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Originally published as JCO Early Release 10.1200/JCO.2008.17.6065 on December 8 2008 © 2009 American Society of Clinical Oncology. Prognostic Value of Minimal Residual Disease Quantification Before Allogeneic Stem-Cell Transplantation in Relapsed Childhood Acute Lymphoblastic Leukemia: The ALL-REZ BFM Study Group
From the Children's Hospital of the J.W. Goethe University, Frankfurt; Charité, Pediatric Oncology/Hematology, Berlin; University Medical Center, Pediatric Oncology/Hematology, Düsseldorf; University Children's Hospital Tübingen, Tübingen; Medizinische Hochschule Hannover, Hannover; University Children's Hospital, Erlangen, Erlangen; University Children's Hospital Hamburg, Hamburg, Germany; and St Anna Kinderspital, Pediatric Oncology/Hematology, Vienna, Austria Corresponding author: Peter Bader, MD, University Children's Hospital, Division for Stem Cell Transplantation, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany; e-mail: peter.bader{at}kgu.de
Purpose Minimal residual disease (MRD) before allogeneic stem-cell transplantation was shown to predict outcome in children with relapsed acute lymphoblastic leukemia (ALL) in retrospective analysis. To verify this, the Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group conducted a prospective trial.
Patients and Methods Between March 1999 and July 2005, 91 children with relapsed ALL treated according to the ALL-REZ BFM 96 or 2002 protocols and receiving stem-cell transplantation in
Results Probability of event-free survival (pEFS) and cumulative incidence of relapse (CIR) in 45 patients with MRD Conclusion MRD is an important predictor for post-transplantation outcome. As a result, new strategies with modified stem-cell transplantation procedures will be evaluated in ALL-BFM trials.
During the last decades, progress has been made in the treatment of childhood acute lymphoblastic leukemia (ALL) by conventional chemotherapy. Even at relapse, approximately one third of patients can be treated successfully with salvage chemotherapy/radiotherapy and stem-cell transplantation.1,2 A variety of risk factors have been established to predict outcome after chemotherapy and radiotherapy. In the Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) 96 and 2002 trials, patients were divided into strategic groups (S1 to S4) based on the time interval to relapse, the site of relapse, and the immunophenotype (Appendix Table A1, online only). Time point of relapse is considered very early if a relapse occurs within 18 months after diagnosis, early if relapse occurs between 18 and less than 30 months after diagnosis, and late if relapse occurs 6 months or later after cessation of chemotherapy.1 These three clinical parameters form the basis for clinical risk stratification resulting in event-free survival (EFS) rates ranging from 5% for S3/4 patients to 75% for S1 patients after chemotherapy/radiotherapy; the large S2 group has an intermediate risk, with an EFS rate of 35% to 40%.3,4
For high-risk patients (S3/4), an obligatory indication for allogeneic stem-cell transplantation has been established; whereas transplantation indication in intermediate-risk patients remains controversial.5 In this context, minimal residual disease (MRD) after induction therapy has been shown to be a powerful predictor of EFS in intermediated-risk patients and is used as stratification criteria in several trials.6 So far, the indication for allogeneic stem-cell transplantation in S2 patients with poor MRD response has been restricted to matched sibling donors (MSDs) or exactly matched unrelated donors (MUDs). Thus, for a majority of patients, allogeneic stem-cell transplantation has become an important treatment option.7 Nevertheless, relapse remains a cause for treatment failure.8-10 During the last 10 years, three major reports have been published presenting the importance of MRD before allogeneic transplantation.11-13 These studies were performed retrospectively and included heterogeneous patient cohorts who received transplantation in first complete remission (CR) and
Patients Between March 1999 and July 2005, a total of 275 children and adolescents with ALL in CR2 or CR3 underwent allogeneic stem-cell transplantation in pediatric centers in Germany. Among these patients, 91 patients were eligible for assessment of MRD as a result of the availability of a sufficiently sensitive clonal marker at relapse diagnosis, the availability of diagnostic material before stem-cell transplantation, and the decision of the transplanting center to participate in this prospective blinded study. Except for a lower rate of transplantations in CR3 patients (15%) compared with the total cohort (27%, P = .24), frequencies of all other clinical characteristics are equally distributed, confirming a representativeness of the investigated cohort (data not shown). Consequently, the probability of EFS (pEFS) at 5 years was not different between the investigated patients (0.46 ± 0.04) and the patients who were not included in the study (0.44 ± 0.05; n = 184; P = .887). All patients were pretreated according to the ALL-REZ BFM 96 protocol (n = 36) or the ALL-REZ BFM 2002 protocol (n = 55). Written informed consent was obtained from the patients and/or their guardians. The protocols were approved by the local ethical committees. Data were obtained for analysis until April 2007. All patients were in complete hematologic remission before transplantation as defined by less than 5% blasts in the bone marrow aspirate. Patient characteristics are listed in Table 1. The median time from MRD detection before start of conditioning was 13 days (range, 1 to 39 days); median time from relapse to transplantation was 134 days (range, 12 to 276 days); and median age at transplantation was 11.1 years (range, 3.0 to 22.6 years). Follow-up time, which was defined as time from transplantation to last observation in clinical complete remission, was 3.4 years (range, 0.5 to 6.6 years). Median observation time, which was defined as time from transplantation to death or last observation alive, was 1.8 years (range, 0.4 to 6.6 years). As could be shown in our previous study, patients in S3/4 could not be successfully treated by chemotherapy alone.7 Therefore, patients in S3/4 were eligible for transplantation with either an MSD, MUD, or mismatched donor; patients in S2 were only able to receive transplantation if either an MSD or a 9/10 HLA-identical unrelated donor was available.
Graft-versus-host disease (GVHD) prophylaxis was administered to patients who received their grafts either from an MSD or MUD and consisted of cyclosporine 3 mg/kg starting on day –1. For MUD, methotrexate was administered additionally on days 1, 3, and 6. Patients who received transplantation with a T-cell–depleted graft did not receive additional GVHD prophylaxis, except for five patients who received cyclosporine or mycophenolate mofetil. In patients older than 2 years, the conditioning regimen was based on total-body irradiation (TBI; n = 86) at a dose of 12 Gy in 3 days and 6 fractions. Patients younger than 2 years received a busulfan-based conditioning regimen (n = 5). In all patients with a matched donor who received TBI, etoposide was added (n = 38), which was further supplemented with cyclophosphamide in patients who received their grafts before 2002 (n = 30). Patients older than 2 years of age who were grafted from a mismatched donor received TBI, etoposide, and fludarabine together with antithymocyte globulin (n = 18).
MRD Detection
Statistical Analysis
Cumulative incidences of relapse (CIRs) were calculated according to Kalbfleisch and Prentice.28 Death and subsequent relapse were included as competing events; survival was counted as a censored event. Differences in CIR between subgroups were tested according to Gray29 using the R software for statistical computing.30 A two-sided P < .05 was regarded as significant. To test the independence of factors predictive for EFS, multivariate Cox regression analysis and the forward Wald tests have been applied. The independence of categoric parameters was calculated using the
According to the MRD level before allogeneic stem-cell transplantation, patients were categorized into the following four groups: group 1 = patients with undetectable MRD load (n = 36); group 2 = patients with a detectable MRD load less than the quantitative range (< 10–4 leukemic cells; n = 10); group 3 = patients with MRD load between  10–4 leukemic cells and less than 10–3 leukemic cells (n = 12); and group 4 = patients with MRD load of 10–3 leukemic cells (n = 33). pEFS and CIR were 0.64 ± 0.09 and 0.11 ± 0.06, respectively, for patients in group 1 (n = 36); 0.48 ± 0.16 and 0.20 ± 0.14, respectively, in patients in group 2; 0.19 ± 0.12 and 0.64 ± 0.16, respectively in patients in group 3; and 0.31 ± 0.09 and 0.54 ± 0.16, respectively, in patients in group 4 (Fig 1).
As can be seen from the data in Figure 1, pEFS and CIR were similar in groups 1 and 2 and in groups 3 and 4. Consequently, using 10–4 leukemic cells as a cutoff divided the patients into two prognostic groups; patients with MRD less than 10–4 leukemic cells (n = 46) had a significantly higher pEFS of 0.60 ± 0.08 and a lower CIR of 0.13 ± 0.06 compared with patients with MRD greater than 10–4 leukemic cells (n = 45) who had a pEFS of 0.27 ± 0.07 and a CIR of 0.57 ± 0.08 (EFS, log-rank test, P = .004; CIR, Gray, P < .001; Fig 2).
Distribution of Clinical Parameters in Different MRD Groups Univariate analysis was performed to see whether differences in survival between these two groups were caused by hazardous distribution of other risk factors. As shown in Table 1, clinical risk factors among patients with high and low MRD load did not differ. There was also no difference in both groups regarding presence or absence of TEL/AML1 expression, interval from MRD to transplantation, time to transplantation, age at transplantation, follow-up times, and observation times (data not shown). Only one patient showed BCR/ABL, and two patients showed MLL/AF4 fusion transcripts (data not shown).
Influence of MRD in CR2 Intermediate-Risk Patients
Influence of MRD in High-Risk CR2 Patients and Patients Who Received Transplantation in CR3 Because patients who received transplantation in CR3 (n = 14) had equally unfavorable outcomes after transplantation (data not shown) as high-risk patients in CR2 (S3/4, n = 42), these patients were grouped together in a high-risk cohort for final analysis. Among these 56 high-risk patients, 16 (29%) received an MSD transplantation, 16 (29%) received a mismatched related or unrelated transplantation, and 24 (43%) received an MUD transplantation. Compared with intermediate-risk patients, the rate of mismatched unrelated donor or MUD transplantation was significantly higher (P = .39). Patients who received transplantation with an MRD load of less than 10–4 leukemic cells (n = 25) had a pEFS and CIR of 0.53 ± 0.11 and 0.18 ± 0.08, respectively. In contrast, pEFS and CIR were 0.30 ± 0.09 and 0.50 ± 0.09, respectively, in patients who received transplantation with an MRD load of 10–4 leukemic cells (Fig 4).
Outcome According to MRD Levels Post-transplantation events were differently distributed between the groups with high and low MRD load before transplantation (P < .001). Of all 91 patients, 19 (21%) had transplantation-related deaths (TRDs). Twenty-nine (32%) of 91 patients developed relapse, and 43 (47%) of 91 patients remained in CR. Forty-nine patients survived, six of them after subsequent relapse after stem-cell transplantation. Events were more frequent in patients who received transplantation with an MRD load of 10–4 leukemic cells. Among 45 patients who received transplantation with an MRD load of 10–4 leukemic cells, 24 (53%) experienced a relapse; among 46 patients who received transplantation with an MRD load of less than 10–4 leukemic cells, five (11%) experienced relapse. Twelve TRDs (26%) occurred in the 46 patients who received transplantation with an MRD load of less than 10–4 leukemic cells, whereas seven TRDs (16%) occurred in the 45 patients who received transplantation with an MRD load 10–4 leukemic cells.
Prognostic Impact of Other Clinical and Therapeutic Parameters
Multivariate Analysis of the Prognostic Impact of MRD
In a prospective and blinded study, we investigated the prognostic significance of MRD before allogeneic stem-cell transplantation in patients with ALL treated according to the ALL-REZ BFM 96 or 2002 protocol. MRD proved to be the most important determinant for subsequent relapse and survival after transplantation in univariate and multivariate analysis. The cutoff of less than 10–4 leukemic cells turned out to be a feasible discriminator between patients at high ( 10–4 leukemic cells) or low risk (< 10–4 leukemic cells) for subsequent relapse. Thus, we confirmed the results of three major retrospective analyses that suggested the prognostic impact of MRD before stem-cell transplantation in heterogeneous patient cohorts with less standardized methods.11-13 Each of these studies showed that children with high MRD loads have a dismal prognosis. Imashuku et al31 challenged the relevance of MRD before transplantation, showing a high proportion of MRD-positive patients before transplantation (96%) and an intriguing high frequency of clonal evolution hampering MRD detection itself. However, the authors did not use an up-to-date methodology, and it became important for a standardized, quality-reassuring MRD approach to be established before final conclusions could be drawn. Although clinical consequences from these findings have been extensively discussed, the ALL-REZ BFM Study Group decided to prove the data under well-controlled conditions.15,32,33 Although this study was performed prospectively, it included only patients with ALL in more than first CR, and the results were blinded to the clinicians, several limitations remain. The study cohort included patients in CR2 and CR3, included transplantations from different donors, used several conditioning regimen, and covered a long period of time. A data set on a larger homogeneous patient cohort who received transplantation in CR2 with only one donor type and one conditioning regimen, leaving pretransplantation MRD as the only important variable, would be the ideal setting to assess the prognostic importance of MRD. Nevertheless, the multivariate model considering the mentioned covariates revealed MRD to be the only independent predictive parameter and provides enough evidence to consider MRD as a reliable surrogate marker for EFS and relapse-free survival after stem-cell transplantation.
The importance of MRD proved to be valid in intermediate-risk (S2) and high-risk patients (S3/4, CR3). In intermediate-risk patients, MRD after induction proved to be of major prognostic importance.6 Therefore, patients with an MRD load of more than 10–3 leukemic cells are candidates for allogeneic stem-cell transplantation in the ongoing ALL-REZ BFM 2002 trial. The association of MRD after induction and MRD before stem-cell transplantation has to be demonstrated in the ongoing study. So far, the data presented here suggest that intermediate-risk patients with an MRD load of less than 10–4 leukemic cells before transplantation are at a low risk for relapse after stem-cell transplantation. Furthermore, in intermediate-risk patients with an MRD load of
In our study, a patient group with a high risk for subsequent relapse can be defined by the MRD quantification before transplantation. Patients with an MRD load of Although late effects have to be kept in mind,36 new leukemia-targeted drugs (eg, kinase inhibitors,37,38 monoclonal antibodies,39 and new antimetabolites, such as clofarabine40) might be an option to improve the remission quality. Further attempts might be directed at increasing the alloreactive potential of the transplantation (eg, by lowering doses of cyclosporine).41 The effect of pre-emptive immunotherapy based on chimerism or MRD demonstrated inconclusive results.9,15,42-45 In conclusion, our study demonstrates that assessment of MRD before transplantation is a powerful tool for predicting relapse in children after allogeneic stem-cell transplantation for ALL. These results are forming the basis of further intervention strategies to improve the perspective within the ALL-BFM-REZ trials.
The author(s) indicated no potential conflicts of interest.
Conception and design: Peter Bader, Günter H.R. Henze, Thomas Klingebiel, Arend von Stackelberg Administrative support: Peter Bader, Günter H.R. Henze, Thomas Klingebiel Provision of study materials or patients: Peter Bader, Cornelia Eckert, Arndt Borkhardt, Rupert Handgretinger, Karl-Walter Sykora, Wolfgang Holter, Hartmut Kabisch, Thomas Klingebiel, Arend von Stackelberg Collection and assembly of data: Peter Bader, Hermann Kreyenberg, Günter H.R. Henze, Cornelia Eckert, Andrea Barth, Arndt Borkhardt, Arend von Stackelberg Data analysis and interpretation: Peter Bader, Hermann Kreyenberg, Günter H.R. Henze, Miriam Reising, Andre Willasch, Andrea Barth, Christina Peters, Rupert Handgretinger, Karl-Walter Sykora, Wolfgang Holter, Hartmut Kabisch, Thomas Klingebiel, Arend von Stackelberg Manuscript writing: Peter Bader, Günter H.R. Henze, Andre Willasch, Arend von Stackelberg Final approval of manuscript: Peter Bader, Hermann Kreyenberg, Günter H.R. Henze, Cornelia Eckert, Miriam Reising, Andre Willasch, Arndt Borkhardt, Christina Peters, Rupert Handgretinger, Karl-Walter Sykora, Wolfgang Holter, Hartmut Kabisch, Thomas Klingebiel, Arend von Stackelberg
We thank all participating centers and all colleagues who included less than six patients in the study: B. Kremens, MD, University Children's Hospital Essen; C. Niemeyer, MD, University Children's Hospital Freiburg; J. Beck, MD, University Children's Hospital Jena; S. Burdach, MD, University Children's Hospital Muenchen-Schwabing; I. Schmidt, MD, Muenchen v Haunersches Kinderspital; and D.W. Friedrich, MD, University Children's Hospital Ulm.
published online ahead of print at www.jco.org on December 8, 2008 Supported by the Wilhelm Sander Stiftung, München, Germany (P.B.) and the Deutsche Kinderkrebsstiftung, Bonn, Germany (Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster Study Group). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Einsiedel HG, von Stackelberg A, Hartmann R, et al: Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: Results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Munster Group 87. J Clin Oncol 23:7942-7950, 2005 2. von Stackelberg A, Hartmann R, Buhrer C, et al: High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood 111:2573-2580, 2008 3. Henze G, von Stackelberg A: Treatment of relapsed acute lymphoblastic leukemia, in Pui CH (ed): Treatment of Acute Leukemias: New Directions for Clinical Research. Totowa, NJ, Humana Press, 2002, pp 199-219 4. Gaynon PS, Qu RP, Chappell RJ, et al: Survival after relapse in childhood acute lymphoblastic leukemia: Impact of site and time to first relapse—The Children's Cancer Group Experience. Cancer 82:1387-1395, 1998[CrossRef][Medline] 5. Peters C, Schrauder A, Schrappe M, et al.:Allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukaemia: The BFM/IBFM/EBMT concepts. Bone Marrow Transplant 35:S9-S11, 2005 (suppl 1) 6. Eckert C, Biondi A, Seeger K, et al: Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 358:1239-1241, 2001[CrossRef][Medline] 7. Borgmann A, von Stackelberg A, Hartmann R, et al: Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: A matched-pair analysis. Blood 101:3835-3839, 2003 8. Bader P, Beck J, Frey A, et al: Serial and quantitative analysis of mixed hematopoietic chimerism by PCR in patients with acute leukemias allows the prediction of relapse after allogeneic BMT. Bone Marrow Transplant 21:487-495, 1998[CrossRef][Medline] 9. Bader P, Kreyenberg H, Hoelle W, et al: Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: Possible role for pre-emptive immunotherapy? J Clin Oncol 22:1696-1705, 2004 10. Chessells JM: Recent advances in management of acute leukaemia. Arch Dis Child 82:438-442, 2000 11. Knechtli CJ, Goulden NJ, Hancock JP, et al: Minimal residual disease status as a predictor of relapse after allogeneic bone marrow transplantation for children with acute lymphoblastic leukaemia. Br J Haematol 102:860-871, 1998[CrossRef][Medline] 12. van der Velden VH, Joosten SA, Willemse MJ, et al: Real-time quantitative PCR for detection of minimal residual disease before allogeneic stem cell transplantation predicts outcome in children with acute lymphoblastic leukemia. Leukemia 15:1485-1487, 2001[CrossRef][Medline] 13. Bader P, Hancock J, Kreyenberg H, et al: Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL. Leukemia 16:1668-1672, 2002[CrossRef][Medline] 14. Uzunel M, Mattsson J, Jaksch M, et al: The significance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia. Blood 98:1982-1984, 2001 15. Sramkova L, Muzikova K, Fronkova E, et al: Detectable minimal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 48:93-100, 2007[CrossRef][Medline] 16. Krejci O, van der Velden VH, Bader P, et al: Level of minimal residual disease prior to haematopoietic stem cell transplantation predicts prognosis in paediatric patients with acute lymphoblastic leukaemia: A report of the Pre-BMT MRD Study Group. Bone Marrow Transplant 32:849-851, 2003[CrossRef][Medline] 17. Sánchez J, Serrano J, Gomez P, et al: Clinical value of immunological monitoring of minimal residual disease in acute lymphoblastic leukaemia after allogeneic transplantation. Br J Haematol 116:686-694, 2002[CrossRef][Medline] 18. Pongers-Willemse MJ, Seriu T, Stolz F, et al: Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets: Report of the BIOMED-1 CONCERTED ACTION—Investigation of minimal residual disease in acute leukemia. Leukemia 13:110-118, 1999[CrossRef][Medline] 19. Szczepa 20. Brüggemann M, Droese J, Bolz I, et al: Improved assessment of minimal residual disease in B cell malignancies using fluorogenic consensus probes for real-time quantitative PCR. Leukemia 14:1419-1425, 2000[CrossRef][Medline] 21. Verhagen OJ, Willemse MJ, Breunis WB, et al: Application of germline IGH probes in real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia. Leukemia 14:1426-1435, 2000[CrossRef][Medline] 22. van der Velden VH, Wijkhuijs JM, Jacobs DC, et al: T cell receptor gamma gene rearrangements as targets for detection of minimal residual disease in acute lymphoblastic leukemia by real-time quantitative PCR analysis. Leukemia 16:1372-1380, 2002[CrossRef][Medline] 23. Kerst G, Kreyenberg H, Roth C, et al: Concurrent detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia by flow cytometry and real-time PCR. Br J Haematol 128:774-782, 2005[CrossRef][Medline] 24. van der Velden VH, Cazzaniga G, Schrauder A, et al: Analysis of minimal residual disease by Ig/TCR gene rearrangements: Guidelines for interpretation of real-time quantitative PCR data. Leukemia 21:604-611, 2007[Medline] 25. Pongers-Willemse MJ, Verhagen OJ, Tibbe GJ, et al: Real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia using junctional region specific TaqMan probes. Leukemia 12:2006-2014, 1998[CrossRef][Medline] 26. Eckert C, Landt O: Real-time PCR to detect minimal residual disease in childhood ALL. Methods Mol Med 91:175-182, 2004[Medline] 27. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 28. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, Wiley, 1980, p 169 29. Gray RJ: A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988[CrossRef] 30. The R Foundation for Statistical Computing, Institut für Statistik und Wahrscheinlichkeitstheorie der Technischen Universität Wien: R, A Language and Environment for Statistical Computing and Graphics. Vienna, Austria, University of Vienna, 2003 31. Imashuku S, Terui K, Matsuyama T, et al: Lack of clinical utility of minimal residual disease detection in allogeneic stem cell recipients with childhood acute lymphoblastic leukemia: Multi-institutional collaborative study in Japan. Bone Marrow Transplant 31:1127-1135, 2003[CrossRef][Medline] 32. Goulden N, Bader P, van der Velden VH, et al: Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia. Br J Haematol 122:24-29, 2003[CrossRef][Medline] 33. Schilham MW, Balduzzi A, Bader P: Is there a role for minimal residual disease levels in the treatment of ALL patients who receive allogeneic stem cells? Bone Marrow Transplant 35:S49-S52, 2005 (suppl 1)[CrossRef][Medline] 34. Borgmann A, Zinn C, Hartmann R, et al: Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood. Eur J Cancer 44:257-268, 2008[CrossRef][Medline] 35. Wassmann B, Pfeifer H, Goekbuget N, et al: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 108:1469-1477, 2006 36. Ottmann OG, Hoelzer D: The ABL tyrosine kinase inhibitor STI571 (Glivec) in Philadelphia positive acute lymphoblastic leukemia: Promises, pitfalls and possibilities. Hematol J 3:2-6, 2002[CrossRef][Medline] 37. Lang P, Barbin K, Feuchtinger T, et al: Chimeric CD19 antibody mediates cytotoxic activity against leukemic blasts with effector cells from pediatric patients who received T-cell-depleted allografts. Blood 103:3982-3985, 2004 38. Pui CH, Jeha S, Kirkpatrick P: Clofarabine. Nat Rev Drug Discov 4:369-370, 2005[CrossRef][Medline] 39. Locatelli F, Bruno B, Zecca M, et al: Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: Results of a GITMO/EBMT randomized trial. Blood 96:1690-1697, 2000 40. Formánková R, Sedlacek P, Krskova L, et al: Chimerism-directed adoptive immunotherapy in prevention and treatment of post-transplant relapse of leukemia in childhood. Haematologica 88:117-118, 2003 41. Dominietto A, Lamparelli T, Raiola AM, et al: Transplant-related mortality and long-term graft function are significantly influenced by cell dose in patients undergoing allogeneic marrow transplantation. Blood 100:3930-3934, 2002 42. Spinelli O, Peruta B, Tosi M, et al: Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia. Haematologica 92:612-618, 2007 43. Bader P, Koscielnak E, Schlegel PG, et al: Combined chemo-immunotherapy in children with ALL who relapse after allogeneic stem cell transplantation: An option to induce long term remission. Bone Marrow Transplant 33:220, 2004 Submitted April 13, 2008; accepted September 12, 2008.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
-deleting element (IGV
(TCRV
(TCRV
2 test or the Fisher's exact test. The distribution of continuous variables was calculated using the Mann-Whitney U test. 
ski T, Orfao A, van der Velden VH, et al: Minimal residual disease in leukaemia patients. Lancet Oncol 2:409-417, 2001
