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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

[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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]