Superiority of Allogeneic Hematopoietic Stem-Cell Transplantation Compared With Chemotherapy Alone in High-Risk Childhood T-Cell Acute Lymphoblastic Leukemia: Results From ALL-BFM 90 and 95

  1. Martin Schrappe
  1. From the Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel; Department of Pediatric Hematology and Oncology, Justus-Liebig University, Gieβen; Department of Pediatric Hematology and Oncology, University Hospital, Tübingen; Department of Pediatric Hematology and Oncology, Johann Wolfgang Goethe University, Frankfurt; Department of Pediatric Hematology and Oncology, University Hospital, Essen; Department of General Pediatrics and Bone Marrow Transplantation, Charité, University Medicine Berlin, Berlin; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover; Department of Hematology, Oncology and Tumor Immunology, Robert-Rössle-Clinic at the HELIOS Clinic Berlin-Buch, Charité, Germany; Children's Hospital St Anna, Wien, Austria; and the Department of Pediatric Hematology and Oncology, University Hospital, Zürich, Switzerland
  1. Address reprint requests to Martin Schrappe, MD, PhD, Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Schwanenweg 20, 24105 Kiel, Germany; e-mail: m.schrappe{at}pediatrics.uni-kiel.de
 
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Abstract

Purpose The role of hematopoietic stem-cell transplantation (SCT) in first complete remission (CR1) for children with very high–risk (VHR) acute lymphoblastic leukemia (ALL) is still under critical discussion.

Patients and Methods In the ALL–Berlin-Frankfurt-Münster (BFM) 90 and ALL-BFM 95 trials, 387 patients were eligible for SCT if there was a matched sibling donor (MSD). T-cell ALL (T-ALL) patients with poor in vivo response to initial treatment represented the largest homogeneous subgroup within VHR patients.

Results Of 191 high-risk (HR) T-ALL patients, 179 patients (94%) achieved CR1. Twenty-three patients received an MSD-SCT. Furthermore, in trial ALL-BFM 95, eight matched unrelated donors (MUDs) and five mismatched family donors (MMFDs) were used. The median time to SCT was 5 months (range, 2.4 to 10.8 months) from diagnosis. The 5-year disease-free survival (DFS) was 67% ± 8% for 36 patients who received an SCT in CR1 and 42% ± 5% for the 120 patients treated with chemotherapy alone having an event-free survival time of at least the median time to transplantation (Mantel-Byar, P = .01). Overall survival (OS) rate for the SCT group was 67% ± 8% at 5 years, whereas patients treated with chemotherapy alone had an OS rate of 47% ± 5% at 5 years (Mantel-Byar, P = .01). Outcome of patients who received MSD-SCT versus MUD-/MMFD-SCT was comparable (DFS, 65% ± 10% v 69% ± 13%, respectively). However, relapses only occurred after MSD-SCT (eight of 23 patients), whereas treatment-related mortality only occurred after MUD-/MMFD-SCT (four of 13 patients).

Conclusion SCT in CR1 is superior to treatment with chemotherapy alone for childhood HR-T-ALL.

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INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common indication for allogeneic stem-cell transplantation (SCT) in children. For ALL patients in first complete remission (CR1), SCT has been restricted to treatment of high-risk (HR) ALL patients because conventional chemotherapy provides excellent results for non-HR patients in CR1.1-3 Research on childhood ALL has focused on biologic and clinical prognostic markers to identify patients at highest risk of relapse4-9 who, therefore, have an indication for SCT.

A satisfying definition of indications associated with a true benefit of transplantation in CR1 of ALL is still under discussion.10 Recently, Hahn et al11 showed, in an evidence-based review, that studies comparing SCT and chemotherapy alone are mainly performed on patients in second CR (CR2).12-14 Only a few large studies are addressing this question for very high–risk (VHR) ALL patients in CR115-18 or have analyzed SCT in childhood ALL in biologic subsets.17-19 The broad biologic heterogeneity within childhood ALL may have prevented the unraveling of the benefit of SCT in subgroups.

Based on results from the ALL–Berlin-Frankfurt-Münster (BFM) 83 and 86 trials,4,5 HR-ALL was defined in the ALL-BFM 90 and 95 trials by prednisone poor response (PPR; ≥ 1,000 blasts/μL in peripheral blood after 1 week of prednisone and one intrathecal dose of methotrexate), nonresponse on day 33 (NRd33), or chromosomal translocations t(9;22) or t(4;11). Patients with T-cell ALL (T-ALL) and inadequate in vivo response to initial treatment (PPR and/or NRd33) are known to have a poor prognosis and represent a well-defined, biologically homogeneous treatment group with particularly high risk of relapse,5,20 for whom matched sibling donor (MSD) SCT is recommended.

The aim of this study was to compare the outcome of HR-T-ALL patients after chemotherapy plus SCT with outcome after chemotherapy alone. Furthermore, the importance of chemotherapy administered before the myeloablative regimen could also be analyzed because this treatment was intensified in trial ALL-BFM 95 compared with trial ALL-BFM 90.

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PATIENTS AND METHODS

Patients

From April 1, 1990, until June 30, 2000, 4,628 patients up to 18 years old were enrolled onto the ALL-BFM 90 and 95 studies on treatment of childhood ALL in 96 participating centers in Germany, Austria, and Switzerland. According to previously published criteria, 4,347 patients were eligible for analysis (2,178 patients in ALL-BFM 90 and 2,169 patients in ALL-BFM 95).3,21 For each patient, informed consent was obtained from parents or guardians. Trials ALL-BFM 90 and ALL-BFM 95 were approved both by the central ethical committee at the Medical School Hannover and by the local institutional review boards of the participating institutions.

Diagnostics and Assessment of Treatment Response

The diagnosis of ALL including CNS involvement and immunophenotyping were performed as previously described.22-25 Cytogenetic studies were carried out using standard techniques.26 Since November 1992, reverse transcriptase polymerase chain reaction–based screening for BCR/ABL was offered to participating centers.27 In trial ALL-BFM 95, all patients were screened for MLL/AF4 and BCR/ABL rearrangement by multiplex reverse transcriptase polymerase chain reaction.28 Definitions of the BFM risk factor (BFM-RF), a leukemic cell mass estimate, and of the prednisone response were as described previously.4,29 CR was defined as the absence of leukemic blasts in peripheral blood and cerebrospinal fluid, less than 5% lymphoblasts in bone marrow (BM) aspiration smears, and no evidence of localized disease. Relapse was defined as recurrence of ≥ 25% lymphoblasts in BM or localized leukemic infiltrates at any site.

Definition of HR and VHR Groups

In both trials, patients were assigned to a standard-risk group, medium-risk group, or HR group (HRG). The main criteria for stratification in ALL-BFM 90 were the BFM-RF and the prednisone response. In ALL-BFM 95, WBC count and age were used instead of BFM-RF.3,21

HRG was defined by PPR, NRd33 (≥ 5% blasts in BM on day 33), or positivity for translocations t(9;22) or t(4;11) or MLL/AF4 or BCR/ABL rearrangement. The eligibility criteria for allogeneic SCT were predefined as the following HR characteristics identifying ALL children who had a very high risk of failure: (1) t(9;22) or BCR/ABL rearrangement; (2) t(4;11) or MLL/AF4 rearrangement; (3) NRd33; or (4) PPR plus at least one of the following: T-ALL, pro–B-cell ALL, coexpression of myeloid markers, or BFM-RF of 1.7 or higher. In this study, we analyzed the subgroup of VHR patients with T-ALL and a poor in vivo response to initial treatment (PPR and/or NRd33) because these patients represent the largest homogeneous subset of VHR patients.

Treatment in HRG

Treatment of the HRG in trials ALL-BFM 90 and 95 is schematically shown in Figure 1, and details for reconsolidation regarding dosage and exact timing are listed in Table 1. Induction (protocol I/A), delayed reintensification (protocol II), and maintenance therapy have been described previously.3,21 In ALL-BFM 95, only the dose (from 6 × 10,000 U/m2 to 6 × 5,000 U/m2) and preparation of asparaginase in induction were modified. For the subset of VHR patients, allogeneic SCT was recommended if an MSD was available. SCT was performed between the third and sixth HR course. Histocompatibility of patient and MSD was determined by serologic typing of loci HLA-A, HLA-B, and HLA-DRB1 in trial ALL-BFM 90; in trial ALL-BFM 95, class II HLA-DRB1 locus was typed by high-resolution molecular techniques. Stem-cell source was unmanipulated BM (mononuclear cells > 2 × 108/kg body weight). The recommended preparative regimen was based on total-body irradiation (6 fractions of 2 Gy each on days −6 to −4; only indicated for age ≥ 2 years) followed by etoposide (60 mg/kg intravenous [IV] on day −3). For patients less than 2 years of age, busulfan (5 mg/kg/d orally on days −8 to −5), etoposide (40 mg/kg IV on day −4), and cyclophosphamide (60 mg/kg/d IV on days −3 to −2) were administered.31,32 Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (initial IV dose of 3 mg/kg/d) from day −1 until oral intake was possible. Dose adjustment according to blood levels was recommended, and tapering of cyclosporine was started at day 100 in the absence of GVHD. Methotrexate was administered at 15 mg/m2/d IV on day +1 and subsequently at 10 mg/m2/d IV on days +3, +6, and +11. Despite guidelines for MSD transplantation, in trial ALL-BFM 95, matched unrelated donors (MUD) or mismatched family donors (MMFD) were also used. Then, antithymocyte globulin (20 mg/kg/d IV on days −3 to −1) was added to the myeloablative regimen or megadoses of T-cell–depleted haploidentical stem cells were used for transplantation.33

Fig 1.
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Fig 1.

Treatment of the high-risk (HR) group in Acute Lymphoblastic Leukemia–Berlin-Frankfurt-Münster (ALL-BFM) trials 90 and 95. Granulocyte colony-stimulating factor was applied after each HR block (in ALL-BFM 90 patients randomly assigned after each HR block30). Preventive radiotherapy (12 Gy) was indicated for patients more than 1 year of age; patients with CNS involvement received 18 Gy (1 to 2 years of age) or 24 Gy (> 2 years of age). SCT, stem-cell transplantation.

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Table 1.

HR Treatment Blocks of Intensive Reconsolidation in Trials ALL-BFM 90 and ALL-BFM 95

Statistical Analysis

Duration of event-free survival (EFS) was defined as the time from diagnosis until the date of the first event (ie, relapse, death from any reason, secondary malignancy) or, if no such event occurred, until the date of last contact. Patients who did not attain CR by the third block of intensive reconsolidation at the latest were considered as having treatment failure at time zero. Duration of disease-free survival (DFS) for patients who achieved remission was defined as the time from CR until the date of the first event (ie, relapse, death, secondary malignancy) or, if no such event occurred, until the date of last contact. Outcomes of patients receiving SCT were compared with those of patients receiving chemotherapy alone using the Mantel-Byar method and Cox regression analysis including time to SCT as a time-dependent covariable.34 Distributions of EFS and DFS were estimated by the Kaplan-Meier method, with SEs according to Greenwood, and were compared using the log-rank test for comparisons not involving SCT. For Kaplan-Meier plots comparing SCT and chemotherapy alone, only patients with an EFS of at least the median time to SCT were included.

Information on donor availability was not available for patients on the ALL-BFM 90 trial. Thus, an intent-to-treat analysis was only performed on the data of the patients of the ALL-BFM 95 trial. Outcomes of patients who had a suitable related donor were compared with the outcomes of patients who did not, irrespective of whether they were actually treated with chemotherapy alone or any kind of SCT in CR1. All other comparisons between SCT and chemotherapy alone were performed using as-treated analyses.

Cumulative incidence functions for relapse and death in CR were calculated by the method of Kalbfleisch and Prentice and compared with Gray's test.35 Differences in the distribution of variables among patient subsets were analyzed using the χ2 test for categorized variables.

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RESULTS

Of 4,347 patients treated in trials ALL-BFM 90 and 95, 556 patients had T-ALL, and of these, 191 patients were eligible for MSD-SCT because of PPR and/or NRd33 (104 patients in ALL-BFM 90 and 87 patients in ALL-BFM 95). These 191 HR-T-ALL patients represented the largest cohort among the heterogeneous group of all 387 VHR patients. One hundred seventy-nine (94%) of 191 HR-T-ALL patients achieved a stable CR1. The patients treated according to the ALL-BFM 95 protocol were already part, but not the focus, of the report by Balduzzi et al.16

Patient Characteristics

The 179 patients who reached CR (96 patients in ALL-BFM 90 and 83 patients in ALL-BFM 95) had a median follow-up time of 6.5 years. Thirty-six patients (20%) received an SCT. According to the recommendations, 23 MSD-SCTs were performed (10 in ALL-BFM 90 and 13 in ALL-BFM 95). Deviating from guidelines, in trial ALL-BFM 95, MUD (n = 8) and MMFD (n = 5) were also used. The median time to SCT was 5 months (range, 2.4 to 10.8 months) from diagnosis. MSD-SCT was performed somewhat earlier than MUD-/MMFD-SCT (median time to SCT, 5 v 7 months, respectively). Characteristics of HR-T-ALL patients in the different treatment groups (Table 2) showed no significant differences regarding age, WBC at diagnosis, and initial response. In the MSD-SCT group, there were more female patients compared with both other treatment groups (χ2 test, P = .02).

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Table 2.

Characteristics of HR-T-ALL Patients Who Achieved CR1 in the Different Treatment Groups

Outcome of HR-T-ALL Patients in the Two Subsequent Trials

Trial ALL-BFM 90.

After a median observation time of 8 years, the EFS rate of all 104 assessable patients was 29% ± 4% at 5 years (Fig 2). Eight patients (7.7%) did not achieve CR1. In the 96 patients who achieved CR1, the DFS rate at 5 years was 31% ± 5%. Sixty-four patients experienced relapse, and two patients died in CR. Thirty patients are in continuous CR.

Fig 2.
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Fig 2.

Kaplan-Meier estimate of event-free survival (EFS) at 5 years of high-risk patients in Acute Lymphoblastic Leukemia–Berlin-Frankfurt-Münster (ALL-BFM) trials 90 and 95. pEFS, probability of EFS.

Trial ALL-BFM 95.

The EFS rate at 5 years for all 87 patients was 51% ± 5%, which was a significant improvement compared with the ALL-BFM 90 trial (log-rank, P = .003; Fig 2). The DFS rate at 5 years of all 83 patients who achieved CR1 was 53% ± 5%, reflecting the significant improvement for HR-T-ALL patients in ALL-BFM 95 (log-rank, P = .004). Thirty-nine events occurred, including 29 relapses, nine deaths in CR, and one secondary malignancy. Forty-four patients are still in continuous CR.

Comparison of SCT Versus Chemotherapy Alone

In trial ALL-BFM 90, MSD-SCT was performed in 10 patients. Eighty-six patients were treated with chemotherapy alone. Adjustment for a minimum follow-up of 0.43 years after diagnosis (medium time to transplantation) resulted in a DFS rate at 5 years of 35% ± 6% for the patients treated with chemotherapy alone and 50% ± 16% for the SCT group (Mantel-Byar, P = .27; Fig 3).

Fig 3.
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Fig 3.

Kaplan-Meier estimate of disease-free survival (DFS) at 5 years in matched sibling donor stem-cell transplantation (MSD-SCT) patients versus patients treated with chemotherapy alone (Acute Lymphoblastic Leukemia–Berlin-Frankfurt-Münster trial 90; analysis as treated). From the group of patients treated with chemotherapy alone, patients with an event before 0.43 years (medium time to transplant) were excluded.

In trial ALL-BFM 95, 57 of the 83 patients were treated with chemotherapy alone, whereas SCT was performed in 26 patients. Eighteen patients had an MSD, but only 13 patients received a transplantation from this type of donor. In eight additional patients, a MUD-SCT was performed, and in five patients, a MMFD-SCT was performed, despite trial recommendations. In an intent-to-treat analysis by donor availability, the 5-year DFS rate was 72% ± 11% for patients who had an MSD and 48% ± 6% for patients who did not have an MSD (P = .07). When the patients from the non-MSD group who received a MUD-SCT or MMFD-SCT were censored at the time of SCT, the 5-year DFS rate for the non-MSD group was even lower (45% ± 7%; P = .045).

Because results in trial ALL-BFM 95 for MSD-SCT and for MUD-/MMFD-SCT were similar (DFS rate at 5 years, 77% ± 12% v 69% ± 13%, respectively, treatment as given), both were combined to form the SCT group for further analysis. Comparing the DFS rate at 5 years of patients treated with chemotherapy alone (51% ± 7%) with the DFS rate of the SCT group (73% ± 9%), no statistically significant difference could be demonstrated within trial ALL-BFM 95 (Mantel-Byar, P = .09; Fig 4).

Fig 4.
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Fig 4.

Kaplan-Meier estimate of disease-free survival (DFS) at 5 years in stem-cell transplantation (SCT) patients versus patients treated with chemotherapy alone (Acute Lymphoblastic Leukemia–Berlin-Frankfurt-Münster trial 95; analysis as treated). From the group of patients treated with chemotherapy alone, patients with an event before 0.43 years (medium time to transplantation) were excluded. Despite trial guidelines to use match sibling donors, eight matched unrelated donors and five mismatched family donors were used.

For both treatment regimens (chemotherapy alone and SCT), results were better in trial ALL-BFM 95. The difference in DFS between both regimens and the risk ratio were similar in both trials (ALL-BFM 90: difference, 15%; risk ratio = 0.56; ALL-BFM 95: difference, 22%; risk ratio = 0.45). Therefore, the data of both trials could be combined to increase the power of the comparison. As shown in Figure 5, treatment with allogeneic SCT significantly improved the results achieved by chemotherapy alone (DFS at 5 years, 67% ± 8% v 42% ± 5%, respectively; Mantel-Byar, P = .01). For the combined data of both trials, the DFS rate at 5 years in patients treated with MSD-SCT versus patients treated with MUD-/MMFD-SCT was similar (65% ± 10% v 69% ± 13%, respectively; Fig 6). In Cox regression analysis including trial (ALL-BFM 90 v ALL-BFM 95), WBC at diagnosis (cut point, 100,000/μL), NRd33, and SCT as time-dependent factors, the risk ratio for SCT was 0.46 (95% CI, 0.23 to 0.91; P = .026).

Fig 5.
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Fig 5.

Kaplan-Meier estimate of disease-free survival (DFS) at 5 years in stem-cell transplantation (SCT) patients versus patients treated with chemotherapy alone (Acute Lymphoblastic Leukemia–Berlin-Frankfurt-Münster trials 90 and 95; analysis as treated). From the group of patients treated with chemotherapy alone, patients with an event before 0.43 years (medium time to transplantation) were excluded.

Fig 6.
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Fig 6.

Kaplan-Meier estimate of disease-free survival (DFS) at 5 years in match sibling donor (MSD) stem-cell transplantation (SCT) patients versus matched unrelated donor (MUD) and mismatched family donor (MMFD) SCT patients (Acute Lymphoblastic Leukemia–Berlin-Frankfurt-Münster trials 90 and 95).

Overall survival (OS) analysis at 5 years revealed similar results. For the SCT group, the OS rate was 67% ± 8% at 5 years, whereas patients treated with chemotherapy alone had an OS rate of 47% ± 5% at 5 years (Mantel-Byar, P = .01). Cox regression analysis of OS with the covariables listed earlier revealed a risk ratio of 0.3 for SCT (P = .0005).

Events in Treatment Groups

Chemotherapy alone.

The decrease of relapse incidence from 69% ± 5% (59 of 86 patients) in trial ALL-BFM 90 to 46% ± 8% (26 of 57 patients) in trial ALL-BFM 95 was significant (Gray's test, P = .004). In contrast, the incidence of death in CR increased from 2% (two of 86 patients) in trial ALL-BFM 90 to 9% (five of 57 patients) in trial ALL-BFM 95 (Gray's test, P = .09); four deaths were a result of infection, one was a result of cerebral hemorrhage, and two were caused by thromboembolism. In addition, in trial ALL-BFM 95, one secondary malignancy occurred.

SCT.

Relapses only occurred after MSD-SCT (eight of 23 patients), whereas no relapses occurred after MUD-/MMFD-SCT (zero of 13 patients; Gray's test, P = .0001). However, treatment-related mortality (TRM) only occurred after MUD-/MMFD-SCT (four of 13 patients; Gray's test, P = .001): two deaths were caused by infection, one was caused by infection plus graft failure, and one was caused by veno-occlusive disease plus multiorgan failure.

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DISCUSSION

In this analysis, we compared the outcome of pediatric HR-T-ALL patients treated with chemotherapy plus SCT with the outcome of patients treated with chemotherapy alone. Previous reports only describe single-center experiences,13,36 analyze outcome after SCT without any comparison to a biologically equivalent control group,37-39 combine patients in CR1 and relapsed patients,36 or report on patients in CR2.12-14 Only a few prospective studies compared SCT versus chemotherapy alone for childhood HR-ALL in CR1.15,16 Wheeler et al15 could not show an advantage of transplantation in CR1 possibly because biologic heterogeneity was too large, and more importantly, the better disease control in the transplantation group was counterbalanced by a higher TRM rate. Also within our heterogeneous group of non-T, non–Philadelphia chromosome-positive VHR-ALL patients (combined data of trials ALL-BFM 90 and 95), survival rates at 8 years after chemotherapy (n = 76) and SCT (n = 16) were comparable (46% ± 7% v 42% ± 13%, respectively). In an intergroup study of the International BFM Study Group focusing on VHR patients with different biologic characteristics treated between 1995 and 1999, an advantage of allogeneic MSD-SCT with regard to DFS but not to OS was demonstrated.16 HR-T-ALL patients from the German-Austrian trial ALL-BFM 95 were part, but not the focus, of that study. Our study demonstrates that VHR-T-ALL patients benefit from SCT in CR1, a procedure that, up until recently, was shown to be superior over chemotherapy only for BCR/ABL-positive HR-ALL patients.17

In any analysis of SCT data not based on the so-called biologic random assignment of donor availability, one has to face possible biases of unknown size and direction. Unfortunately, data on donor availability were prospectively collected only in trial ALL-BFM 95. Using an intent-to-treat approach, we found an improved DFS rate in the donor group (72% v 48%) in trial ALL-BFM 95, thus revealing a benefit of SCT in HR-T-ALL patients, although this was not statistically significant (P = .07). This is concordant with data published by others15 and with our results based on the analysis of treatment as performed.

Despite trial guidelines to perform MSD-SCT, MUD-SCT and MMFD-SCT were also performed in trial ALL-BFM 95; the DFS rate at 5 years in both transplantation groups was identical (65% ± 10% v 69% ± 13%, respectively). Remarkably, we found that relapses only occurred after MSD-SCT and not after MUD-/MMFD-SCT. Although this was a statistically significant difference, the low number of events does not allow definite conclusions. The distinct distribution of relapses between the two SCT groups may refer to an additional biologic impact of the graft used in MUD-/MMFD-SCT. Whether this may be explained by natural killer cell alloreactivity is the subject of controversial discussions.40-43 However, TRM only occurred in the MUD-/MMFD-SCT group. The TRM rate of 30% is comparable to other unbiased prospective analyses in this time period,44,45 but more experience and standardized SCT procedures should reduce complications.46 HLA matching including HLA-C, HLA class I high-resolution typing,47,48 improvement in algorithm of donor selection (eg, regarding cytomegalovirus serostatus),49 molecular monitoring and pre-emptive treatment strategies of viral infections,50,51 and a more standardized management of GVHD will contribute.52

Having achieved an EFS rate of approximately 50% with chemotherapy alone, it becomes obvious that almost half of all HR-T-ALL patients defined by BFM criteria may need treatment alternatives such as SCT to be cured in CR1. To identify this subset of patients, detection of minimal residual disease (MRD)7,53 may play a role in the near future. Subgroup analysis revealed that T-cell ALL may have a different response pattern than B-precursor ALL.54 It has been shown that MRD measured before myeloablative conditioning is of predictive value with regard to disease recurrence.55-57

Our study is the first to demonstrate for T-cell ALL that SCT in CR1 results in superior outcome compared with treatment with chemotherapy alone. If the improved outcome for HR-ALL after chemotherapy alone is considered (which was shown also by other investigators)17,58 and if the complications associated with SCT are taken into account, it remains challenging to optimize stratification strategies within HR-T-ALL patients regarding indication and optimal time point for SCT. This may be achieved by prospective evaluation of MRD kinetics measured during HR treatment, providing a more dynamic insight into molecular response of individual patients and thereby defining new subgroups within HR-T-ALL patients.

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Appendix

Study committee (ALL-BFM 90).

Members of the study committee of the German-Austrian-Swiss ALL-BFM Study Group were as follows (all locations are in Germany, unless otherwise indicated): J. Beck, Erlangen; U. Bode, Bonn; A. Feldges, St Gallen, Switzerland; H. Gadner, Wien, Austria; W. Havers, Essen; G. Henze, Berlin; A. Jobke, Nürnberg; B. Kornhuber, Frankfurt; J. Kühl, Würzburg; F. Lampert, Gieβen; U. Mittler, Magdeburg; C. Niemeyer, Freiburg; D. Niethammer, Tübingen; H. Plüss, Zürich, Switzerland; A. Reiter, Hannover; H. Riehm, Hannover; J. Ritter, Münster; G. Schellong, Münster; M. Schrappe, Hannover; C. Urban, Graz, Austria; H. Wehinger, Kassel; K. Welte, Hannover; and F. Zintl, Jena.

Study committee (ALL-BFM 95).

Members of the study committee of the German-Austrian-Swiss ALL-BFM Study Group were as follows (all locations are in Germany, unless otherwise indicated): J. Beck, Erlangen; U. Bode, Bonn; J. Boos, Münster; A. Feldges, St Gallen, Switzerland; H. Gadner, Wien, Austria; W. Havers, Essen; G. Henze, Berlin; B. Kornhuber, Frankfurt; J. Kühl, Würzburg; F. Lampert, Gieβen; E. Maass, Stuttgart; U. Mittler, Magdeburg; C. Niemeyer, Freiburg; D. Niethammer, Tübingen; F. Niggli, Zürich, Switzerland; A. Reiter, Hannover; H. Riehm, Hannover; J. Ritter, Münster; M. Schrappe, Hannover; C. Urban, Graz, Austria; H. Wehinger, Kassel; K. Welte, Hannover; and F. Zintl, Jena.

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Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

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Author Contributions

Conception and design: Alfred Reiter, Helmut Gadner, Dietrich Niethammer, Thomas Klingebiel, Bernhard Kremens, Wolfram Ebell, Martin Zimmermann, Hansjörg Riehm, Karl Welte, Martin Schrappe

Provision of study materials or patients: Alfred Reiter, Thomas Klingebiel, Wolfram Ebell, Felix Niggli, Wolf-Dieter Ludwig, Martin Schrappe

Collection and assembly of data: André Schrauder, Helmut Gadner, Bernhard Kremens, Christina Peters, Martin Zimmermann, Felix Niggli, Wolf-Dieter Ludwig, Martin Schrappe

Data analysis and interpretation: André Schrauder, Alfred Reiter, Helmut Gadner, Dietrich Niethammer, Thomas Klingebiel, Bernhard Kremens, Christina Peters, Wolfram Ebell, Martin Zimmermann, Wolf-Dieter Ludwig, Hansjörg Riehm, Karl Welte, Martin Schrappe

Manuscript writing: André Schrauder, Alfred Reiter, Dietrich Niethammer, Thomas Klingebiel, Christina Peters, Martin Zimmermann, Martin Schrappe

Final approval of manuscript: Helmut Gadner, Martin Zimmermann, Hansjörg Riehm, Karl Welte, Martin Schrappe

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Acknowledgments

We thank all participating medical centers and stem-cell transplantation units for their input in performing this study, and the members of the study committees for their contributions. We appreciate the support provided by all colleagues in the study center, especially Anja Möricke, Martin Stanulla, Alexander Claviez, and Gunnar Cario.

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Footnotes

  • Supported by the Madeleine-Schickedanz-Kinderkrebsstiftung (Fürth, Germany) and the Deutsche Krebshilfe (Bonn, Germany; Project 50-2614-Ri 6).

  • Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Received February 24, 2006.
  • Accepted September 29, 2006.
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  1. doi: 10.1200/JCO.2006.06.2679 JCO vol. 24 no. 36 5742-5749
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