukemia/ lymphoma in active disease who died of gram-negative sepsis. Infections with gram-positive organisms continue to be major causes of morbidity in pediatric oncology patients receiving contemporary CCG protocols. However, infection-related mortality, especially with gram-negative organisms, occurs less frequently than does malignancy-related mortality. Common childhood infections (such as otitis media) seem equally as prevalent as bacteremia in pediatric oncology patients. Thus, a comprehensive physical examination is as imperative as the microbiologic evaluation in diagnosing infection in this patient population.
Publication Types: Multicenter Study
PMID: 10598661 [PubMed - indexed for MEDLINE]
J Natl Cancer Inst 1999 Dec 1;91(23):2001-8 Related Articles, Books, LinkOut
Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus.
Comment in: J Natl Cancer Inst. 1999 Dec 1;91(23):1983-5.
Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. mary.relling@stjude.org
BACKGROUND: Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes. METHODS: We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided. RESULTS: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8) erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/-1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average weekly prescribed dose of 6-mercaptopurine (P=.49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P<.001), with average (+/- standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/-160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations. CONCLUSION: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.
Publication Types: Clinical Trial Randomized Controlled Trial
PMID: 10580024 [PubMed - indexed for MEDLINE]
Syndrome of recurrent increased secretion of antidiuretic hormone following multiple doses of vincristine.
Stuart MJ, Cuaso C, Miller M, Oski FA.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been recognized to occur following treatment with vincristine. None of the reports have provided information regarding its potential for recurrence on further challenge with vincristine (VCR), an agent generally required for repeated use in patients with malignancies. Symptomatic hyponatremia and SIADH that occurred 8 days following administration of VCR in a child with acute lymphatic leukemia was documented with specific radioimmunoassay of urinary ADH levels. The further occurrence of recurrent elevations in ADH excretion 8-10 days following repeated treatment with VCR was also observed. However, SIADH was prevented by prophylactic rigorous fluid restriction. The occurrence of SIADH following VCR therefore does not preclude the further safe usage of this drug.
PMID: 1054263 [PubMed - indexed for MEDLINE]
Gen Pharmacol 1999 Oct;33(4):341-6 Related Articles, Links
The interaction of 6-mercaptopurine (6-MP) and methotrexate (MTX).
Giverhaug T, Loennechen T, Aarbakke J.
Department of Pharmacology, Institute of Pharmacy, University of Tromso, Norway. trudeg@farmasi.uit.no
The antimetabolites 6-mercaptopurine (6-MP) and methotrexate (MTX) are the cornerstones in the maintenance treatment of children's acute lymphoblastic leukemia (ALL). The biochemical mechanisms underlying the increased therapeutic efficacy of the combination of these drugs have not yet been elucidated. However, both drugs interact with important pathways. such as purine de novo synthesis (PDNS), purine salvage, and methylation reactions. A review of the mechanistic aspects of the interactions between 6-MP and MTX is given.
Publication Types: Review Review, Tutorial
PMID: 10523073 [PubMed - indexed for MEDLINE]
Adv Exp Med Biol 1999;457:621-9 Related Articles, Books, LinkOut
The three asparaginases. Comparative pharmacology and optimal use in childhood leukemia.
Asselin BL.
Children's Hospital at Strong, University of Rochester Medical Center, New York 14642, USA. basselin@mail.urmc.rochester.edu
Asparaginase (ASP) is a standard component of the antileukemia armamentarium. There are currently 3 preparations of asparaginase available: (1) E. coli (ASP, Elspar); (2) the enzyme derived from Erwinia chrysanthemi (ERW, Erwinase); (3) pegaspargase (PEG, Oncaspar), the E. coli enzyme modified by covalent attachment of polyethylene glycol. This report describes the findings of 3 pharmacologic end points: ASP enzyme activity in patients' sera, depletion of asparagine and the development of anti-ASP antibodies. Pharmacokinetics and pharmacodynamic studies in a group of naive children with newly diagnosed ALL demonstrate a significant difference in apparent half-life (1.24 days E. coli vs. 0.65 ERW vs. 5.73 PEG; p < 0.001) and days of asparagine depletion (14-23 E. coli vs. 7-15 ERW vs. 26-34 PEG; p < 0.01) for the 3 different preparations. Data from Pediatric Oncology Group (POG) Protocol #8866 show that high antibody levels correlated with rapid ASP clearance and a significantly lower response rate (NR = 26% vs. CR + PR + 64%). The pharmacologic characteristics of ASP in terms of clearance of enzyme activity and ability to deplete serum asparagine was dependent upon the nature of the enzyme and are significantly altered in patients who develop anti-ASP antibodies regardless of their clinical status. In addition, these data demonstrate that ASP pharmacokinetics are directly related to its anti-leukemic effect. In order to maximize the therapeutic benefits of ASP, the optimal dose and schedule of treatment should be determined based on pharmacologic testing rather than by clinical criteria alone. Future studies will focus on the role of "silent hypersensitivity" as a mechanism of resistance to ASP and strategies to maximize the therapeutic efficacy of ASP as part of ALL therapy.
PMID: 10500842 [PubMed - indexed for MEDLINE]
Adv Exp Med Biol 1999;457:297-303 Related Articles, Books, LinkOut
Apoptosis corrected proliferation fraction in childhood ALL is related to karyotype.
Ball LM, Pyesmany AF, Yhap M, Lannon CL, Henry M, Laybolt K, Riddell DC, van Velzen D.
Department of Pathology, Dalhousie University, IWK Grace Health Centre, Halifax, Nova Scotia, Canada.
BACKGROUND: Tumour doubling time, a parameter in drug sensitivity testing, reflects both cell proliferation and apoptosis. Variable apoptosis fractions may explain the poor correlation of S-fraction and drug response. DNA aneuploidy (reflecting intrinsic DNA instability) may, by increasing apoptosis, affect drug response. AIM: To assess the relationship between apoptosis corrected proliferation fraction and DNA ploidy in childhood acute lymphoblastic leukemia (ALL). METHODS: 1.3.1. Study Groups. Thirty two consecutive, unselected diagnostic cases of childhood ALL were included in the study. 1.3.2. Karyotype. A normal karyotype was found in 15 cases (7M, 8F, age 8 m-12 yrs); high hyperdiploid aneuploidy (DNA index > 1.5) was found in 7 patients (1M, 7F, age 3-12 yrs) whereas complex karyotypic anomalies, but with 2n or near 2n DNA were present in 10 patients (7M, 3F, age 1 y 7 m -16 yrs). 1.3.3. Proliferation Fraction Assessment. Immunocytochemical demonstration of S-phase associated nuclear expression of the Ki-67 antigen (MM1, NovaCastra, UK). 1.3.4. Apoptosis Fraction Assessment. Binding of a horse radish peroxidase labelled DNA probe for the 3'-OH ends of apoptosis derived Klenow fragments (Frag-EL, CalBiochem, USA). 1.3.5. Quantitation. Computer assisted image analysis (Quantimet 570C), of 10 systematically random fields of a minimum of 20 nuclei each. A nuclear size bias correcting counting frame and rule were used to correct for cell proliferation associated nuclear volume increase and for the expected nuclear volume reduction resulting from apoptosis. RESULTS: Corrected for apoptosis, proliferation fraction was highest (mean 57.5%, range 1-100) in poor prognosis, complex karyotype anomalies. Good prognosis, high hyper diploidy showed significantly lower proliferation rates (mean 24.7%, range 12-40) (p < 0.01, t-test). CONCLUSION: Apoptosis corrected cell proliferation rate in childhood ALL is not independent of karyotype abnormality which may partly explain a relation to therapy response and prognosis.
PMID: 10500805 [PubMed - indexed for MEDLINE]
J Clin Oncol 1999 Jan;17(1):197-207 Related Articles, Books, LinkOut
Allogeneic bone marrow transplantation versus chemotherapy for the treatment of childhood acute lymphoblastic leukemia in second remission: a single-institution study.
Boulad F, Steinherz P, Reyes B, Heller G, Gillio AP, Small TN, Brochstein JA, Kernan NA, O'Reilly RJ.
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. bouladf@mskcc.org
PURPOSE: A retrospective analysis of the treatment of childhood acute lymphoblastic leukemia (ALL) in second remission (CR2) was undertaken at our institution to compare the outcome and prognostic factors of patients treated with chemotherapy or allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: Seventy-five children who suffered a medullary relapse and achieved a second remission were treated with either an unmodified allogeneic HLA-matched sibling BMT after hyperfractionated total body irradiation (TBI) and cyclophosphamide (n = 38) or chemotherapy according to institutional chemotherapy protocols (n = 37). To avoid the bias of survival from the attainment of second remission in favor of BMT, the final comparative statistical analysis used the landmark approach and comprised 37 and 29 patients from the BMT and chemotherapy groups, respectively RESULTS: The disease-free survival (DFS) rate was 62% and 26% at 5 years, respectively, for the BMT and the chemotherapy groups (P = .03), with relapse rates of 19% and 67%, respectively, for these two groups (P = .01). There was an overall advantage for the BMT therapeutic approach, as compared with chemotherapy, for patients with ALL in CR2 (1) for patients with a WBC count (at diagnosis) of 20 x 10(9)/L or higher (DFS, 40% v 0%) and those with a WBC count of less than 20 x 10(9)/L (DFS, 73% v35%), (2) for patients whose duration of CR1 was less than 24 months (DFS 48% v 9%) and for patients whose duration of CR1 was 24 months or longer (DFS, 81% v 37%) and (3) for patients who were initially treated with intensive regimens incorporating more than five chemotherapy agents (DFS, 57% v 20%) and for patients treated with five agents or fewer (DFS, 72% v 32%). CONCLUSION: In our single-institution series, unmodified HLA-matched allogeneic sibling transplants using hyperfractionated TBI and cyclophosphamide for patients with ALL in CR2 have resulted in superior outcome with a significantly improved probability of DFS and a lower relapse rate, as compared with those for patients treated with chemotherapy, regardless of the duration of first remission, the disease characteristics at diagnosis, or the intensity of prior treatment during first remission.
PMID: 10458234 [PubMed - indexed for MEDLINE]
Xenobiotica 1999 Jun;29(6):615-28 Related Articles, Books, LinkOut
In vitro metabolism of 6-mercaptopurine by human liver cytosol.
Rowland K, Lennard L, Lilleyman JS.
University of Sheffield, Division of Clinical Sciences (CSUH), Royal Hallamshire Hospital, UK.
1. The aim of this study was to investigate 6-mercaptopurine (6MP) metabolism by human liver cytosol in vitro. 2. Cytosol was prepared from seven human livers (A-G). A single cytosol (C) was used to optimize incubation conditions. 3. Cytosols A-G were incubated with 6MP at 2, 10 and 500 microM for two fixed times (5 and 48 h). Parent drug, thiopurine and thionucleotide metabolites were quantitated by high performance liquid chromatography at all time points. 4. At 5 and 48 h the 2 microM and 10 microM 6MP incubations contained both 6MP and its initial nucleotide metabolite, thioinosine 5'-monophosphate (TIMP). In addition, the 10 microM 6MP 48 h incubates contained small amounts of 6-thioguanine (6TG, median 0.12 microM). At 500 microM 6MP all seven liver incubates produced a range of metabolites. At 48 h these included thiouric acid, 8-hydroxy-6-mercaptopurine and 6-methylmercaptopurine (median 31, 19.5 and 8.8 microM respectively), with TIMP, 6TG, thioxanthine and thioxanthine nucleotide at median concentrations of 61, 0.79, 2.11 and 0.80 microM respectively. Thioguanine nucleotides, major metabolites measured in vivo, were not detected. 5. These results indicate that the human liver 6MP metabolic profile is dependent upon drug concentration.
PMID: 10426560 [PubMed - indexed for MEDLINE]
Br J Cancer 1999 Jul;80(9):1483-9 Related Articles, Books, LinkOut
Infections, vaccinations, and the risk of childhood leukaemia.
Dockerty JD, Skegg DC, Elwood JM, Herbison GP, Becroft DM, Lewis ME.
Childhood Cancer Research Group, University of Oxford, UK.
A nationwide case-control study was conducted in New Zealand, to test hypotheses about the role of infections in the aetiology of childhood leukaemia. Children aged 0-14 years with leukaemia were matched on age and sex to controls selected from birth records. Case ascertainment was virtually complete and 121 (92%) of 131 eligible case families took part. The participation rate among the 303 first-choice eligible controls was 69%. Home interviews and serological tests were conducted. Adjusted relative risks were estimated by logistic regression. There was an increased risk of leukaemia in relation to reported influenza infection of the child during the first year of life (adjusted odds ratio 6.8, 95% confidence interval 1.8-25.7). This could be a chance finding due to multiple comparisons, and it should be tested elsewhere. Some key variables relevant to Greaves' hypothesis were not associated with B-cell precursor acute lymphoblastic leukaemia (numbers of infections and vaccinations, firstborn status, attendance at preschool groups), although a small effect could not be ruled out with a study of this size. Leukaemia risk was higher among children in poorer social circumstances, and this was true for all eligible children as well as for the participants.
PMID: 10424755 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1999 Jun;23(12):1257-60 Related Articles, Books, LinkOut
Allogeneic bone marrow transplantation vs chemotherapy for the treatment of childhood acute lymphoblastic leukaemia in second complete remission (revisited 10 years on).
Torres A, Alvarez MA, Sanchez J, Flores R, Martinez F, Gomez P, Rojas R, Herrera C, Garcia JM, Andres P, Velasco F, Serrano J, Roman J, Rodriguez A, Martin C, Tabares S, Rodriguez JM, Parody R, Plaza E, Leon A, Romero R, Jean-Paul E, Prados D, Aljama R, Fernandez A.
Department of Haematology, University Hospital Reina Sofia Cordoba, Spain.
In 1989 we carried out a trial comparing allogeneic BMT to chemotherapy (CT) in 76 children with relapsed acute lymphoblastic leukaemia (ALL). Ten years on we have clinically revised outcome to firmly establish the role of each treatment, to analyse the importance of length of first remission and to provide long-term actuarial results for disease-free survival (DFS) and relapse rate in each group. For 21 patients within the transplantation group, probability of DFS and relapse are 42.8 +/- 10.8% and 40.2 +/- 11.7% (s.e.), respectively. In the chemotherapy group, probability of DFS is 10.0 +/- 4.74% (P = 0.001) and probability of relapse 87.5 +/- 5.2% (P = 0.0004). These results strongly reflect those at initial analysis, confirming a key role of BMT in the management of ALL in second remission. Moreover, on univariate analysis only two factors influenced DFS: treatment group and length of first complete remission (less or more than 30 months from first CR). Thus, it seems clear that the best therapeutic option in early relapse is BMT, whereas DFS in late relapse is at the limit of significance (P = 0.07), with a higher relapse rate in the CT group. Although encouraging results using intensified rotational combination chemotherapy have been published, prospective randomised studies are needed to assess with certainty the best therapeutic option in these patients.
Publication Types: Clinical Trial
PMID: 10414912 [PubMed - indexed for MEDLINE]
Bone Marrow Transplant 1999 Mar;23(6):555-60 Related Articles, Books, LinkOut
Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries.
Schroeder H, Gustafsson G, Saarinen-Pihkala UM, Glomstein A, Jonmundsson G, Nysom K, Ringden O, Mellander L.
Department of Pediatrics, University Hospital of Aarhus, Denmark.
This study compares allogeneic BMT with conventional chemotherapy for childhood ALL in second remission. Seventy-five children were transplanted between July 1981 and December 1995. For each patient two control patients matching the following criteria were selected from the Nordic database of ALL: (1) time of diagnosis, (2) T vs. non-T ALL, (3) site of relapse, (4) initial risk group, (5) sex and (6) relapse < or > or =6 months after cessation of therapy. The minimal time of follow-up was 24 months. Mortality rate in CR2, leukemic relapse rate and the proportion in continued second remission were 16/75 (21%), 22/75 (29%) and 37/75 (50%), respectively. P2.-EFS for the BMT group was significantly better than that for the control group (0.40 vs. 0.23, P = 0.02). Children transplanted for bone marrow relapses in particular had a higher P2.-EFS (0.35 vs. 0.15 for the control group, P<0.01). Also, children grafted for early BM relapses had a higher P2.-EFS (0.32 vs. 0.11 for the control group P = 0.01). The outcome was similar when children were transplanted after early or late relapse. Also, there was no difference in outcome between the BMT and the chemotherapy group for children with late relapses. We conclude that allogeneic BMT with an HLA-identical sibling donor or other family donor should be performed in children relapsing in bone marrow during therapy or within 6 months of discontinuing therapy.
PMID: 10217185 [PubMed - indexed for MEDLINE]
Blood 1999 May 1;93(9):2817-23 Related Articles, Links
Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia.
Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE.
Departments of Pharmaceutical Sciences, Hematology/Oncology, and Biostatistics and Epidemiology, St Jude Children's Research Hospital, Memphis, TN, USA.
6-Mercaptopurine (6MP) and methotrexate are the backbone of continuation therapy for childhood acute lymphoblastic leukemia (ALL). In studies of oral 6MP and methotrexate, indices of chronic systemic exposure to active metabolites of these agents, namely, red blood cell (RBC) concentrations of methotrexate polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) have positively correlated with event-free survival (EFS). Our objective was to evaluate whether MTXPGs, TGNs, and the dose intensity of administered methotrexate and 6MP were prognostic in the setting of a treatment protocol in which all treatment was coordinated through a single center, and the weekly doses of methotrexate were given parenterally. On protocol Total XII, 182 children achieved remission and received weekly methotrexate 40 mg/m2 parenterally and daily oral 6MP, interrupted every 6 weeks during the first year by pulse chemotherapy. A total of 709 TGN, 418 MTX-PG, and 267 thiopurine methyltransferase (TPMT) measurements, along with complete dose intensity information (dose received divided by protocol dose per week) for 19,046 weeks of 6MP and methotrexate, were analyzed. In univariate analyses, only higher dose intensity of 6MP and of weekly methotrexate were significant predictors of overall EFS (P =.006 and .039, respectively). The occurrence of neutropenia was associated with worse outcome (P =.040). In a multivariate analysis, only higher dose intensity of 6MP (P =.020) was a significant predictor of EFS, with lower TPMT activity (P =.096) tending to associate with better outcome. 6MP dose intensity was also associated (P =.007) with EFS among patients with homozygous wild-type TPMT phenotype. Lower 6MP dose intensity was primarily due to missed weeks of therapy and not to reductions in daily dose. We conclude that increased dose-intensity of oral 6MP is an important determinant of EFS in ALL, particularly among those children with a homozygous wild-type TPMT phenotype. However, increasing intensity of therapy such that neutropenia precludes chemotherapy administration may be counterproductive.
Publication Types: Clinical Trial
PMID: 10216075 [PubMed - indexed for MEDLINE]
Cancer Genet Cytogenet. 1999 Apr;110(1):44-53.
Clinical significance of cytogenetic findings at diagnosis and in remission in childhood and adult acute lymphoblastic leukemia: experience from India.
Amare P, Gladstone B, Varghese C, Pai S, Advani S.
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
We report cytogenetic findings in 114 patients of acute lymphoblastic leukemia (ALL), which includes 78 children (< or = 15 years) and 36 adults (16-60 years). Chromosome aberrations were detected in 109 (95%) cases. A lower frequency of hyperdiploidy (15%) in children and a higher frequency of hypodiploidy both in children (38.4%) and adults (44.4%) were found, in contrast to literature. Translocations were detected in one third of adult and pediatric cases. The incidence of t(9;22) was comparatively low in adults (7.7%). Frequency of t(1:19) was also low in overall ALL cases. Various other recurrent abnormalities such as del(6q), abn(11q23), i(9p), abn(12q13), del(7q), and i(17q) were seen in our cases; a striking difference in the incidence of del(6q) (41%) and abn(11q23) (30%) was found in our series versus reported literature. Ploidy distribution indicated association of pseudo- and hypodiploidy with B-lineage, and hypodiploidy with T-lineage in children. The occurrence of del(6q) was more frequent in pediatric ALL with highly aberrant pattern and also with lymphadenopathy. Abn(11q23) was found to be early-B and pre-B specific. Kaplan-Meier analysis of overall survival revealed prognostic value of sex, FAB, immunophenotype, and cytogenetic findings. Females and T-ALL patients had a better prognosis, whereas males and B-ALL patients had poor outcome in overall and pediatric age groups. Prognostic evaluation of cytogenetics indicated translocations as an independent high-risk predictor in childhood (P < 0.008) and adult ALL (P < 0.01). Childhood ALL with t(8;14) and t(4;11) and adults with t(9;22) had poor survival. Cytogenetics of remission marrows demonstrated disappearance of abnormal clones in 31.4%, and expansion in normal clones in 50% of patients. Persistence of original clones and development of new clones were observed in 20% and 33% of patients, respectively; whereas karyotype evolution was identified in 10% of patients. The prognostic significance of cytogenetic findings at diagnosis, and differential cytogenetic response in so-called clinical remission in our study indicated the utmost need for more intensive therapy for eradication of resistant clones, and necessity of sequential cytogenetic follow-up in these patients for identification of minimal residual disease.
PMID: 10198622 [PubMed - indexed for MEDLINE]
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