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]

New treatment strategies in childhood acute lymphoblastic leukaemia.

Schrappe M, Beier R, Burger B.

Department of Paediatric Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

Today, 80% of paediatric patients with acute lymphoblastic leukaemia (ALL) can be cured. To reduce the rate of relapses, but also to limit treatment morbidity, risk-adapted treatment has been attempted after identifying the most specific prognostic factors. In addition to clinical factors (e.g. age, WBC), the immunophenotype and cytogenetic results, the early in vivo treatment response as determined by cytology had evolved as the most important predictor for relapse. The lack of specificity of most prognostic factors stimulated the search for more relevant parameters. Detection of minimal residual disease (MRD) at defined time points by identifying clone-specific T-cell receptor- (TCR) or immunoglobulin (Ig) gene rearrangements can provide new, highly specific prognostic information which allows definition of new risk groups. The high sensitivity of the method is a prerequisite for applying treatment reduction in patients with fast clearance of leukaemia. Persistent disease is an indication for treatment modification and intensification. Logistics and quality control are demanding but are essential for the introduction of this new technology into clinical practice.

PMID: 12617873 [PubMed - in process]

Flow cytometric follow-up of minimal residual disease in bone marrow gives prognostic information in children with acute lymphoblastic leukemia.

Bjorklund E, Mazur J, Soderhall S, Porwit-MacDonald A.

Department of Pathology, Karolinska Hospital and Institutet, Stockholm, Sweden.

Using flow cytometry (FC) and live gate (LG) analysis we have followed levels of minimal residual disease (MRD) in the bone marrow (BM) of 70 consecutive patients with childhood acute lymphoblastic leukemia (59 B precursor ALL and 11 T-ALL) treated according to the Nordic (NOPHO-92) protocols. Thorough studies of B and T cell antigen expression patterns in normal BM performed during BIOMED 1 Concerted Action on MRD, made it possible to tailor individual protocols of marker combinations for follow-up in 97% of patients. In 12% of LG analyses, the numbers of cells exceeded 10(6) and in 82% exceeded 10(5), giving the sensitivity level of MRD detection 10(-5) and 10(-4), respectively. The median follow-up time was 53 months. Patients with MRD levels >/=0.01% at follow-up time-points during and after first induction, and at the end of treatment had significantly lower disease-free survival by comparison to patients with MRD values <0.01%. Seven of nine patient with recurrence in the BM showed under treatment persisting MRD levels >/=0.01% of BM cells. This was also observed in another two patients with infant leukemia who relapsed. In conclusion, the investigation of levels and the dynamics of MRD by sensitive and quantitative FC can provide a basis for further clinical studies for at least upgrading of therapy.Leukemia (2003) 17, 138-148. doi:10.1038/sj.leu.2402736

PMID: 12529671 [PubMed - in process]

Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia.

Coustan-Smith E, Sancho J, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, Pui CH, Campana D.

Departments of Hematology-Oncology, Biostatistics, and Pathology, St Jude Children's Research Hospital, and the University of Tennessee, Memphis.

In children with acute lymphoblastic leukemia (ALL), response to treatment is assessed by bone marrow aspiration. We investigated whether minimal residual disease (MRD) can be effectively monitored in peripheral blood. We used flow cytometric techniques capable of detecting 1 leukemic cell among 10 000 or more normal cells to compare MRD measurements in 718 pairs of bone marrow and peripheral blood samples collected from 226 children during treatment for newly diagnosed ALL. MRD was detected in marrow and blood in 72 pairs and in marrow but not in blood in 67 pairs; it was undetectable in the remaining 579 pairs. Remarkably, findings in marrow and blood were completely concordant in the 150 paired samples from patients with T-lineage ALL: for each of the 35 positive marrow samples, the corresponding blood sample was positive. In B-lineage ALL, however, only 37 of 104 positive marrow samples had a corresponding positive blood sample. Notably, peripheral blood MRD in these patients was associated with a very high risk for disease recurrence. The 4-year cumulative incidence of relapse in patients with B-lineage ALL was 80.0% +/- 24.9% for those who had peripheral blood MRD at the end of remission induction therapy but only 13.3% +/- 9.1% for those with MRD confined to the marrow (P =.007). These results indicate that peripheral blood may be used to monitor MRD in patients with T-lineage ALL and that peripheral blood MRD may provide strong prognostic information in patients with B-lineage ALL. (Blood. 2002;100:2399-2402)

PMID: 12239148 [PubMed - in process]

Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia.

Coustan-Smith E, Sancho J, Behm FG, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, Pui CH, Campana D.

Department of Hematology-Oncology, St Jude Children's Research Hospital and the University of Tennessee, Memphis, TN 38105, USA.

Early clearance of leukemic cells is a favorable prognostic indicator in childhood acute lymphoblastic leukemia (ALL). However, identification of residual leukemic cells by their morphologic features is subjective and lacks sensitivity. To improve estimates of leukemia clearance, we applied flow cytometric techniques capable of detecting 1 leukemic cell in 10,000 or more normal cells and prospectively measured residual leukemia in bone marrow samples collected on day 19 of remission-induction chemotherapy from 248 children with newly diagnosed ALL. In 134 samples (54.0%), we identified at least 0.01% leukemic cells (0.01%-< 0.1% in 51 samples [20.6%], 0.1%-< 1% in 36 [14.5%], and > or = 1% in 47 [19.0%]). Among 110 children treated within a single chemotherapy program, the 5-year mean +/- SE cumulative incidence of relapse or failure to achieve remission was 32.2% +/- 6.5% for the 59 patients with 0.01% residual leukemic cells or greater on day 19 and 6.0% +/- 3.4% for the 51 patients with less than 0.01% leukemic cells (P <.001). The prognostic value of day-19 bone marrow status defined by flow cytometry was superior to that defined by morphologic studies and remained significant after adjustment for other clinical and biologic variables. Lack of detectable leukemic cells on day 19 was more closely associated with relapse-free survival than was lack of detectable residual disease at the end of remission induction (day 46). Thus, approximately half of the children with ALL achieve profound clearance of leukemic cells after 2 to 3 weeks of remission-induction chemotherapy, and these patients have an excellent treatment outcome.

PMID: 12070008 [PubMed - indexed for MEDLINE]

Treatment results of childhood acute lymphoblastic leukemia in Austria--a report of 20 years' experience.

Comment in: Wien Klin Wochenschr. 2002 Feb 28;114(4):141-2.

Attarbaschi A, Mann G, Dworzak M, Urban C, Fink FM, Dieckmann K, Riehm H, Gadner H; Austrian Cooperative Study Group.

St. Anna Children's Hospital, Vienna.

Between 1981 and 1999, 890 Austrian children with acute lymphoblastic leukemia (ALL) were treated in 5 consecutive trials using protocols from the Berlin-Frankfurt-Munster (BFM) Group. In the trials BFM-A (Austria) 81 and ALL A 84, treatment stratification was performed using a risk factor, which was calculated from the initial peripheral blast cell count, and size of liver and spleen. In the following studies (BFM-A 86, 90 and 95) early response to a 7-day systemic mono-therapy with prednisone (as measured by the peripheral blast cell count) was used as an overriding stratification factor; in order to reduce the need for cranial radiotherapy, all patients received high-dose methotrexate (5 g/m2) for preventive central nervous system treatment. Event-free survival (EFS) rates increased from study BFM-A 81 (n = 141, probability (p) of EFS: 59% +/- 4%) and study ALL A 84 (n = 127, pEFS: 67% +/- 4%) to 77% +/- 4% in trial BFM-A 86 (n = 142), 79% +/- 3% in trial BFM-A 90 (n = 256), and 84% +/- 3% in trial BFM-A 95 (n = 224). However, the prognosis for high-risk patients has not significantly improved within the last 20 years (pEFS: 50%). Furthermore, conventional risk factors such as leukocyte count and age at time of diagnosis, could not be used to indicate patients in the low and intermediate risk group who might eventually relapse. Thus, in trial BFM-A 2000, detection of minimal residual disease by polymerase chain reaction-based methods after 5 and 12 weeks of therapy was introduced for treatment stratification. Minimal residual disease was prospectively shown to predict relapses more precisely and, as a matter of fact, may allow a more exact definition of which patients are at risk and which patients belong to the subgroup with a good prognosis despite reduced treatment.

PMID: 12060981 [PubMed - indexed for MEDLINE]

Evidence that continued remission in patients treated for acute leukaemia is dependent upon autologous natural killer cells.

Lowdell MW, Craston R, Samuel D, Wood ME, O'Neill E, Saha V, Prentice HG.

Department of Haematology, Royal Free Campus, Royal Free and University College Medical School, London NW3 2PF, UK. m.lowdell@rfc.ucl.ac.uk

Although it has been known for more than 40 years that allogeneic immune responses cure leukaemias after bone marrow transplantation, autologous leukaemia-specific immunity remains controversial and its impact upon survival has not been established. Here we have tested 25 patients with de novo acute leukaemias, while in remission at completion of their anti-leukaemia therapy, for evidence of autologous cytolytic immunity to their leukaemic cells taken and cryopreserved at disease presentation. We have measured this degree of cell-mediated cytotoxicity in vitro and termed it "leukaemia cytolytic activity" (LCA). Patients whose disease ultimately relapsed had significantly lower LCA than those who remained in remission beyond 2 years (P < 0.001); the absence of LCA when in remission predicted subsequent relapse within 2 years with a sensitivity of 100% and specificity of 77%. LCA was mediated in vitro by CD56+/CD8alpha+/CD3- natural killer cells. We propose that it is this immune response, rather than the chemotherapy per se, which is responsible for continued remission and that measurement of LCA in patients at completion of therapy may be used as an indicator of risk of subsequent relapse. Patients lacking this response will require further treatment, either with an allogeneic donor transplant or an alternative immunotherapeutic strategy.

PMID: 12060116 [PubMed - in process]

Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial.

Duval M, Suciu S, Ferster A, Rialland X, Nelken B, Lutz P, Benoit Y, Robert A, Manel AM, Vilmer E, Otten J, Philippe N.

Service d'Hemato-Immunologie, Hopital Robert-Debre, Paris, France. michel.duval@umontreal.ca

Asparaginase is an enzyme used in the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in children. It has minimal bone marrow toxicity. Its major side effects are anaphylaxis, pancreatitis, diabetes, coagulation abnormalities, and thrombosis, especially intracranial. It is derived from 2 different sources: Escherichia coli and Erwinia chrysanthemi. Nonrandomized clinical studies have suggested a similar efficacy of these 2 types of asparaginases and a lower toxicity for Erwinia-asparaginase. The European Organisation for Research and Treatment of Cancer-Children's Leukemia Group (EORTC-CLG) 58881 trial randomized 700 children with acute lymphoblastic leukemia or lymphoblastic lymphoma to either E coli- or Erwinia-asparaginase at the same dosage of 10 000 IU/m(2) twice weekly to compare toxicity and efficacy. Coagulation abnormalities were more frequent in the E coli-asparaginase than in the Erwinia-asparaginase arm of the study (30.2% versus 11.9%, P <.0001). The incidence of other toxicity was not significantly different. In the Erwinia-asparaginase arm, more patients failed to achieve complete remission (4.9% versus 2.0%; P =.038) and the relapse rate was higher, leading to shorter event-free survival (hazard ratio,1.59; 95% CI, 1.23-2.06; P =.0004). The estimate of event-free survival rate (SE) at 6 years was 59.8% (2.6%) versus 73.4% (2.4%). Overall survival rate at 6 years was also lower in the Erwinia-asparaginase arm at 75.1% (2.3%) versus 83.9% (2.0%), P =.002. With the dose scheduling used in this protocol, E coli-asparaginase induced more coagulation abnormalities but was superior to Erwinia-asparaginase for the treatment of childhood lymphoid malignancies.

Publication Types: Clinical Trial Clinical Trial, Phase III Randomized Controlled Trial

PMID: 11929760 [PubMed - indexed for MEDLINE]

Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia.

Dworzak MN, Froschl G, Printz D, Mann G, Potschger U, Muhlegger N, Fritsch G, Gadner H; Austrian Berlin-Frankfurt-Munster Study Group.

Children's Cancer Research Institute, St Anna Kinderspital, Kinderspitalgasse 6, A-1090 Vienna, Austria. dworzak@ccri.univie.ac.at

Detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) predicts outcome. Previous studies were invariably based on relative quantification and did not investigate sample-inherent parameters that influence test accuracy, which makes comparisons and clinical conclusions cumbersome. Hence, we conducted a prospective, population-based MRD study in 108 sequentially recruited children with ALL uniformly treated with the ALL-Berlin-Frankfurt-Munster (ALL-BFM) 95 protocol in Austria (median follow-up of 40 months). Using sensitive, limited antibody panel flow cytometry applicable to 97% of patients, we investigated 329 bone marrow samples from 4 treatment time points. MRD was quantified by blast percentages among nucleated cells (NCs) and by absolute counts (per microliter). Covariables such as NC count, normal B cells, and an estimate of the test sensitivity were also recorded. Presence and distinct levels of MRD correlated with a high probability of early relapse at each of the time points studied. Sequential monitoring at day 33 and week 12 was most useful for predicting outcome independently from clinical risk groups: patients with persistent disease (> or =1 blast/microL) had a 100% probability of relapse, compared to 6% in all others. Absolute MRD quantification was more appropriate than relative, due to considerable variations in total NC counts between samples. Regeneration of normal immature B cells after periods of rest from treatment limited the test sensitivity. In conclusion, MRD detection by flow cytometry is a strong and independent outcome indicator in childhood ALL. Standardization regarding absolute quantification on the basis of NCs and assessment during periods of continuous treatment promise to increase the accuracy, simplicity, and cost efficiency of the approach.

PMID: 11877265 [PubMed - in process]

[Detection of minimal residual disease in childhood hematological malignancies and its clinical significance]

[Article in Chinese]

Tang S, Lu S, Zhang X, et Al.

No. 301 Hospital, Beijing 100853, China.

OBJECTIVE: Expoloring the detection of minimal residual malignant cells in bone marrow from children with hematological malignancies to predict the prognosis. METHODS: Seventy-five patients with acute lymphoblastic leukemia (ALL), stage IV non-Hodgkin's lymphoma or stage IV neuroblastoma were studied. Complete remission was maintained for over 3 months before the detection. Minimal residual disease was detected by polymerase chain reaction (PCR) for IgH and TcRgamma rearrangements in lymphoid tumors by reverse transcriptase-polymerase chain reaction (RT-PCR) for neuroblastoma patients. RESULTS: Thirty five patients were positive for minimal residual disease, and 21 of them (60%) relapsed 3 similar 40 months later, while only 7 (17%) negative patients relapsed (chi(2) = 12.59, P < 0.01). CONCLUSION: Minimal residual disease detection in bone marrow by PCR might predict prognosis in some childhood hematological malignancies.

PMID: 11876957 [PubMed - in process]

Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia.

Mortuza FY, Papaioannou M, Moreira IM, Coyle LA, Gameiro P, Gandini D, Prentice HG, Goldstone A, Hoffbrand AV, Foroni L.

Department of Hematology, Royal Free and University College School of Medicine, London, United Kingdom.

PURPOSE: Investigation of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) using molecular markers has proven superior to other standard criteria (age, sex, and WBC) in distinguishing patients at high, intermediate, and low risk of relapse. The aim of our study was to determine whether MRD investigation is valuable in predicting outcome in Philadelphia-negative adult patients with ALL. PATIENTS AND METHODS: MRD was assessed in 85 adult patients with B-lineage ALL by semiquantitative immunoglobulin H gene analysis on bone marrow samples collected during four time bands in the first 24 months of treatment. Fifty patients received chemotherapy only and 35 patients received allogeneic (n = 19) or autologous (n = 16) bone marrow transplantation (BMT) in first clinical remission. The relationship between MRD status and clinical outcome was investigated and compared with age, sex, immunophenotype, and presenting WBC count. RESULTS: Fisher's exact test established a statistically significant concordance between MRD results and clinical outcome at all times. Disease-free survival (DFS) rates for MRD-positive and -negative patients and log-rank testing established that MRD positivity was associated with increased relapse rates at all times (P <.05) but was most significant at 3 to 5 months after induction and beyond. MRD status after allogeneic BMT rather than before was found to be an important predictor of outcome in 19 adult patients with ALL tested. In patients receiving autologous BMT (n = 16), the MRD status before BMT was more significant (P =.005). CONCLUSION: The association of MRD test results and DFS was independent of and greater than other standard predictors of outcome and is therefore important in determining treatment for individual patients.

PMID: 11844835 [PubMed - indexed for MEDLINE]

TEL/AML1 rearrangement and the prognostic significance in childhood acute lymphoblastic leukemia in Hong Kong.

Tsang KS, Li CK, Chik KW, Shing MM, Tsoi WC, Ng MH, Lau TT, Leung Y, Yuen PM.

Hematology and Bone Marrow Transplantation Division, Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.

The TEL/AML1 rearrangement has been implicated as an independent good prognostic factor in pediatric acute lymphoblastic leukemia (ALL). We examined TEL/AML1 using nested reverse-transcription polymerase chain reaction (RT-PCR) and correlated TEL/AML1 with cytogenetics and immunophenotypes in 75 consecutively analyzed Chinese children with ALL in Hong Kong. TEL/AML1 was detected in 17.9% (12/67) B-lineage ALL at diagnosis but not in 8 T-ALL children or in 34 adults with ALL. E2A/PBX1, MLL/AF4, and BCR/ABL were not found in TEL/AML1+ patients. Coexpression of cross-lineage antigens was associated with TEL/AML1 gene fusion (p = 0.032), with CD13 in 80% (4/5) TEL/AML1+ cohort. Chromosomal abnormalities were demonstrated in 50% of the TEL/AML1+ ALL; however, a cryptic t(12;21) was not detected in these cases. Hyperdiploidy of 47-48 chromosomes was encountered in 25%. Deletion of 12p resulting in the loss of the normal allele of TEL and nonspecific del(6q) were noted in 8% (1/12) and 25% (3/12) of the TEL/AML1+ children, respectively. Rapid clearance of TEL/AML1 was noted in 50% of the patients on completion of the induction therapy; however, 16.7% (2/12) TEL/AML1+ ALL relapsed at a mean of 48.6 months from diagnosis (25 months off-therapy). The incidence of relapses of TEL/AML1+ ALL was comparable to that at diagnosis in B-lineage ALL (14.3% [2/14] vs. 17.9% [12/67], p > 0.05). The relapse rate in TEL/AML1+ ALL was similar to that of TEL/AML1- ALL (16.7% [2/12] vs. 20.6% [13/63], p > 0.05). The duration of first complete remission in TEL/AML1+ ALL was significantly longer as compared to TEL/AML1- ALL (mean [range] in month: 48.6 [47.2 - 50] vs 14.6 [2.9 - 42.3], p < 0.0001). Irrespective of TEL/AML1 rearrangement, the probabilities of the five-year overall survival and the event-free survival of patients were comparable (overall survival: 100% vs. 72.3%, p = 0.166 and event-free survival: 60% vs. 56.2%, p = 0.343). Our data would not suggest a less aggressive treatment regimen for TEL/AML1+ ALL. Copyright 2001 Wiley-Liss, Inc.

PMID: 11559948 [PubMed - indexed for MEDLINE]

Relapse of TEL-AML1--positive acute lymphoblastic leukemia in childhood: a matched-pair analysis.

Seeger K, Stackelberg AV, Taube T, Buchwald D, Korner G, Suttorp M, Dorffel W, Tausch W, Henze G.

Department of Pediatric Oncology/Hematology, Charite Medical Center, Humboldt-University, Berlin, Germany. karl.seeger@charite.de

PURPOSE: The aim of this study was to investigate whether, in relapsed childhood acute lymphoblastic leukemia (ALL), the frequent genetic feature of TEL-AML1 fusion resulting from the cryptic chromosomal translocation t(12;21)(p13;q22) is an independent risk factor. PATIENTS AND METHODS: A matched-pair analysis was performed within a homogeneous group of children with first relapse of BCR-ABL-negative B-cell precursor (BPC) ALL treated according to relapse trials ALL-Rezidiv (REZ) of the Berlin-Frankfurt-Munster Study Group. A total of 249 patients were eligible for this study: 53 (21%) were positive for TEL-AML1, and 196 (79%) were negative. Positive patients were matched for established most-significant prognostic determinants at relapse, time point, and site of relapse, as well as age and peripheral blast cell count at relapse. RESULTS: Fifty pairs matching the aforementioned criteria could be determined. The probabilities with SE of event-free survival and survival at 5 years for matched TEL-AML1 positives and negatives are 0.63 +/- 0.10 versus 0.38 +/- 0.10 (P =.09) and 0.82 +/- 0.09 versus 0.42 +/- 0.19 (P =.10), respectively. These results were confirmed by multivariate analysis, revealing an independent prognostic significance of time point and site of relapse (both P <.001) but not of TEL-AML1 expression (P =.09). CONCLUSION: TEL-AML1 expression does not constitute an independent risk factor in relapsed childhood BCP-ALL after matching for relevant prognostic parameters. It undoubtedly characterizes genetically an ALL entity associated with established favorable prognostic parameters. High-risk therapeutic procedures such as allogeneic SCT should be considered restrictively.

Publication Types: Multicenter Study

PMID: 11432885 [PubMed - indexed for MEDLINE]

Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies.

Uderzo C, Dini G, Locatelli F, Miniero R, Tamaro P.

Centro TMO, Clinica Pediatrica, Ospedale S. Gerardo di Monza, Universita di Milano Bicocca, via Donizetti 106, 20052 Monza, Milano, Italy. ctmomonza@libero.it

BACKGROUND AND OBJECTIVES: Treatment of recurrent childhood acute lymphoblastic leukemia (ALL) has been controversial in the last decade. Conventional intensive chemotherapy (CHEMO) can cure up to 30% of children who have relapsed after ALL: similar results have been obtained with autologous bone marrow transplantation (ABMT), but allogeneic bone marrow transplantation (AlloBMT) seems to be the best therapeutic option. In this review the authors point out the contribution of current strategy in the setting of children with ALL who experience a first relapse and should be offered optimal treatment in order to obtain the best disease-free survival (DFS). The principal objective of this issue is to reach a possible consensus on the more controversial points regarding factors considered strong predictors of the outcome of the relapsed patients, second-line chemotherapy, optimal timing and type of transplantation. EVIDENCE AND INFORMATION SOURCE: Data published in the literature over the last decade concerning early and late relapse in childhood ALL suggest that improvements in cure rates may be achieved by intensification of the relapse treatment both with chemotherapy and with different types of transplantation. An accurate search for Medline data has been performed in order to understand the risk-benefit ratio of aggressive therapy adopted in this setting. STATE OF ART: Modern first-line treatment protocols for childhood ALL have contributed to curing an ever larger number of patients but this strategy could be responsible for creating a more resistant leukemic clone at the time of systemic or extramedullary relapse. This hypothesis emerges from a number of single or multicenter experiences; thus clinical and biological features in relapsed patients are being studied carefully in order to understand which risk-directed second-line therapy should be best adopted. The BFM group classified ALL relapses as "very early", "early", or "late" according to the time from diagnosis to first relapse (i.e. < 18, > 18 and < 30 or more than 30 months) and has shown that about 2/3 of the small fraction of children with late extramedullary relapses or late non T-marrow relapses or early combined non T-relapses can be rescued by chemotherapy; in contrast ALL early relapses or T-immunophenotype ALL relapses can be rescue only by AlloBMT. Since 1990 the AIEOP group adopted BFM-like first-line treatment and experienced similar situations for relapsed patients so that, even in absence of a real common relapse protocol, they went in the same direction as the BFM group as far as hematopoietic stem cell transplantation (HSCT) procedures and decision were concerned. A recent AIEOP study on the destiny of 192 consecutive patients with ALL in 2nd complete remission and not having an HLA suitable sibling donor is presented in this issue. The value of different HSCT procedures is addressed and the protection against a new relapse seems to be real, although, of course, the risk-benefit ratio should always be evaluated. PERSPECTIVES: Very few prospective studies on the treatment of childhood ALL relapse have been set up in the last decade because of many difficulties regarding common second-line therapies, some reluctance versus HSCT in consideration of the transplant-related mortality and the so-called late effects. Additional modifications of allogeneic family and unrelated donor HSCT strategies and the promising results both of cord HSCT and auto-grafting methods including in vitro purging or post-transplant immunotherapy, are making transplantation procedures for ALL relapsed patients more appropriate and increasing confidence in their use. The possibility of performing common prospective international studies should be encouraged over the next years in order to elucidate an area of great research as is that of the treatment of childhood ALL relapse.

Publication Types: Review Review, Tutorial

PMID: 11268324 [PubMed - indexed for MEDLINE]

Correlation of clinical picture (event free survival and overall survival) in childhood acute leukemia patients with immunophenotype and chromosomal abnormalities.

Babusikova O, Sejnova D, Kirschnerova G, Kirsnerova Z, Cap J.

Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovak Republic. exonobab@savba.sk

In a group of 102 children with different immunological subtypes of acute leukemia, both lymphoblastic and nonlymphoblastic, the clinical parameters - event free survival and overall survival were correlated with numerical and structural chromosomal abnormalities. In a group of 80 ALL patients genetic abnormalities were observed in 40 patients, from those 19 of numerical type, 17 of structural type and 4 with both, numerical and structural anomalies. From the whole ALL group observed 23 patients (28.75%) died. In 10 died patients genetic abnormalities were found and in 6 cases less mature T-phenotype ALL has been documented. It seems, therefore, that immature T-phenotype with pathological karyotypes of all types of genetic anomalies presents the most risk group of patients of which all children died. ALL patients, as a whole, with pathological karyotype have shown significantly lower event free survival rate, comparing to the group of ALL patients with normal karyotype. Overall survival rate was also lower in the first group, but statistically not significant. In T-ALL patients, in both groups, with and without pathological karyotype, event free survival rate and overall survival rate were also lower in the first group, but statistically not significant. In B-ALL patients with pathological karyotypes vs. normal ones overall survival rate was lower in the first group, but statistically not significant. There was no difference in overall survival rate in these patients between pathological and normal karyotypes. In ANNL group of patients pathological karyotype was observed in 14 of them, with numerical anomalies in 6 patients, structural in 4 patients and both of them - numerical + structural in 4 children. From the whole ANLL group observed 11 (50%) patients died during the follow-up period (9 in relapse and 2 of treatment complications). From 11 died patients in 81.8% pathological karyotype was present. The prevalence of pathological karyotypes was observed in less mature M0-M2 ANLL subtype (71.4%). ANLL patients with pathological karyotype have shown significantly lower event free survival rate (in one of the two statistical log-rank analyses), comparing to the group of ANLL patients with normal karyotype. Overall survival rate was also lower in the first group, but statistically not significant. The presence/absence of CD34 marker expression in blast cells of our group of acute leukemia patients did not show any difference in event free survival and overall survival rates.

PMID: 11263863 [PubMed - indexed for MEDLINE]

Age, sex, haemoglobin level, and white cell count at diagnosis are important prognostic factors in children with acute lymphoblastic leukemia treated with BFM-type protocol.

Ng SM, Lin HP, Ariffin WA, Zainab AK, Lam SK, Chan LL.

Department of Paediatrics, University Hospital, Kuala Lumpur, Malaysia. ngszemay@hotmail.com

The presenting features and treatment outcome for 575 Malaysian children (< or = 12 years of age) with newly diagnosed acute lymphoblastic leukemia (ALL), admitted to the University Hospital, Kuala Lumpur, Malaysia between 1 January 1980 and 30 May 1995 were evaluated to determine their prognostic significance. Two-year overall survival was achieved in 67 per cent of all patients and 55 per cent of patients were relapse-free at 2 years. All except 10 patients, with identified French-American-British L3 morphology were treated with the modified Berlin-Frankfurt-Munster 78 treatment protocol. Univariate analyses of failure rate conferred age, sex, white cell count and hemoglobin level as potentially significant prognostic factors. All four presenting features retained their prognostic strength in a multivariate analysis. Race, platelet count, morphological subtype, liver/spleen size, lymphadenopathy, central nervous system and mediastinal mass involvement did not show any significant effect on treatment outcome. The 2-year survival rate was significantly different with regard to age, white cell count and hemoglobin level. However, sex was not significantly related to overall survival. These prognostic factors may have implications on future stratification of risk-adjusted initial treatment in the management of childhood ALL. Our analysis of Malaysian children is similar to what could be predicted based on previous studies in other populations.

PMID: 11191144 [PubMed - indexed for MEDLINE]

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]

Minimal residual disease studies are beneficial in the follow-up of TEL/AML1 patients with B-precursor acute lymphoblastic leukaemia.

de Haas V, Oosten L, Dee R, Verhagen OJ, Kroes W, van den Berg H, van der Schoot CE.

Emma Kinderziekenhuis/AMC, University of Amsterdam, The Netherlands.

The t(12;21)(p13;q22) translocation has been identified as the most common chromosomal abnormality in childhood acute lymphoblastic leukaemia (ALL). Initially, several investigators reported an excellent prognosis in paediatric leukaemias with this translocation, but other studies showed a 20% incidence in relapsed ALL. We performed an extensive analysis of 90 ALL patients. In 17 (19%) cases a TEL/AML1 fusion was found. However, this group was not representative as it included a high number of relapsed patients compared with the normal incidence in B-precursor ALL [54 in continuous complete remission (CCR) and 36 relapsed patients] and only a slightly better prognosis for TEL/AML1-positive patients was found (not significant) (four relapses in 17 TEL/AML1-positive patients vs. 32 relapses in 73 TEL/AML1-negative patients). Comparison of known prognostic factors (age, sex, ploidy, white blood cell count and immunophenotype) between relapsed TEL/AML1-positive and TEL/AML1-positive patients in CCR did not reveal differences, except that the white blood cell count was significantly higher in the relapsed group (P = 0.001). Time between diagnosis and relapse was not different for the relapsed TEL/AML1-positive group vs. the relapsed TEL/AML1-negative group. In 11 TEL/AML1-positive patients, the minimal residual disease (MRD) level at the end of induction therapy was quantified in a limiting dilution assay using IGH or TCRD junctional regions as polymerase chain reaction (PCR) targets. In all four relapsed patients, the level of MRD at the end of induction therapy was high (range 0.24-1.2%), whereas in all seven CCR patients, the MRD level was extremely low (0.02 to < 0.001%). In agreement with previous studies in which MRD levels at the end of induction therapy were found to be the strongest risk factor independent of other risk factors, in the present study we show that the MRD level remains a risk factor independent of the presence of a TEL/AML1 fusion gene.

PMID: 11167743 [PubMed - indexed for MEDLINE]

High-dose methotrexate in childhood all.

Moe PJ, Holen A.

Children Hospital, Regionsykehuset i Trondheim, Trondheim, Norway.

An event-free survival is currently achieved in 70-80% of children diagnosed with acute lymphocytic leukemia (ALL). A decline in the long-term sequalae from therapy is a challenge at present. Due to the high incidence of central nervous system (CNS) relapse in ALL patients, cranial irradiation was introduced as a prophylactic measure in the beginning of the 1970s. Cranial irradiation, however, may cause secondary malignancies in the CNS. In recent years neurotoxicities have been demonstrated to follow cranial irradiation in a large proportion of ALL patients. Because of these deleterious effects, most ALL protocols are limited to the combination intrathecal and intravenous methotrexate as the standard for CNS prophylaxis. In the 1970s, an intermediate dose was administered, while from the 1980s a high dose of methotrexate was combined with intrathecal methotrexate. The regular methotrexate dose of later years has been in the range of 5-8 g/m2. The intravenous methotrexate dose has actually varied from 2 to 33.6 g/m2. The highest dose, 33.6 g/m2, has been without intrathecal instillation. In a study from Norway, high-dose methotrexate (6-8 g/m2) was used, and only two (2.2%) of 89 ALL cases showed CNS relapse, both of reversible kind. In the United Kingdom, a randomized controlled study was started in 1990. Results published so far are based on a segment of cases characterized by standard risk and white blood cell count below 50 x 10(9); a 4% reduction in CNS relapse was found for high-dose methotrexate in comparison to those treated only with long-term intrathecal methotrexate. The use of methotrexate unalterably warrants some precautions. Rescue therapy with folinic acid is usually started 36 h after initiating the methotrexate infusion. Steps are also taken to secure adequate intake of fluids and alkalinization of the urine. Provided irradiation is avoided, neurotoxicities rarely occur. For regular high-dose methotrexate adverse effects mostly involve mucositis and myelosuppresion.

Publication Types: Review Review, Tutorial

PMID: 11127393 [PubMed - indexed for MEDLINE]

Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party.

Harrison G, Richards S, Lawson S, Darbyshire P, Pinkerton R, Stevens R, Oakhill A, Eden OB.

Clinical Trial Service Unit, Radcliffe Infirmary, Oxford, UK.

BACKGROUND: Although reinduction rates are good for children with relapsed acute lymphoblastic leukaemia there is no consensus on whether bone marrow transplantation (BMT) is the most effective treatment to prolong second remission. PATIENTS AND METHODS: Analyses comparing the outcome of related donor allogeneic BMT (related allograft) with chemotherapy are unreliable because of selection biases. To avoid these biases, the MRC UKALL R1 trial was analysed by HLA-matched donor availability. RESULTS: No significant difference in outcome was found between the donor and no donor groups. The donor group had a non-significant eight-year event-free survival (EFS) advantage of 8%, (95% confidence interval -9%-24%) over the no donor group. Patients with a first remission less than two years appeared to benefit most from having a donor, although the effect was only marginally significantly different from patients with longer first remission. Analysis by treatment received gave similar results, with BMT patients having a 5% (P = 0.8) eight-year EFS advantage over patients who received chemotherapy. CONCLUSIONS: Related allograft was not found to be significantly better than chemotherapy, but there was the possibility of a moderate EFS benefit with related allograft. especially in patients with a short first remission.

Publication Types: Clinical Trial Multicenter Study

PMID: 11038037 [PubMed - indexed for MEDLINE]

Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI.

Wheeler KA, Richards SM, Bailey CC, Gibson B, Hann IM, Hill FG, Chessells JM.

John Radcliffe Hospital, Headington, Oxford, England. kate.wheeler@paediatrics.oxford.ac.uk

The role of bone marrow transplantation (BMT) in first remission of children with high-risk acute lymphoblastic leukemia (ALL) remains unclear. There were 3676 patients (aged 1 to 15 years) entered into the United Kingdom (UK) Medical Research Council (MRC) trials UKALL X and XI from 1985 to 1997. Of these patients, 473 patients (13%) were classified as very high (VH) risk and were eligible for a transplantation from a matched histocompatible sibling donor (MSD). We tissue-typed 286 patients; 99 patients had a matched related donor, and 76 patients received transplantations. Additionally, 25 children received transplantations from a matched unrelated donor (MUD) despite trial guidelines for MSD transplantations only. The median time to transplantation was 5 months (range, 2 to 19 months), and the median follow-up was 8 years. The 10-year event-free survival (EFS) adjusted for the time to transplantation, diagnostic white blood cell (WBC) count, Ph chromosome status, and ploidy was 6. 0% higher (95% confidence interval (CI), -10.5% to 22.5%) for 101 patients who received a first-remission transplantation (MSD and MUD) than for the 351 patients treated with chemotherapy (transplantation, 45.3%, vs chemotherapy, 39.3%). The transplantation group had fewer relapses (31%) compared to relapses in the chemotherapy group (55%); however, the transplantation group had more remission deaths (18%) compared to remission deaths in the chemotherapy group (3%). In contrast the adjusted 10-year EFS was 10. 7% higher (95% CI, -2.6% to 24.0%) for patients without a human leukocyte antigen (HLA)-matched donor than for those patients with a donor (no donor, 50.4%, vs donor, 39.7%). In conclusion, for the majority of children with VH-risk ALL, the first-remission transplantation has not improved EFS.

Publication Types: Clinical Trial Randomized Controlled Trial

PMID: 11001892 [PubMed - indexed for MEDLINE]

Cytogenetic and FISH studies of a single center consecutive series of 152 childhood acute lymphoblastic leukemias.

Andreasson P, Hoglund M, Bekassy AN, Garwicz S, Heldrup J, Mitelman F, Johansson B.

Department of Clinical Genetics, Lund University Hospital, Sweden. Patrik.Andreasson@klingen.lu.se

Between 1977 and 1996, cytogenetic investigations were performed on 182 childhood (< or = 16 yr) acute lymphoblastic leukemias (ALL), constituting 94% (182 of 194) of all ALL patients diagnosed and treated at the Departments of Pediatrics, Lund and Malmo University Hospitals, Sweden, during these two decades. The cytogenetic analyses were successful in 152 cases (84%). The failure rate was higher for the ALL investigated before 1987 (30% vs. 4%, p < 0.0001), and also the incidence of cytogenetically normal cases was higher during 1977-86 (43% vs. 25%, p < 0.05). Clonal chromosomal abnormalities were found in 103 (68%) ALL. Structural rearrangements were detected, by chromosome banding alone, in 76 cases (50%). Fluorescence in situ hybridization (FISH) was used to identify cases with t(12;21), 11q23 rearrangements, and 9p deletions, using probes for ETV6/CBFA2, MLL, and CDKN2A/B, in 72 cases from which cells in fixative and/or unstained metaphase preparations were available. In total, the most common structural rearrangements were del(9p) (17%), t(12;21) (15%), del(6q) (8%), and MLL rearrangements (4%). Six (32%) of nineteen cytogenetically normal ALL analyzed by FISH harbored cryptic abnormalities; three displayed t(12;21) and four had del(9p), one of which also carried a t(12;21). Five (45%) of the t(12;21)-positive ALL showed +der(21)t(12;21) or ider(21)(q10)t(12;21), resulting in the formation of double fusion genes. Among the more rare aberrations, eight structural rearrangements were identified as novel recurrent ALL-associated abnormalities, and nine cases harbored rearrangements previously not reported. Sixteen cases displayed karyotypically unrelated clones at different investigations. Seven ALL (5%) showed simple chromosomal changes, unrelated to the aberrations detected at diagnosis, during morphologic and clinical remission, and in all but one instance the patients remained in remission, with the abnormal clone disappearing in subsequent investigations. This indicates that the emergence of novel clonal chromosomal aberrations during remission in childhood ALL is rather common and does not by necessity predict a forthcoming relapse.

PMID: 10914938 [PubMed - indexed for MEDLINE]

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]

The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study.

Lawson SE, Harrison G, Richards S, Oakhill A, Stevens R, Eden OB, Darbyshire PJ.

Department of Haematology, Birmingham Children's Hospital, Birmingham, UK. isaac.lawson@btinternet.com

We have examined the toxicity and overall outcome of the Medical Research Council UKALL R1 protocol for 256 patients with relapsed childhood acute lymphoblastic leukaemia (ALL). Second remission was achieved in over 95% of patients. Two patients died during induction and seven patients died of resistant disease. The overall actuarial event-free survival (EFS) at 5 years for all patients experiencing a first relapse was 46% (95% CI 40-52). Duration of first remission, site of relapse, age at diagnosis and sex emerged as factors of prognostic significance. Five-year EFS was only 7% for children relapsing in the bone marrow within 2 years of diagnosis, but was 77% for those relapsing without bone marrow involvement > 2.5 years from diagnosis. All analyses in this report are by treatment received. For those receiving chemotherapy alone, the 5-year EFS was 48%; for autologous bone marrow transplantation (BMT), the 5-year EFS was 47%; for unrelated donor BMT, it was 52%; and for related donor BMT, the 5-year EFS was 45%. The groups, however, were not comparable with respect to risk factor profile, and therefore direct comparison of EFS is misleading. Adjustment for time to transplant and prognostic factors was used to reduce the effects of biases between treatment groups, but did not suggest benefit for any particular treatment. There was failure of our planned randomization scheme in this trial with only 9% of those eligible being randomized, which highlights the difficulties in running randomized trials especially in patients who have relapsed from a previous trial. The optimal treatment for relapsed ALL therefore remains uncertain. Alternative approaches are clearly needed for those with early bone marrow relapse if outcome is to improve.

Publication Types: Clinical Trial Controlled Clinical Trial

PMID: 10759711 [PubMed - indexed for MEDLINE]

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]

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission - long-term follow-up.

Comment in: Bone Marrow Transplant. 2000 Nov;26(10):1136-7.

Vaidya SJ, Atra A, Bahl S, Pinkerton CR, Calvagna V, Horton C, Milan S, Shepherd V, Brain C, Treleaven J, Powles R, Tait D, Meller ST.

Paediatric Oncology, The Royal Marsden NHS Trust, Sutton, UK.

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.

Publication Types: Clinical Trial

PMID: 10734293 [PubMed - indexed for MEDLINE]

Allogeneic bone marrow transplantation versus chemotherapy for the treatment of childhood acute lymphoblastic leukemia in second remission: a single-institution study.

Boulad F, Steinherz P, Reyes B, Heller G, Gillio AP, Small TN, Brochstein JA, Kernan NA, O'Reilly RJ.

Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. bouladf@mskcc.org

PURPOSE: A retrospective analysis of the treatment of childhood acute lymphoblastic leukemia (ALL) in second remission (CR2) was undertaken at our institution to compare the outcome and prognostic factors of patients treated with chemotherapy or allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: Seventy-five children who suffered a medullary relapse and achieved a second remission were treated with either an unmodified allogeneic HLA-matched sibling BMT after hyperfractionated total body irradiation (TBI) and cyclophosphamide (n = 38) or chemotherapy according to institutional chemotherapy protocols (n = 37). To avoid the bias of survival from the attainment of second remission in favor of BMT, the final comparative statistical analysis used the landmark approach and comprised 37 and 29 patients from the BMT and chemotherapy groups, respectively RESULTS: The disease-free survival (DFS) rate was 62% and 26% at 5 years, respectively, for the BMT and the chemotherapy groups (P = .03), with relapse rates of 19% and 67%, respectively, for these two groups (P = .01). There was an overall advantage for the BMT therapeutic approach, as compared with chemotherapy, for patients with ALL in CR2 (1) for patients with a WBC count (at diagnosis) of 20 x 10(9)/L or higher (DFS, 40% v 0%) and those with a WBC count of less than 20 x 10(9)/L (DFS, 73% v35%), (2) for patients whose duration of CR1 was less than 24 months (DFS 48% v 9%) and for patients whose duration of CR1 was 24 months or longer (DFS, 81% v 37%) and (3) for patients who were initially treated with intensive regimens incorporating more than five chemotherapy agents (DFS, 57% v 20%) and for patients treated with five agents or fewer (DFS, 72% v 32%). CONCLUSION: In our single-institution series, unmodified HLA-matched allogeneic sibling transplants using hyperfractionated TBI and cyclophosphamide for patients with ALL in CR2 have resulted in superior outcome with a significantly improved probability of DFS and a lower relapse rate, as compared with those for patients treated with chemotherapy, regardless of the duration of first remission, the disease characteristics at diagnosis, or the intensity of prior treatment during first remission.

PMID: 10458234 [PubMed - indexed for MEDLINE]

Allogeneic bone marrow transplantation vs chemotherapy for the treatment of childhood acute lymphoblastic leukaemia in second complete remission (revisited 10 years on).

Torres A, Alvarez MA, Sanchez J, Flores R, Martinez F, Gomez P, Rojas R, Herrera C, Garcia JM, Andres P, Velasco F, Serrano J, Roman J, Rodriguez A, Martin C, Tabares S, Rodriguez JM, Parody R, Plaza E, Leon A, Romero R, Jean-Paul E, Prados D, Aljama R, Fernandez A.

Department of Haematology, University Hospital Reina Sofia Cordoba, Spain.

In 1989 we carried out a trial comparing allogeneic BMT to chemotherapy (CT) in 76 children with relapsed acute lymphoblastic leukaemia (ALL). Ten years on we have clinically revised outcome to firmly establish the role of each treatment, to analyse the importance of length of first remission and to provide long-term actuarial results for disease-free survival (DFS) and relapse rate in each group. For 21 patients within the transplantation group, probability of DFS and relapse are 42.8 +/- 10.8% and 40.2 +/- 11.7% (s.e.), respectively. In the chemotherapy group, probability of DFS is 10.0 +/- 4.74% (P = 0.001) and probability of relapse 87.5 +/- 5.2% (P = 0.0004). These results strongly reflect those at initial analysis, confirming a key role of BMT in the management of ALL in second remission. Moreover, on univariate analysis only two factors influenced DFS: treatment group and length of first complete remission (less or more than 30 months from first CR). Thus, it seems clear that the best therapeutic option in early relapse is BMT, whereas DFS in late relapse is at the limit of significance (P = 0.07), with a higher relapse rate in the CT group. Although encouraging results using intensified rotational combination chemotherapy have been published, prospective randomised studies are needed to assess with certainty the best therapeutic option in these patients.

Publication Types: Clinical Trial

PMID: 10414912 [PubMed - indexed for MEDLINE]

Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries.

Schroeder H, Gustafsson G, Saarinen-Pihkala UM, Glomstein A, Jonmundsson G, Nysom K, Ringden O, Mellander L.

Department of Pediatrics, University Hospital of Aarhus, Denmark.

This study compares allogeneic BMT with conventional chemotherapy for childhood ALL in second remission. Seventy-five children were transplanted between July 1981 and December 1995. For each patient two control patients matching the following criteria were selected from the Nordic database of ALL: (1) time of diagnosis, (2) T vs. non-T ALL, (3) site of relapse, (4) initial risk group, (5) sex and (6) relapse < or > or =6 months after cessation of therapy. The minimal time of follow-up was 24 months. Mortality rate in CR2, leukemic relapse rate and the proportion in continued second remission were 16/75 (21%), 22/75 (29%) and 37/75 (50%), respectively. P2.-EFS for the BMT group was significantly better than that for the control group (0.40 vs. 0.23, P = 0.02). Children transplanted for bone marrow relapses in particular had a higher P2.-EFS (0.35 vs. 0.15 for the control group, P<0.01). Also, children grafted for early BM relapses had a higher P2.-EFS (0.32 vs. 0.11 for the control group P = 0.01). The outcome was similar when children were transplanted after early or late relapse. Also, there was no difference in outcome between the BMT and the chemotherapy group for children with late relapses. We conclude that allogeneic BMT with an HLA-identical sibling donor or other family donor should be performed in children relapsing in bone marrow during therapy or within 6 months of discontinuing therapy.

PMID: 10217185 [PubMed - indexed for MEDLINE]

Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia.

Knechtli CJ, Goulden NJ, Hancock JP, Grandage VL, Harris EL, Garland RJ, Jones CG, Rowbottom AW, Hunt LP, Green AF, Clarke E, Lankester AW, Cornish JM, Pamphilon DH, Steward CG, Oakhill A.

Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, UK.

The efficacy of allografting in acute lymphoblastic leukemia (ALL) is heavily influenced by remission status at the time of transplant. Using polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis, we have investigated retrospectively the impact of submicroscopic leukemia on outcome in 64 patients receiving allogeneic bone marrow transplantation (BMT) for childhood ALL. Remission BM specimens were taken 6 to 81 days (median, 23) before transplant. All patients received similar conditioning therapy; 50 received grafts from unrelated donors and 14 from related donors. Nineteen patients were transplanted in first complete remission (CR1) and 45 in second or subsequent CR. MRD was analyzed by PCR of Ig or T-cell receptor delta or gamma rearrangements, electrophoresis, and allele-specific oligoprobing. Samples were rated high-level positive (clonal band evident after electrophoresis; sensitivity 10(-2) to 10(-3)), low-level positive (MRD detected only after oligoprobing; sensitivity 10(-3) to 10(-5)), or negative. Excluding 8 patients transplanted in CR2 for isolated extramedullary relapse (all MRD-), MRD was detected at high level in 12 patients, low level in 11, and was undetectable in 33. Two-year event-free survival for these groups was 0%, 36%, and 73%, respectively (P <.001). Follow-up in patients remaining in continuing remission is 20 to 96 months (median, 35). These results suggest that MRD analysis could be used routinely in this setting. This would allow identification of patients with resistant leukemia (who may benefit from innovative BMT protocols) and of those with more responsive disease (who may be candidates for randomized trials of BMT versus modern intensive relapse chemotherapy).

PMID: 9834212 [PubMed - indexed for MEDLINE]

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]

Duration of first remission predicts remission rates and long-term survival in children with relapsed acute myelogenous leukemia.

Stahnke K, Boos J, Bender-Gotze C, Ritter J, Zimmermann M, Creutzig U.

University Children's Hospital, Ulm, Germany.

Although treatment of childhood acute myelogenous leukemia (AML) has substantially improved in the last 15 years, in nearly half of the patients disease recurs. The aim of this study was to establish the prognosis of relapsed childhood AML and to identify prognostic factors for achievement of second remission and survival. From February 1988 to July 1996, 134 children with first relapse of AML were reported to the study center of the AML-BFM group. 102 patients treated intensively to induce second remission were prospectively followed. With various regimens, complete remission was achieved in 52 of 102 patients (51%), 27 children were alive in median 2.5 years (range, 0.4-7 years) after relapse. Disease-free survival was observed in seven of 16 patients transplanted from a matched sibling donor, one of four after matched unrelated bone marrow transplantation, 10 of 22 after autologous transplantation and five of nine patients after chemotherapy alone (two patients were lost to follow-up). Time until relapse reflecting the duration of first remission is the only variable correlating CR and survival rates. Defining early relapse as less than 1.5 years from diagnosis to relapse resulted in a 5-year survival of 10%, s.e. 5% for early relapses and 40%, s.e. 10% for late relapses (P-logrank test, 0.0001). Duration of first remission is a strong predictor for achievement of second CR and survival. It should be considered in reporting results of experimental therapies.

PMID: 9766496 [PubMed - indexed for MEDLINE]

Preferential loss of maternal 9p alleles in childhood acute lymphoblastic leukemia.

Morison IM, Ellis LM, Teague LR, Reeve AE.

Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand. ian.morison@otago.ac.nz

Germ-line events, such as paternal mutation or genomic imprinting, contribute to the early onset of childhood cancers such as retinoblastoma, Wilms tumors, and neuroblastoma. Given the high frequency of deletion involving chromosome 9p in childhood acute lymphoblastic leukemia (ALL), this study investigated whether 9p deletion might reflect preexisting germ-line gene inactivation. To do this the parental origin of deletion was determined in 10 cases of ALL with 9p21 loss of heterozygosity. Of these cases, 9 showed loss of the maternally derived allele, suggesting that a germ-line event involving a 9p gene may play a role in the onset of childhood ALL.

27: Blood 1998 Oct 1;92(7):2334-7 Related Articles, Books, LinkOut

Late relapsing childhood lymphoblastic leukemia.

Vora A, Frost L, Goodeve A, Wilson G, Ireland RM, Lilleyman J, Eden T, Peake I, Richards S.

Molecular Haematology Unit, Children's and Royal Hallamshire Hospital, Sheffield, UK. A.J.Vora@Sheffield.ac.uk

Childhood lymphoblastic leukemia (ALL) is usually assumed to have been permanently eradicated in patients in long-term remission, but occasionally can recur after many years. To learn more about the problem, we studied a group of children whose leukemia had been in remission for 10 or more years before relapse and tried to determine whether they had true recurrences or second malignancies. We studied children treated on Medical Research Council ALL protocols between 1970 and 1984 and followed up by the Clinical Trial Service Unit in Oxford. Detailed clinical and laboratory data was collected from the centers concerned on all who were reported to have had a recurrence of their leukemia after 10 or more years from the time of achieving first complete remission (CR1). To prove that the relapse was a true recurrence rather than a second or secondary leukemia, DNA extracted from archived marrow smears was subjected to polymerase chain reaction (PCR) analysis for the presence of an identical Ig heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement at initial diagnosis and subsequent relapse. A total of 1,134 of 2,746 children had survived 10 years or more (range, 10 to 24 years) in CR1 and of those, 12 (approximately 1%) had subsequently relapsed. Relapse blast cells were shown to express the common ALL antigen (CD 10) in all cases and an identical clonal IgH or TCR gene rearrangement was found on PCR analysis of DNA from diagnosis and relapse in all eight cases where DNA extraction was successful. A further program of therapy was successful in inducing a second CR in all patients, four of whom have succumbed to a second relapse after 12 to 27 months. The remaining eight are in continuing CR2 at a follow-up of 12 to 108 months (median, 52) from relapse. Although the risk of relapse of childhood ALL after 10 years in remission appears to be small (around 1%), it persists. This raises questions about how blasts can survive quiescent for so long and when we can truly be confident of cure, if ever.

PMID: 9746771 [PubMed - indexed for MEDLINE]

Outcome of acute lymphoblastic leukaemia in Danish children after allogeneic bone marrow transplantation. Superior survival following transplantation with matched unrelated donor grafts.

Lausen BF, Heilmann C, Vindelov L, Jacobsen N.

Paediatric Clinic II, Rigshospitalet, University of Copenhagen, Denmark.

Outcome of allogeneic BMT for childhood ALL performed at a national centre was evaluated for the period between 1985 and 1996. Sixty-seven patients representing all Danish children and adolescents (1-19 years) transplanted for ALL, were evaluated. Patients transplanted with a family donor (n = 51) had a 3-year probability of leukaemia-free survival (P-LFS) of 56% (95% confidence limits 41-69%) and patients receiving marrow from a matched unrelated donor (MUD) (n = 16) had a 3-year P-LFS of 67% (34-86%) (P = 0.38). Relapse was responsible for 48% of the deaths and occurred with increasing frequency among children transplanted with marrow from HLA-identical siblings. Patients transplanted with family donors from 1985-1989 had P-LFS of 72% (54-84%) compared to patients transplanted after 1990 who revealed a significantly reduced P-LFS of 28% (10-49%, P = 0.01). Furthermore, the risk of relapse was increased (65% (24-88%)) (P = 0.02) in the later period. In contrast, patients transplanted with marrow from a MUD (1990-1996) had a lower risk of relapse (11%, 5-20%) (P = 0.002) but a comparable risk of transplant-related mortality. Children who experience relapse after modern, intensive treatment for ALL may have an increased propensity for relapse even after BMT. Therefore, when performing BMT for childhood ALL, there may be a benefit in overall survival from the increased graft-versus-leukaemia effect that follows less intensive GVHD prophylaxis or transplantation with a MUD.

PMID: 9722066 [PubMed - indexed for MEDLINE]

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in Italy. AIEOP/FONOP-TMO Group. Italian Association of Paediatric Haemato-Oncology.

Comment in: Bone Marrow Transplant. 2000 Nov;26(10):1136-7.

Messina C, Cesaro S, Rondelli R, Rossetti F, Locatelli F, Pession A, Miniero R, Dini G, Uderzo C, Dallorso S, Meloni G, Vignetti M, Andolina M, Porta F, Amici A, Favre C, Basso G, Sotti G, Varotto S, Destro R, Gazzola MV, Pillon M, Petris MG, Rabusin M, Scarzello G, et al.

Clinica Onco-Ematologia Pediatrica, Universita di Padova, Italy.

From January 1984 to December 1994, ABMT was performed on 154 children (101 males, 53 females; median age 10, range 3-21 years) with ALL and registered for BMT by the AIEOP (Italian Association of Paediatric Haemato-Oncology). All patients were in CR: 98 were in 2nd CR and 56 were in >2nd CR. Fifteen children (9.7%) died of transplant-related mortality. Ninety-five patients (61.6%) relapsed at a median of 5 (range 1-42) months after ABMT. The 8-year EFS according to pre-BMT status was 34.6% (s.e. 4.9) for 2nd CR patients and 10.6% (s.e. 5.6) for patients in >2nd CR. By univariate analysis, site of relapse (isolated extramedullary (IE) vs BM: EFS = 68.5% vs 18.2%; P < 0.0001) and TBI containing regimen (TBI vs no TBI: EFS = 48.1 vs 15.4%; P = 0.0023) were significant factors for 2nd CR patients. When the 2nd CR subset with BM involvement was analysed, TBI became insignificant (EFS = 25.4 vs 11.8%). No factors influenced EFS in patients in >2nd CR. By multivariate analysis, site of relapse was the only significant factor in 2nd CR patients (P < 0.0001). In conclusion, ABMT is an effective treatment after one early IE relapse. Few patients can be rescued after BM relapse.

PMID: 9632275 [PubMed - indexed for MEDLINE]

Clinical presentation, hematologic features and treatment outcome of childhood acute lymphoblastic leukemia: a review of 73 cases in Hong Kong.

Ma SK, Chan GC, Ha SY, Chiu DC, Lau YL, Chan LC.

Department of Pathology, University of Hong Kong, Queen Mary Hospital.

Seventy-three consecutive cases of childhood acute lymphoblastic leukemia (ALL) diagnosed and managed in Queen Mary Hospital over a 10-year period from 1985 to 1994 were retrospectively analysed for their presenting features and treatment outcome. The 48 boys and 25 girls ranged in age from 0.4 to 14.2 years (median: 4.3 years). Bone and joint pain was a relatively common presenting feature besides fever, hepatosplenomegaly and lymphadenopathy. Immunophenotyping of blast cells showed: 51 B-cell precursor ALL, one B-ALL, 10 T-ALL and three myeloid-antigen positive ALL. Eight cases were unclassified since immunophenotyping had not been performed. Out of the 73 patients, treatment outcome was analysed in 20 cases treated with UKALL-VIII regimen and 28 cases treated with either the UKALL-XI regimen or the Hong Kong Children Cancer Study Group (HKCCSG) protocol which was modelled upon UKALL-XI. Although complete remission rates were similar between the two groups, patients treated with the former regimen that was less intensified suffered more relapses than the latter (56 per cent versus 21 per cent, P = 0.04). There were, however, no significant differences both in event-free survival (38.2 +/- 11.2 per cent versus 71.3 +/- 9.3 per cent, P = 0.12) and overall survival (70.0 +/- 10.2 per cent versus 79.6 +/- 8.3 per cent, P = 0.41) between the two groups at 3 years by long-rank test. With the use of risk-directed therapy and improved supportive care, two-thirds of our patients are able to enjoy long-term event-free survival.

Publication Types: Review Review, Multicase

PMID: 9600113 [PubMed - indexed for MEDLINE]

Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia.

Wheeler K, Richards S, Bailey C, Chessells J.

Department of Paediatrics, Oxford Radcliffe Hospital.

We examined the outcome of the 489 children with acute lymphoblastic leukaemia (ALL) who relapsed in the UKALL X trial, and produced graphical displays of adjusted comparisons of event-free survival (EFS) for chemotherapy versus bone marrow transplantation (BMT) from a sibling or volunteer unrelated donor, and autologous BMT (ABMT). EFS at 5 years was only 3% (95% CI 0-6%) for children who relapsed in the bone marrow (BM) within 2 years of diagnosis, irrespective of type of post-relapse treatment, whereas for those with late extramedullary relapse it was 66% (95% CI 48-85%). Comparison of the types of treatment did not show benefit for ABMT. For allogeneic BMT the overall reduction in the odds of an event was 26% (95% CI 1-51%) (2P= 0.05), resulting in an absolute increase in 5-year event-free survival of 14% (from 26.4% to 40.7%). New approaches are needed for children with early BM relapses whose prognosis is virtually hopeless with current therapy; however, a conventional chemotherapy approach may be justifiable for late extramedullary relapses. For the remaining patients (71%), with later BM or early extramedullary relapses, the optimal treatment is still not clear. This uncertainty warrants a formal randomized comparison of BMT and chemotherapy, to avoid the biases due to unmeasurable selection factors.

PMID: 9576189 [PubMed - indexed for MEDLINE]

Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: a conceivable alternative?

Borgmann A, Baumgarten E, Schmid H, Dopfer R, Ebell W, Gobel U, Niethammer D, Gadner H, Henze G.

Department of Paediatric Haematology and Oncology of the Virchow Medical Center, Berlin, Germany.

In the BFM Relapse Study registry we retrospectively identified 136 patients with a first marrow relapse who had undergone BMT in second complete remission (CR2) (group A) and 33 patients who received transplants only after a 2nd bone marrow (BM) relapse had occurred (group B). Event-free survival (EFS) rates at 6 years after BMT were 0.49 +/- 0.05 and 0.48 +/- 0.09 for patients transplanted in CR2 and CR3, respectively. In context with the BFM chemotherapy trials for relapsed childhood ALL there is a clear benefit from BMT in 2nd CR for children with unfavorable prognostic features (isolated early BM relapse, very early BM relapse or BM relapse of T cell ALL). Similar control of leukemia can be achieved with either chemotherapy or BMT in late BM relapse of ALL. Assuming a 60% failure rate with chemotherapy for patients in second relapse, a third remission can be achieved in about 60% of patients who have received chemotherapy, rendering them eligible for BMT in 3rd CR. With this strategy 58% of these patients would survive and late sequelae of BMT be restricted to a minority. To withhold BMT in CR2 and not perform BMT before a 2nd BM relapse has occurred, may be a conceivable alternative for children with late ALL BM relapse, at least if no related donor is available.

PMID: 9422472 [PubMed - indexed for MEDLINE]

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]

A prospective study of minimal residual disease in childhood B-lineage acute lymphoblastic leukaemia: MRD level at the end of induction is a strong predictive factor of relapse.

Jacquy C, Delepaut B, Van Daele S, Vaerman JL, Zenebergh A, Brichard B, Vermylen C, Cornu G, Martiat P.

Haematologic Molecular Biology Unit, University of Louvain Medical School, Brussels, Belgium.

We prospectively investigated minimal residual disease (MRD) in 51 children with B-lineage acute lymphoblastic leukaemia (ALL) treated according to the Fralle 93 protocol. PCR follow-up was performed in children in morphological and cytogenetic complete remission, provided an immunoglobulin (IgH) gene rearrangement could be detected using FR 3/J(H) amplimers. MRD was studied according to our previously described methodology, with a few modifications including the use of a consensus J(H) probe to control for PCR efficiency variations. Out of the initial 51 patients, 34 were assessable for MRD at the end of induction at the time of analysis. MRD levels were as follows: > 1/10(3) in 26%, 1/10(3) to 1/10(4) in 50% and < 1/10(4) or not detectable in 24%. With a median follow-up of 20 months there were five relapses, all of which occurred in the group of patients with MRD > 1/10(3). To date, none of the patients with MRD < or = 1/10(3) (good molecular responder) has relapsed. Classification according to molecular response at the end of induction did not correlate with the conventional risks groups: there were no statistically significant differences between good and bad molecular responders. Of particular interest is the absence of correlation between WBC at diagnosis and MRD level at the end of induction. We conclude that classification of patients into good and bad molecular responders using PCR seems to be a better prognostic indicator than conventional risk factors in childhood B-lineage ALL. Patients with MRD level > 1/10(3) have a particularly poor outcome and should always be considered for alternative therapeutic strategies in the future, whereas in good molecular responders belonging to poor or intermediate risk categories, treatment de-escalation might be contemplated.

PMID: 9233577 [PubMed - indexed for MEDLINE]

On the prognostic value of systemic methotrexate clearance in childhood acute lymphocytic leukemia.

Comment in: Leuk Res. 1997 May;21(5):435-7.

Seidel H, Nygaard R, Moe PJ, Jacobsen G, Lindqvist B, Slordal L.

Department of Paediatrics, Norwegian University of Science and Technology, Trondheim, Norway.

The prognostic value of systemic methotrexate clearance (ClMTX) during high-dose therapy was evaluated in a cohort of 42 children with acute lymphocytic leukemia (ALL). As part of an extensive chemotherapy protocol, they had received a total of 293 methotrexate (MTX) infusions in the 6-8 g/m2 dose range. At the termination of the study, when they had all been followed up for 3.5 years or more, 26 of these patients were still in continuous complete remission, whereas 16 had suffered relapse. The intrapatient variability in ClMTX during the eight courses was up to six-fold. In 67% of the patients, the maximum level of ClMTX reached at least twice the minimum value. The coefficients of variation for the intra- and interindividual variability in ClMTX were 9-57% and 26-41%, respectively. The cumulative probability of relapse, estimated by the Kaplan-Meier procedure, was increased for patients with a high ClMTX during the initial treatment course, but the difference was not significant on a 5% level. There was no significant relationship between high individual median ClMTX and subsequent relapse of ALL. However, ClMTX during the initial infusion, the time-dependent mean for ClMTX, and the individual patient's median ClMTX, were significant predictors for event-free survival in a Cox proportional hazards regression analysis. The present study demonstrates gross pharmacokinetic variability and unpredictable values of ClMTX in subsequent courses after standardized administration of MTX to paediatric patients with ALL. In spite of the association between ClMTX and prognosis shown by some of the analyses, estimates of ClMTX rates may not necessarily be related to disease outcome in a way that can be exploited to the benefit of the individual patient.

PMID: 9225071 [PubMed - indexed for MEDLINE]

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]

Which children do benefit from bone marrow transplant? The EBMT Paediatric Diseases Working Party.

Niethammer D, Klingebiel T, Ebell W, Henze G, Paolucci P, Riehm H.

Dept. of Paediatrics, Univ. of Tubingen, Germany.

The development of chemotherapy in childhood ALL has been the leader of the success story of paediatric oncology. At least 2/3 of the children can be cured nowadays at the first attempt of treatment. From the remaining again 1/3 can be treated successfully for the relapse of their disease with conventional therapeutic strategies. This means, however, that there is no chance for cure with chemotherapy alone for 20 to 25% of the children. BMT has been shown for a long time to be an alternative therapy especially in those cases in which conventional chemotherapy fails. In spite of the fact that many children with ALL have been transplanted during recent years there is still no general agreement on the question which children need BMT. However a few statements can be made: The value of ABMT in ALL is probably not better than that of chemotherapy alone. In 1st CR a group of children can be defined, which might benefit from BMT. In 2nd CR the value of chemotherapy depends very much from the duration of 1st remission. Allogeneic BMT is the only chance for cure in very early relapses, superior to chemotherapy in early and late relapses and possibly equal to chemotherapy in very late relapses. The paper tries to summarise our current knowledge about the situation.

Publication Types: Review Review, Tutorial

PMID: 8932798 [PubMed - indexed for MEDLINE]

Bone marrow transplant indications for childhood leukemias: achieving a consensus. The EBMT Pediatric Diseases Working Party.

Dini G, Cornish JM, Gadner H, Souillet G, Vossen JM, Paolucci P, Manfredini L, Miano M, Niethammer D.

G.Gaslini Institute, Genova, Italy.

During the "2nd International Course on Bone Marrow Transplantation in Children" a multiple choice questionnaire on bone marrow transplant indications for children with acute leukemias was distributed with the aim of achieving a consensus. The answers obtained from the twenty representatives of fourteen European countries during the meeting were analyzed and assigned to one of the following groups: I. definitive indication: when more than 75% participants were in favour; II. acceptable indication: when 50% to 74% participants were in favour; III. requires further investigation: when 25% to 49% participants were in favour; IV. no indication: when less than 24% participants were in favour. In acute lymphoblastic leukemia the following circumstances were considered a definitive indication for allogeneic bone marrow transplant (BMT) from a matched sibling donor (MSD): infancy, "high risk" (HR) patients in 1st complete remission (CR1); CR2 patients after an early bone marrow relapse (defined as a relapse occurring up to six months after stopping therapy). Patients experiencing an early meningeal relapse and CR2 patients after a late relapse (defined as a relapse occurring later than six months after stopping therapy) were considered an acceptable indication. Further investigation was required in order to better define the role of BMT for patients experiencing an early isolated testicular relapse. If a MSD is not available, HR patients in CR1 and CR2 patients, after an early bone marrow relapse, were considered a definite indication for a matched unrelated donor (MUD). This latter group was considered an acceptable indication for a haploidentical BMT if a MUD was not available. Further investigation was required to better define the role of autologous bone marrow transplant (ABMT) for patients experiencing an early extramedullary relapse and for HR patients in CR1 all of whom lacked MSD's. In acute myeloblastic leukemia (AML), CR2 patients were considered a definitive indication and CR1 patients were considered an acceptable indication for BMT from a MSD. CR2 patients were considered a definitive indication for ABMT and CR1 patients an acceptable indication in cases lacking a MSD. AML was not considered an indication for MUD BMT.

PMID: 8932789 [PubMed - indexed for MEDLINE]

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]

Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission.

Oakhill A, Pamphilon DH, Potter MN, Steward CG, Goodman S, Green A, Goulden P, Goulden NJ, Hale G, Waldmann H, Cornish JM.

Royal Hospital for Sick Children, Bristol.

Allogeneic sibling bone marrow transplantation (BMT) is the recommended treatment for relapsed childhood acute lymphoblastic leukaemia (ALL), but appropriate donors are only available in 30% of cases. Unfortunately, BMT from unrelated donors (UD) has been associated with high rates of severe graft-versus-host disease (GvHD) and transplant-related mortality (TRM). In an attempt to improve outcome in UD-BMT we have assessed the impact of T-cell depletion using CAMPATH-1 (anti-CD52) monoclonal antibodies in 50 consecutively referred patients with relapsed ALL in second remission. All were previously treated according to MRC protocols UKALL X and XI, and then given chemotherapy on MRC R1 from relapse until UD-BMT, 19 patients had relapsed on and 31 off therapy. Patients and donors were fully matched at HLA-A, -B, -DR and -DQ loci in 29 cases and mismatched in 21 (four mismatched for more than one antigen). Pre-transplant conditioning comprised CAMPATH-1G, cyclophosphamide and total body irradiation. Bone marrow was T-cell depleted in vitro using CAMPATH-1 antibodies. Additional GvHD prophylaxis consisted of cyclosporin A (42 cases), cyclosporin plus methotrexate (four) or none (four). 47 patients engrafted. The incidence of acute GvHD was very low: two patients with grade II disease in the matched group, four with grade II-IV in the mismatched group. Only four patients have chronic GvHD. The actuarial event-free survival (EFS) at 2 years is 53%, with no significant difference between the matched and mismatched group. Further leukaemic relapse was the most important cause of failure. These results are similar to the most favourable published reports for HLA-matched sibling BMT in relapsed ALL.

PMID: 8790160 [PubMed - indexed for MEDLINE]

Detection of minimal residual disease in childhood acute lymphoblastic leukemia after termination of therapy.

Wu NH, Lu SG, Zhu P, Peng YY.

Department of Pediatrics, Yanjing Hospital, Beijing, China.

Using IgH and TCR gamma gene rearrangements as gene markers, we detected minimal residual disease (MRD) by means of the polymerase chain reaction (PCR) and restriction analysis. Of 18 children with acute lymphoblastic leukemia (ALL), MRDs were detected in 9 patients after termination of therapy. All 18 patients had been followed for 1.5 to 102 months after detection. Three of the nine MRD-positive patients relapsed within 3 to 6 months; none of the nine MRD-negative patients relapsed. We suggest that MRD negativity at the end of therapy might be an important factor for long-term disease-free survival, because the negative cases had a very low risk of relapse. Because the outcome for MRD-positive cases is more difficult to evaluate, patients with MRD after termination of therapy should be monitored.

PMID: 8735342 [PubMed - indexed for MEDLINE]

Relapsed acute lymphoblastic leukemia: similar outcomes for autologous and allogeneic marrow transplantation in selected children.

Parsons SK, Castellino SM, Lehmann LE, Eickhoff CE, Tarbell NJ, Sallan SE, Weinstein HJ, Billett AL.

Division of Hematology@Oncology, Children's Hospital, Boston, MA, USA

The therapy of choice for relapsed childhood acute lymphoblastic leukemia is controversial. We retrospectively compared the outcome of 57 patients who received autologous bone marrow transplantation (BMT) with 17 patients who underwent allogeneic BMT for B cell lineage acute lymphoblastic leukemia after at least one marrow relapse. The allogeneic BMT cohort included only those who would also have been eligible for autologous BMT had they not had a matched sibling donor. Specifically, patients who were not in complete remission, those with T cell positive leukemia, t(9;22) or those with only an extramedullary relapse were excluded from both groups. Conditioning regimens included total body irradiation and chemotherapy. Age, white blood count at diagnosis, and duration of first and longest complete remissions were comparable for the two groups. The median follow-up of the event-free survivors was 4.8 years for those who received an autologous BMT (n = 26) and 4.6 years for those who received an allogeneic BMT (n = 8). The relapse rate was higher in the autologous BMT group and the incidence of non-leukemic deaths higher in the allogeneic BMT group. Event-free survival at 3 years was comparable for the two groups (47% +/- 7 vs 53% +/- 12, autologous vs allogeneic, respectively; P = 0.77). Based upon these findings, we concluded that the outcome for autologous BMT was equivalent to allogeneic BMT for relapsed childhood B cell lineage acute lymphoblastic leukemia in selected clinical situations.

PMID: 8733695 [PubMed - indexed for MEDLINE]

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]

[The treatment of recurrence in children with acute lymphatic leukemia. Current results and various developments]

[Article in Dutch]

Kaspers GJ, Pieters R, Klumper E, de Waal FC, Veerman AJ.

Afd. Kindergeneeskunde, Academisch Ziekenhuis, Vrije Universiteit, Amsterdam.

The results of current treatment of relapsed childhood acute lymphoblastic leukemia (ALL) are discussed, together with some recent developments which (might) influence such treatment. At present more than 95% of children with ALL will achieve a complete remission (CR), and +/- 70% will remain in CR. Nevertheless, 20-30% of the patients suffer a relapse, which implies a less favorable prognosis. However, after intensive treatment a part of these patients will have a prolonged second complete remission: 30-50% of children with a late relapse and 0-20% of children with an early relapse. It is important to prevent the occurrence of a relapse. The identification at diagnosis of patients at high risk for a relapse, and a subsequent more specific and more intensive treatment of these patients might contribute to that goal. Well-known risk factors are briefly mentioned, factors of which the prognostic significances is therapy-dependent. In addition, the treatment of relapsed ALL needs further improvement. Some alternatives to achieve this goal are discussed, including the role of in vitro cytostatic drug resistance testing.

PMID: 8493696 [PubMed - indexed for MEDLINE]

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]

A second course of treatment for childhood acute lymphoblastic leukaemia: long-term follow-up is needed to assess results.

Chessells JM, Leiper AD, Richards SM.

Department of Haematology and Oncology, Hospitals for Sick Children, London.

We report the results of long-term follow-up of 94 children who completed treatment for acute lymphoblastic leukaemia (ALL) between 1974 and 1986 and subsequently experienced a bone marrow relapse before 1992. 91 children received further induction, intensification and CNS directed therapy; 19 proceeded to BMT or ABMT and the remainder were treated on one of three protocols which increased in intensity. The duration of second remission improved significantly with increasing intensity of treatment and bone marrow transplantation was followed by fewer relapses than chemotherapy. Analysis of factors influencing the duration of second remission showed that only length of first remission was of additional significance; the median duration of second remission being only 19 months in children with a first remission of less than 4 years and 62 months in those with longer first remissions. 29 children electively stopped chemotherapy a second time but only 11 of these remain still in second remission with recurrences occurring for up to 7 years from the the time first relapse. Only three of the 24 long-term survivors had no significant late effects of treatment; these were most marked in children who had received a second course of radiotherapy. We conclude that very long follow-up is necessary to determine whether patients may be successfully re-treated following late bone marrow relapse and that all such treatment is associated with a high incidence of late effects.

PMID: 8011547 [PubMed - indexed for MEDLINE]

Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: a 10-year follow-up study. Italian Association of Pediatric Hematology-Oncology (AIEOP).

Miniero R, Saracco P, Pastore G, Zurlo MG, Terracini B, Rosso P, Masera G.

Department of Pediatrics, University of Turin, Italy.

The outcome of 171 children with ALL who relapsed for the first time after elective cessation of therapy (1-86 mo) and followed over 10 years (median 60 mo; range 1-232 mo) has been evaluated. One hundred and three patients relapsed in the bone marrow (BM), 29 in the testis (T), 21 in the central nervous system (CNS), 14 in the BM plus another site and 4 in other sites. Second remission was achieved in 97% of patients (97% BM, 100% T, 90% CNS, respectively) with reinduction schedules including three or more drugs. All but 4 out of 100 patients who relapsed in the BM received cranial reprophylaxis with intrathecal CT alone or CT plus radiotherapy. Seven patients in second CR underwent allogeneic bone marrow transplantation from an HLA matched sibling. The overall survival was 34% and disease-free survival (DFS) probability at 100 years was 22%. A second relapse was observed in 73% of patients. Forty children are alive in second continuous remission and 24 are alive after a second or subsequent relapse. Patients with isolated T relapse showed a significant better outcome than those with BM or CNS involvement. Most patients (62%) with isolated BM relapse showed a further disease recurrence in BM, and DFS was shorter when relapse occurred within 12 months from off-therapy. Eighty-two patients in second CR stopped the treatment a second time and showed a survival and DFS probabilities, respectively, of 69% and 43%. Thus, children with ALL who relapse after cessation of therapy still have a high risk of further late relapses and should be treated with intensive chemotherapy and CNS reprophylaxis. BMT must be considered for all patients relapsing in the BM within 12 months from off-therapy.

Publication Types: Multicenter Study

PMID: 7990766 [PubMed - indexed for MEDLINE]

Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia.

Lilleyman JS, Lennard L.

Department of Haematology, Children's Hospital, Sheffield, UK.

Many months' treatment with daily oral mercaptopurine is an important part of therapy for nearly all children with lymphoblastic leukaemia (ALL). Even when prescribed the same dose based on body surface area, patients have widely different intracellular concentrations of drug metabolites. Whether this variation matters in terms of disease control is not yet clear. To find out, we followed up a large group of children with ALL in whom mercaptopurine-derived thioguanine nucleotides in the red cells were measured during treatment with an identical dose of mercaptopurine early in first remission. 172 unselected children (100 boys, 72 girls) were recruited between 1980 and 1992. At median follow-up of 5 years from diagnosis 42 (24%) had relapsed; 30 had erythrocyte thioguanine nucleotide concentrations below the group median (284 pmol per 8 x 10(8) erythrocytes) and 12 had values above the median. The actuarial relapse-free survival at 5 years was 63% in the below-median group and 84% in the above-median group (difference 21% [95% CI 3-39%], p = 0.0018). Multivariate analysis showed that erythrocyte thioguanine nucleotide concentration was independent of other prognostic variables including age, leukaemia immunophenotype, white-blood-cell count at diagnosis, trial protocol, and sex. Whatever the cause, in childhood ALL variable formation of intracellular mercaptopurine metabolites seems to be clinically important. Therapeutic schedules that include long-term daily oral mercaptopurine might be more effective if such metabolites are monitored.

PMID: 7909868 [PubMed - indexed for MEDLINE]

Bone marrow transplantation for acute lymphoblastic leukemia (ALL).

Lazarus HM, Rowe JM.

Department of Medicine, Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University, Ohio 44106.

Advances in the treatment of childhood acute lymphoblastic leukemia (ALL) have been striking while results have been less impressive in adults who develop this disease. Obvious differences in a patient's ability to withstand cytotoxic therapy may account, in part, for these findings, but the biologic behaviour of the disease in the two age groups appears to be different; relapses are more frequent and cures less common in adults. In fact, age alone appears to be the most important prognostic factor in ALL. The demonstration of the efficacy of bone marrow transplantation in advanced disease as well as the marked improvements in supportive care and the development of effective high-dose cytotoxic preparative regimens, especially those which use total body irradiation, however, have paved the way for transplantation in first complete remission. Formerly, most adult ALL patients who underwent bone marrow transplant did so in relapse, or in second or subsequent remission. In most studies 40-50% of first remission adult patients attain long-term disease-free survival after allogeneic and autologous bone marrow transplant. Relapses are considerably higher in the autologous transplant group when compared to the allogeneic group, but the latter population may experience increased morbidity and mortality due to graft-versus-host disease and opportunistic infection. These differences may reflect the beneficial graft-versus-leukemia effect in the allograft as well as infusion of autologous leukemia cells in the autograft but neither transplant subtype appears superior. Compared to more conventional approaches, however, transplantation may offer improved disease-free survival, although patient selection appears to be significantly influence outcome. These many inherent biases must be noted when comparing markedly different approaches, e.g. transplant versus conventional therapy. The challenge of demonstrating which therapy is superior for adult ALL patients can only be addressed in a well-designed, prospective, randomized trial.

Publication Types: Review Review, Tutorial

PMID: 7850267 [PubMed - indexed for MEDLINE]

Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association.

Uderzo C, Valsecchi MG, Bacigalupo A, Meloni G, Messina C, Polchi P, Di Girolamo G, Dini G, Miniero R, Locatelli F, et al.

Clinica Pediatrica Universita di Milano, Ospedale San Gerardo, Monza, Italy.

PURPOSE: To compare the results of allogeneic bone marrow transplantation (AlloBMT) with those obtained with chemotherapy (CHEMO) in children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) after a marrow relapse. The experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association is summarized. PATIENTS AND METHODS: All children who had a relapse in the period 1980 to 1989 in 27 centers in Italy were eligible for the study. Of 287 eligible patients, 230 were treated with CHEMO, most of them (93%) according to a standard multiple-drug relapse protocol. The remaining 57 children underwent AlloBMT. Preparative regimens included total-body irradiation and chemotherapy (n = 51) or chemotherapy alone (n = 6). Statistical analysis was performed with a Cox regression model adjusting for waiting time to transplant and prognostic factors. RESULTS: In the whole series, minimum and median follow-up after second CR were 3 and 6.2 years, respectively; at 8 years from second CR, disease-free survival (DFS) was 20.0% (SE 2.5) and survival was 26.4% (SE 2.9). In the group of patients with an early first relapse, DFS was significantly longer after AlloBMT than after CHEMO (relative risk [RR] = 0.45, P = .002). No significant advantage of AlloBMT over CHEMO was found for patients with a late relapse (> 30 months since diagnosis). Duration of first CR significantly influenced prognosis in the CHEMO group (RR = 0.32, P = .0001 for patients with late first relapse versus patients with early first relapse). CONCLUSION: Results suggest an advantage in DFS of AlloBMT over CHEMO in ALL patients who experienced an early first medullary relapse. Prospective trials are needed to address efficacy of AlloBMT versus CHEMO in patients with late bone marrow relapse.

Publication Types: Clinical Trial Controlled Clinical Trial

PMID: 7844596 [PubMed - indexed for MEDLINE]

Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia.

Comment in: Lancet. 1995 Mar 11;345(8950):653.

Chessells JM, Bailey C, Richards SM.

Department of Haematology and Oncology, Institute of Child Health, London, UK.

The UK Medical Research Council trial MRC UKALL X was designed to investigate the benefit of one or two courses of additional intensification therapy in children with acute lymphoblastic leukaemia receiving standard treatment. From 1985 to 1990 1612 children, comprising more than 90% of eligible cases in the UK, were treated with intensive induction therapy, central nervous system directed therapy with cranial irradiation and intrathecal methotrexate, and continuing treatment for 2 years. 1171 children were randomised to receive additional intensification therapy at 5 weeks, 20 weeks, both, or neither. At follow-up of at least 3 years disease-free survival for all children at 5 years was 62% (95% confidence interval [Cl] 60.0-64.4), a significant improvement over the 56% (53.0-59.6) found in the preceding MRC UKALL trial. The 5-year disease-free survival was 71% (65.5-76.1) for children randomised to two blocks of intensification therapy, this being significantly better than the 62% (56.6-68.0), 61% (55.7-67.1), and 57% (50.9-62.7) rates for the groups randomised to one intensification block at 5 weeks, one at 20 weeks, and no intensification, respectively. The benefits of intensification therapy were seen irrespective of clinical factors known to influence outcome such as age, sex, and initial leucocyte count. We conclude that the addition of two courses of intensification therapy has produced a 14% improvement in disease-free survival and an 11% improvement in overall survival for the randomised patients. This additional treatment is of benefit to all children with acute lymphoblastic leukaemia, even those traditionally deemed at lower risk of relapse.

Publication Types: Clinical Trial Randomized Controlled Trial

PMID: 7823668 [PubMed - indexed for MEDLINE]

Autologous bone marrow transplantation in acute lymphoblastic leukaemia.

Jackson GH, Taylor PR, Lennard AL, Proctor SJ.

Department of Haematology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

There has been a great deal of interest in the use of high dose chemotherapy and/or radiotherapy, with autologous bone marrow/peripheral blood stem cell rescue, in the treatment of haematological malignancies including acute lymphoblastic leukaemia (ALL). In this review we assess the role of autologous bone marrow transplantation (ABMT) in ALL. The heterogeneity of this disease makes the analysis of treatment results in ALL difficult to interpret. There is some evidence that ABMT may be useful in second complete remission (CR) and increasing interest in ABMT as a therapeutic option in first CR in adults. At the moment there is little evidence that such an approach will have an impact in childhood ALL. ABMT is considerably less toxic than allogeneic bone marrow transplantation and the major cause of 'treatment failure' is disease relapse. There has been considerable effort put into purging autologous bone marrow of malignant stem cells but whether purging is effective remains controversial and not proven. Newer studies involving cytokines post-ABMT to stimulate an artificial 'graft versus leukaemia' effect may prove of value.

Publication Types: Review Review, Tutorial

PMID: 7819818 [PubMed - indexed for MEDLINE]

Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission: factors predictive of survival, relapse and graft-versus-host disease.

Moussalem M, Esperou Bourdeau H, Devergie A, Baruchel A, Ribaud P, Socie G, Parquet N, Traineau R, Hirsch I, Schaison G, et al.

Bone Marrow Transplant Unit, Saint-Louis Hospital, Paris, France.

Between 1983 and 1993, 42 patients with acute lymphoblastic leukemia (ALL) in second complete remission (CR) underwent an allogeneic HLA-identical bone marrow transplant (BMT; there was one family mismatched graft). The conditioning regimens varied, consisting of cyclophosphamide (CY) and total body irradiation (TBI; n = 10); CY, TBI, Ara C, VP-16 (n = 11); TBI, Ara C, melphalan (n = 20) (TAM) or other (n = 1). Cyclosporine A (CsA) (n = 15) or CsA and methotrexate (MTX) (n = 24) were the main regimens for prophylaxis of graft-versus-host disease (GVHD). Nineteen of 42 patients are alive in CR ranging from 1 to 72 months after BMT with a median follow-up of 36 months. The 4-year actuarial survival rate was 53%. The actuarial relapse rate was 17%. Twenty three patients died: 4 patients of leukemic relapse, 9 of infection, 2 of acute GVHD, 2 of multiorgan failure after chronic GVHD, 2 of a secondary tumour and 4 patients died of other causes. Several pre- and post-transplant characteristics were analyzed to determine predictive factors for survival, relapse and GVHD. The relapse rate was significantly influenced by the type of conditioning regimen with no relapse in the TBI, Ara C, melphalan group. The analysis of long-term sequelae shows that there are no severe complications in this last group. Our results confirm that allogeneic BMT can lead to long-term survival for children with ALL in second CR and suggest an advantage of using the TAM conditioning regimen in the eradication of the leukemic disease.

PMID: 7581095 [PubMed - indexed for MEDLINE]

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]

Results of cessation of treatment in childhood acute lymphocytic leukaemia.

Ekert H, Balderas A, Waters KD, Matthews RN.

From 1972 to 1977, 55 of 161 children with acute lymphocytic leukaemia discontinued treatment after being in continuous complete remission for three years. A low total white cell count as diagnosis (less than 10 X 10(9)/L) was significantly associated with cessation of therapy, but there was no significant association with age or sex. Nine patients have relapsed, all but one within 50 weeks of cessation of treatment. Testicular relapse occurred only in one patient. Actuarial complete remission rate with a median duration of follow-up 140 weeks was 76%, and there was no significant sex difference. It is proposed that the relatively good prognosis in boys after cessation of therapy may be related to limited use of steroids during induction chemotherapy.

PMID: 6942206 [PubMed - indexed for MEDLINE]

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]

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]

Poor prognosis of acute lymphoblastic leukemia with translocation (1;19) in childhood: potential interest of allogeneic bone marrow transplantation.

Vagner-Capodano AM, Michel G, Maraninchi D, Tubiana N, Gouzien M, Perrimond H, Carcassonne Y.

Laboratoire de Genetique, Faculte de Medecine, Marseille, France.

We report a new case of childhood acute lymphoblastic leukemia with translocation (1;19). At the time of diagnosis, the only adverse prognosis factor was the existence of this translocation. Under conventional chemotherapy, the girl experienced early marrow relapse (duration of first remission was 2 months). She received allogeneic bone marrow transplantation during the second remission and is alive in continuous complete remission 20 months after transplant. Several earlier reports have suggested that children with the (1;19) have a poor prognosis; If this poor response to conventional therapy is confirmed, an allogeneic bone marrow transplantation should be considered during the first remission.

Publication Types: Review Review of Reported Cases

PMID: 3281571 [PubMed - indexed for MEDLINE]

Medical cost of curing childhood acute lymphoblastic leukaemia.

Wheeler K, Leiper AD, Jannoun L, Chessells JM.

Department of Haematology/Oncology, Hospital for Sick Children, London.

Between 1970 and 1979 acute lymphoblastic leukaemia was diagnosed in 378 children at this hospital. The outcome for the 181 survivors was examined six or more years after diagnosis to assess morbidity in an unselected group of long term survivors. One hundred and thirty seven of the survivors were in first remission and probably cured (group I). Forty four (group II) had had one or more relapses, some of whom, who had isolated extramedullary relapses, also have a good chance of cure. In group I 136 patients had prophylactic cranial or craniospinal irradiation, while patients in group II, in addition to having that treatment, received local testicular (17) or craniospinal radiation (seven) for testicular or central nervous system relapse. Eight had additional prophylactic cranial radiotherapy after bone marrow relapse, and six had total body irradiation before bone marrow transplantation. The incidence of clinically important growth and endocrine morbidity was 20% in group I and 68% in group II. The morbidity in patients in group I was mainly attributable to early pubertal maturation. In group II 30 patients had growth failure, of whom 19 had gonadal failure from testicular or total body irradiation, 14 had growth hormone deficiency after doses of cranial irradiation of over 2400 cGy, and 10 had spinal growth impairment after craniospinal irradiation. Two also had early pubertal maturation. Five out of six patients who received total body irradiation had multiple endocrine deficiency. Neuropsychological sequelae of treatment were seen in 40 (42%) of 96 schoolchildren in group I and in 12 (38%) of 32 schoolchildren in group II. Postinfective sequelae of treatment were found in patients in both groups. These results show that the survivors who were in their first remission had a 42% residual morbidity related to treatment compared with an 82% morbidity in the survivors of one or more relapses who had multiple treatments.

PMID: 3122982 [PubMed - indexed for MEDLINE]

[Leukemia in childhood]

[Article in Italian]

Masera G, Adamoli L, Conter V, Piacentini G.

Clinica Pediatrica, Universita di Milano, Ospedale San Gerardo di Monza, Italia.

The prognosis of leukemia in children has changed remarkably in the last 20 years. Today more than 50% of children with Acute Lymphoblastic Leukemia (ALL) and about 30% of children with Acute non Lymphoblastic Leukemia (ANLL) can be cured with chemotherapy. The German Group BFM has obtained a significant improvement of results, both in ALL and ANLL using multidrug intensive treatment schedules. In Italy, thanks to the Italian Pediatrics Association of Hematology and Oncology (AIEOP), results have been improved in the last 10 years; very recently, new protocols with the BFM strategy have been started. Allogenic matched bone marrow transplantation (BMT) is indicated in children with ALL in 2nd complete remission (CR) following a relapse during or shortly after discontinuing treatment and in patients with Chronic Myeloid Leukemia. Chemotherapy results remain very poor in these patients. Allogenic BMT in usually performed also in children with ANLL in 1st CR. Autologous BMT, and allogenic BMT mismatched or from unrelated donors are being used with promising results when matched donors are not available. Most children cured of leukemia can enjoy a normal quality of life. However long term studies are still needed to determine the incidence of late effects, and to evaluate the psychosocial impact of the disease. In this context is becoming more and more important the role of the family doctor.

Publication Types: Review Review, Tutorial

PMID: 3050901 [PubMed - indexed for MEDLINE]

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]

Bone-marrow transplantation has a limited role in prolonging second marrow remission in childhood lymphoblastic leukaemia.

Chessells JM, Rogers DW, Leiper AD, Blacklock H, Plowman PN, Richards S, Levinsky R, Festenstein H.

Fifty-three children with acute lymphoblastic leukaemia whose first complete remission ended in bone-marrow relapse received similar reinduction and consolidation therapy. Thirteen had an HLA-compatible sibling donor and were eligible to receive a bone-marrow transplant (BMT); five survive, all off treatment in continuing remission. Forty had no donor and received further chemotherapy; sixteen survive, twelve in remission and six off treatment. After 1-5.5 years' follow-up from relapse, there is no significant difference in survival between the groups. The major obstacle to success is marrow relapse which occurred in two eligible patients before BMT could be carried out. The lengths of first and second remissions in both groups were significantly correlated. Morbidity in survivors was substantial. The scope of BMT as retrieval therapy for ALL is limited by the instability of second remissions; this difficulty will not be overcome by increasing the number of potential donors or the use of autologous marrow.

PMID: 2872392 [PubMed - indexed for MEDLINE]

Allogeneic bone marrow transplantation versus chemotherapy in the treatment of childhood acute lymphoblastic leukemia in second complete remission.

Torres A, Martinez F, Gomez P, Fornes G, Rojas R, Herrera C, Gomez JL, Manzanares R, Garcia JM, Andres P, et al.

Department of Haematology of Cordoba, Sevilla, Spain.

Seventy-six patients between the ages of 2 and 17 years with acute lymphoblastic leukemia (ALL) achieved a second complete remission induced by polychemotherapy. Twenty-one had an HLA-identical donor and underwent allogeneic bone marrow transplantation (BMT) after conditioning with total body irradiation and cyclophosphamide. The remaining 55 patients lacked a suitable donor and received intensive chemotherapy as treatment. Fifteen patients were excluded from the analysis because they relapsed within 3 months after achieving a second complete remission. Three of the 21 BMT patients died of transplant-related complications and seven relapsed between 90 and 480 days after transplantation. Eleven patients are alive and disease free at 5.5-71 months with an actuarial survival of 47.1%; eight patients are on a plateau extending from 22 to 71 months. Thirty-three patients treated with chemotherapy died from relapse and seven are alive and disease free 7.5-99 months from the second remission, with an actuarial survival of 9%. The probability of survival was significantly higher in the BMT group (p less than 0.025). The probability of remaining in complete remission in the BMT group was 58.5% versus 10.9% in the chemotherapy group (p less than 0.005). Our results show that BMT is the best alternative therapy for children affected by ALL who have had a relapse in the marrow.

PMID: 2819281 [PubMed - indexed for MEDLINE]

Chronopharmacokinetics of oral methotrexate and 6-mercaptopurine: is there diurnal variation in the disposition of antileukemic therapy?

Balis FM, Jeffries SL, Lange B, Murphy RF, Doherty KM, Arndt CA, Luery N, Poplack DG.

Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.

The chronopharmacokinetics of the orally administered antileukemic drugs, 6-mercaptopurine and methotrexate, were examined in 13 children with acute lymphoblastic leukemia (ALL) to establish if there is a pharmacokinetic basis for the lower relapse rate associated with administration of these agents in the evening. Children with ALL in complete remission had plasma drug concentrations monitored for 8 h following an oral dose of either methotrexate or 6-mercaptopurine administered in the morning (8 a.m.) and the evening (8 p.m.). Total drug exposure to oral methotrexate, as measured by the mean area under the plasma concentration-time curve (AUC), was 2.75 microM.h following the morning dose and 2.77 microM.h in the evening. For 6-mercaptopurine, the mean morning AUC (198 ng.h/ml) was higher than that following the evening dose (167 ng.h/ml) (p greater than 0.05); but compared to the wide interpatient variability observed with this drug, this 20% difference is not likely to be clinically significant. These results indicate that the suggested benefit of evening drug administration is not likely to be a result of diurnal variation in drug disposition.

PMID: 2782561 [PubMed - indexed for MEDLINE]

Chemotherapy for bone marrow relapse of childhood acute lymphoblastic leukemia.

Henze G, Fengler R, Hartmann R, Dopfer R, Gobel U, Graf N, Jurgens H, Niethammer D, Ritter J, Schellong G, et al.

Kinderklinik, Freie Universitat Berlin.

Results of the BMF study group trials ALL-REZ 83 and 85 for relapsed acute lymphoblastic leukemia (ALL) are presented. For children with late marrow relapse, remission rates of about 90% were seen in both studies. In children treated for early marrow relapse, the remission rate in study ALL-REZ 85 was superior (86% vs 62%). The probability of event-free survival for all patients and for those with early marrow relapse was also statistically significant (P less than 0.05). Children with T-cell ALL had an extremely unfavourable prognosis in both studies.

PMID: 2667787 [PubMed - indexed for MEDLINE]

Autologous bone marrow transplantation.

Santos GW, Yeager AM, Jones RJ.

Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.

Autologous bone marrow transplantation in the acute leukemias and lymphomas offers potentially curative treatment in patients who do not have a histocompatible, allogeneic donor. Results of marrow autografting in the lymphomas are especially encouraging, with disease-free survivals of 50-60% in patients who have failed primary and secondary treatment regimens. In the acute leukemias, one may expect 20-40% relapse-free survival after autologous marrow transplantation. We feel that ex vivo treatment ("purging") is necessary to eradicate occult tumor cells from autologous remission marrow in hematological malignancies, but this remains a controversial issue to some investigators. Preliminary studies of autologous bone marrow transplantation are promising in multiple myeloma and certain childhood tumors, and autografting is currently being explored in the treatment of other solid tumors such as adenocarcinoma of the breast.

Publication Types: Review Review, Tutorial

PMID: 2658765 [PubMed - indexed for MEDLINE]

Acute lymphocytic leukemia of childhood: the problem of relapses.

Rivera GK, Santana V, Mahmoud H, Buchanan G, Crist WM.

Department of Hematology-Oncology, St Jude Children's Research Hospital, University of Tennessee, College of Medicine, Memphis.

Developing improved therapy for the one-third or more of patients who can be expected to relapse after initial treatment for acute lymphoblastic leukemia would be less difficult if one could identify potential failures unequivocally at diagnosis. Subgroups of patients who should be considered candidates for highly experimental therapy include infants (less than 1 year of age), patients with the Philadelphia chromosome and perhaps patients with B-cell leukemia. The most important factor that determines the success of therapy after relapse is the length of the patient's initial remission. We recommend bone marrow transplantation for children whose first remission did not exceed 18 months. For all others, it appears that intensive chemotherapy affords as great a potential for cure as one could expect from transplantation. We favor intensive chemotherapy over transplantation in cases of late bone marrow relapse (greater than 18 months), because of the currently high peritransplantation mortality rate. It is not clear whether either modality will be adequate for patients relapsing on contemporary treatment programs.

Publication Types: Review Review, Tutorial

PMID: 2653524 [PubMed - indexed for MEDLINE]

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]

Bone marrow transplantation for childhood acute lymphoblastic leukaemia after marrow relapse.

Vowels MR, Lam-Po-Tang R, Mameghan H, Ford D, Trickett A, White L, Marshall G, Brown R.

Prince of Wales Children's Hospital, Randwick, NSW.

Children with acute lymphoblastic leukaemia in whom relapse in bone marrow occurs have a poor outlook when treated with chemotherapy alone. Twenty-seven patients with childhood acute lymphoblastic leukaemia were treated for marrow relapse with high-dose chemotherapy with or without total body irradiation followed by bone marrow transplantation (BMT). Twenty patients received allogeneic marrow from partially or completely matched histocompatible donors. In this group, nine patients (45%) were free of disease with a median follow-up of 57 months (range, 22 to 126 months) after transplantation, four (20%) died from interstitial pneumonitis and seven (35%) died after a further relapse. Seven patients received autologous marrow collected while they were in remission. In this group, one patient died from infection and six died after a further relapse. We conclude that allogeneic BMT is more effective than autologous transplantation and results in long-term disease-free survival in a significant number of patients. New methods are needed to eradicate residual disease in the patient and to purge marrow ex vivo.

PMID: 2329949 [PubMed - indexed for MEDLINE]

Bone marrow transplantation improves survival for acute lymphoblastic leukemia in relapse: a preliminary report.

de Alarcon PA, Trigg ME, Giller RH, Rumelhart SL, Holida MD, Wen BC.

Department of Pediatrics and Radiology, University of Iowa, Iowa City 52242.

Acute lymphoblastic leukemia of childhood is the most common malignant disease in children greater than 1 year of age. Chemotherapy has improved the survival of children with this disorder. More than 95% of children will achieve a remission with chemotherapy. However, 30% of children with acute lymphoblastic leukemia who achieved a remission will have a relapse sometime after successful remission-inducing chemotherapy. Although a second remission can be induced in most of these children, in 10-40% a remission cannot be induced or they relapse shortly thereafter and develop refractory leukemia. We present in this preliminary report the early results of therapy for refractory leukemia with an intensive preparative regimen for bone marrow transplantation including etoposide, cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Transplantation was done in twenty-three patients with refractory leukemia. Projected survival at 917 days after transplantation in these patients is 43.4% +/- 11%. The survival of these patients so far is similar to the survival of children with acute lymphoblastic leukemia transplanted in second remission. All patients treated with this regimen who had transplantation in relapse were free of leukemia 27 days after transplantation. The results of this preliminary report suggest that an intensive preparative regimen can improve the outlook of refractory leukemia and may rescue some patients who otherwise would have died of their disease.

PMID: 2285128 [PubMed - indexed for MEDLINE]

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]

Role of bone marrow transplantation in childhood lymphoblastic leukemia.

Johnson FL.

Section of Pediatric Hematology/Oncology, University of Chicago Medical Center, Illinois.

Allogeneic bone marrow transplantation is the only therapy introduced in the past 2 decades that has offered a better prognosis for children with ALL who have suffered a marrow relapse within 18 months of starting therapy. Currently, 40 to 50% of such patients are obtaining long remissions and are potentially cured by marrow transplantation. This therapy's effectiveness, however, is diminished by the problems of acute and chronic graft-versus-host disease, infection, and relapse. Further impact of marrow transplantation in the treatment of ALL awaits (1) more effective antileukemic preparative regimens or post-transplant antileukemic strategies, (2) less toxic preparative regimens to decrease the incidence of early and late effects, (3) more effective means of preventing and treating graft-versus-host disease, (4) the ability to safely perform mismatched marrow transplantation, and (5) more effective means of purging leukemic cells from remission bone marrow to expand the role of autologous marrow transplantation.

Publication Types: Review Review Literature

PMID: 2262489 [PubMed - indexed for MEDLINE]

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]

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]

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]

Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALL-protocols: results of the German Cooperative Study.

Dopfer R, Henze G, Bender-Gotze C, Ebell W, Ehninger G, Friedrich W, Gadner H, Klingebiel T, Peters C, Riehm H, et al.

Department of Hematology/Oncology, Children's University Hospital, Tubingen, Germany.

Fifty-one children between 26 and 214 months of age (median, 100 months) with acute lymphoblastic leukemia (ALL) were grafted in second remission from HLA-identical sibling donors (except for two patients who were grafted with a marrow with 1 antigen-mismatch). Initial treatment and relapse therapy were similar in all patients according to the BFM- and CoALL-protocols (front line: 38 patients according to BFM-protocols and 13 patients according to CoALL-protocols; relapse: 12 patients in study ALL-REZ-BFM 83, 17 in ALL-REZ-BFM 85, 20 in ALL-REZ-BFM 87, and two in ALL-REZ-BFM 90). The conditioning regimens were different, consisting of cyclophosphamide (CY) total body irradiation (TBI) plus (n = 27), VP-16-TBI (n = 23), and CY-TBI and ARA-C (n = 1). Three patients had a second graft after conditioning with CY-TBI for the first transplantation. The second ablative regimen consisted of CY plus VP-16 in the first patient and CY plus busulfan in the two other patients, one of whom relapsed again. All patients but three had bone marrow (BM), either isolated or combined, relapses. Twenty-nine of the patients are in continuous complete remission (CCR), ranging from 1 to 67 months after transplantation with a median time of 30 months. One patient was lost to follow-up in continuous remission. Nine patients died from treatment-related complications (infections and graft-versus-host disease) and 12 patients suffered a leukemic relapse; three of them received a second graft and two are in CCR. Kaplan-Meier analysis yields an event-free survival (EFS) of 0.52 +/- 0.08. The probability of a 7-year relapse-free interval (RFI) is 0.68 +/- 0.08. EFS for patients with late relapses is 0.47 +/- 0.12 and for patients with early relapses 0.56 +/- 0.1. The RFI for patients with late relapses is 0.65 +/- 0.12 and for patients with early relapses 0.69 +/- 0.11. There is a nonsignificant trend towards superior results for patients grafted after conditioning with VP-16 plus TBI. When all patients who are not in CCR at day +125 (which is the median interval between relapse diagnosis and BM transplantation [BMT]) are excluded from the chemotherapy results, there is no significant difference between the results of BMT and chemotherapy for late relapses. On the other hand, there is a significant advantage between chemotherapy and BMT for early relapses over chemotherapy (P less than or equal to .01).

Publication Types: Clinical Trial Controlled Clinical Trial Multicenter Study

PMID: 1824271 [PubMed - indexed for MEDLINE]

Allogeneic bone marrow transplantation in childhood leukemia.

Kato S, Yabe M, Yabe H, Kubota C, Hinohara T, Hattori K, Shinohara O.

Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan.

Allogeneic bone marrow transplantation was performed in 94 patients with hematologic malignancies or other various diseases during the period between March 1982 and November 1990 at Tokai University Hospital. Projected disease-free survival rates of HLA genotypically identical marrow recipients were 88.9% for chronic myeloid leukemia transplanted in the first chronic phase (N = 9), 90.9% for acute leukemia in the first complete remission (N = 15), 54.5% for acute leukemia in later remissions (N = 14), 62.5% for solid tumors (N = 8) and 0% for patients transplanted in relapse (N = 7). The rate for HLA-mismatched marrow recipients with leukemia was 27.8% (N = 16). For patients with non-neoplastic diseases it was 100% regardless of HLA-compatibility (N = 26). The quality of life in long-term surviving pediatric marrow recipients has been acceptable. Common abnormalities among survivors are long-lasting hypogonadism due to radiation and subclinical impairment of lung function in the first year post-BMT. About two-thirds of children experienced a transient decrease in growth velocity in the immediate posttransplant period.

Publication Types: Clinical Trial

PMID: 1792915 [PubMed - indexed for MEDLINE]

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]