the Department of Pediatric Oncology/Hematology, Charité Universit?tsmedizin Berlin
    Departments of Pediatric Oncology/Hematology of Universities in Hannover, Hamburg, Düsseldorf, Frankfurt, Germany
    St. Anna Kinderspital, Wien, Austria
    Erasmus MC Sophia Children's Hospital, Rotterdam, the Netherlands
    Department of Oncology/Hematology and Tumorimmunology, Berlin-Buch, Germany

    ABSTRACT

    PURPOSE: Approximately 20% of children with acute lymphoblastic leukemia (ALL) suffer a relapse, and their prognosis is unfavorable. Between 1987 and 1990, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 87 was conducted to establish a uniform treatment for these children in Germany and Austria.

    PATIENTS AND METHODS: Of 207 registered patients, 183 patients were stratified into three groups according to the protocol: A, early bone marrow (BM) relapse (n = 56); B, late BM relapse (n = 101); C, isolated extramedullary relapse (n = 26). Treatment consisted of risk-adapted alternating short-course multiagent systemic and intrathecal chemotherapy, cranial irradiation, if indicated, and conventional maintenance therapy. Additionally, 24 patients with an exceptionally poor prognosis (early BM or any relapse of T-cell ALL) were treated with individual regimens. In 35 patients, stem-cell transplantation was performed.

    RESULTS: The probability of event-free survival (EFS) and overall survival of all registered patients at 15 years was 0.30 ± 0.03 and 0.37 ± 0.03, respectively, with significant differences between the strategic groups (A, 0.18 ± 0.05 and 0.20 ± 0.05; B, 0.44 ± 0.05 and 0.52 ± 0.05; C, 0.35 ± 0.09 and 0.42 ± 0.10). Despite risk-adapted treatment, an early time point of relapse and T-lineage immunophenotype were significant predictors of inferior EFS in uni- and multivariate analyses.

    CONCLUSION: With the ALL-REZ BFM 87 protocol, more than one-third of patients may be regarded as cured from recurrent ALL with second complete remissions lasting more than 10 years. Immunophenotype and time point of relapse are important prognostic factors that allow us to adapt more precisely treatment intensity to individual prognosis in future trials.

    INTRODUCTION

    Considerable advances in treatment of childhood acute lymphoblastic leukemia (ALL) have been made in the past decades, with long-term cure rates approaching 85%.1-4 Yet, results in the treatment of children with ALL-relapse are still unsatisfying. With current salvage protocols, approximately 85% of patients achieve a second remission, and cure rates after relapse of 30% to 40% are reported.5-8

    In the early 1980s, ALL relapse was regarded as an almost incurable disease. Children with relapsed ALL received mostly unstandardized individual treatment regimens. The Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) has performed prospective controlled phase III trials for these children for more than 20 years to establish treatment protocols for standardized use in Germany and Austria. The primary goal was to improve the prognosis of children with relapsed ALL and to evaluate risk factors, thereby allowing for risk-adapted treatment intensity. At the present time, the main risk factors found to be predictive for an inferior outcome are a short duration of first remission, an isolated (versus combined or extramedullary) bone-marrow (BM) relapse, T-cell immunophenotype, and the presence of the BCR-ABL fusion transcript.9-11 Additionally, the peripheral blast count at relapse could be related to prognosis in children with late isolated BM relapse. The addition of cranial irradiation significantly improved the outcome of patients with isolated BM-relapse.12,13 Recently, the prevalence and prognostic impact of the TEL-AML1 fusion-transcript and the INK4-deletion have been assessed.14,15 Although the understanding of the biology of relapsed ALL has been continuously improved, outcome for these patients still remains unsatisfactory. One important goal of our ongoing studies is to prospectively identify patients at high risk of treatment failure to employ alternative, potentially more effective treatment regimens.

    Here, we report the design and results of study ALL-REZ BFM 87 at a follow-up of 15 years. With the preceding trials ALL-REZ BFM 83 and 85, a substantial cure rate could be achieved using intensive multiagent chemotherapy courses, cranial irradiation in some patients, and conventional maintenance therapy.16 The aim of trial 87 was to confirm this finding in a larger, population-based cohort of patients by extending the study duration and recruiting all children with relapsed ALL in Germany and Austria, and to randomly investigate the effect of the timing of methotrexate-application during induction therapy.

    PATIENTS AND METHODS

    Patients

    Between April 1987 and April 1990, a total of 207 children and adolescents up to 18 years of age with a first relapse of B-precursor and T-cell ALL were reported from 58 pediatric medical centers. One hundred eighty three patients received therapy according to the protocol ALL-REZ BFM 87, and 24 patients were treated with individual regimens. Written informed consent was obtained from the patients and/or their guardians. The protocol ALL-REZ BFM 87 was approved by the institutional ethical committees of the participating institutions. A majority of patients had initially been treated according to BFM2 or German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia1 protocols, usually for a total of 24 months. A minor number of patients have been registered from Swiss and Dutch centers. Patient characteristics are summarized in Table 1.

    Definitions and Diagnostics

    Relapse occurring on therapy or up to 6 months after cessation of front-line treatment was defined as early relapse, otherwise as late relapse. An isolated BM relapse was diagnosed with  25% lymphoblasts among nucleated cells in the BM and without evidence of leukemia at extramedullary sites. In children with proven leukemia at extramedullary sites, a combined relapse was diagnosed with marrow involvement of  5% lymphoblasts. Accordingly, isolated extramedullary relapses were those with clinically-overt extramedullary manifestation of leukemia and less than 5% marrow infiltration. CNS relapse was diagnosed in case of at least five leukocytes per microliter CSF and the unequivocal presence of lymphoblasts. Testicular relapse was confirmed by open-wedge biopsy, and a subclinical involvement of the contralateral testis had to be excluded, if applicable. Involvement of any other extramedullary site was confirmed histologically.

    Patients who were not in complete remission (CR, < 5% blast cells in an otherwise normocellular marrow and no evidence of leukemia in any other compartment) after three treatment courses were considered nonresponders to salvage therapy.

    Cytologic preparations have been centrally reviewed in 90% of registered patients.

    Routine immunophenotyping was done as described elsewhere.17 The distribution of immunologic subtypes is included in Table 1.

    Treatment was stratified into three groups: A, B, and C. Regimen A was given to children with early isolated or combined BM relapse, regimen B was given to patients with late isolated or combined BM relapse, and regimen C was given to children with isolated extramedullary relapses irrespective of the time of occurrence.

    Treatment

    Treatment consisted of alternating multiagent chemotherapy courses (R1, R2), followed by conventional maintenance therapy with daily 6-thioguanine 50 mg/m2 orally and bi-weekly methotrexate 50 mg/m2 intravenously (Table 2). Patients of group A received an additional induction regimen (course F). Methotrexate (MTX) was given to all patients at a dose of 1 g/m2 infused for 36 hours with two doses of folinic acid at hours 48 and 54. The treatment design is shown in Figure 1.

    Randomization. Patients of group A were randomly assigned to receive either first cytarabine and then MTX (group F-A) or vice versa (group F-M), during induction therapy.

    CNS-directed therapy. All chemotherapy blocks contained intrathecal therapy. Patients with CNS-involvement received triple intrathecal therapy with 12 mg MTX, 30 mg cytarabine, and 10 mg prednisone (PRED), with standardized dose reductions for patients younger than 3 years, whereas, patients without CNS-involvement received MTX only (Table 2). Patients with CNS involvement over 1 year of age received cranial or cranio-spinal irradiation (depending on the preference of the treating center) before start of maintenance therapy. Children over 2 years of age received a dose of 24 Gy to the neurocranium (reduced to 18/15/12 Gy, if pre-irradiated up to 18/24/ 30 Gy, respectively) and a dose of 20 Gy to the spinal cord. Children between 1 and 2 years of age received a dose of 20 Gy to the neurocranium (reduced to 15/0 Gy, if pre-irradiated up to 24/ 30 Gy, respectively) and a dose of 15 Gy to the spinal cord. During the course of the study, a significant increase in the frequency of subsequent CNS-relapses in patients with first isolated BM relapse was found by retrospective analyses of the ongoing and the previous trial ALL-REZ BFM 85.12 Therefore, at the end of 1988, the study committee decided to introduce cranial irradiation for patients with isolated bone marrow relapse at a dose of 18 Gy in patients over 2 years of age (reduced to 12 Gy, if pre-irradiated with  18 Gy) or of 12 Gy in patients between 1 and 2 years of age (reduced to 0 Gy if pre-irradiated with  30 Gy). All participating centers were advised to perform cranial irradiation retroactively even in patients at a later stage of treatment or off therapy.

    Stem-cell transplantation. Allogeneic stem-cell transplantation (SCT) was performed in patients with BM relapse, if an HLA-matched sibling donor (in rare cases a matched family donor as well) was available. Unrelated donors were not available in the study period. All transplanted patients received conditioning regimens, including total-body irradiation, mostly in combination with etoposide. Prophylaxis against graft-versus-host disease was performed using short-course MTX and cyclosporine. Autologous SCT was allowed as postremission intensification in patients with early or T-lineage extramedullary disease, or, if an allogeneic donor was not available.

    Nonprotocol therapy. During the course of the study, two adverse risk factors (any relapse of T-cell immunophenotype or an early BM-relapse within 18 months from diagnosis) had been identified by an interim analysis, including data of the previous studies. Therefore, in some pediatric centers, patients in this poor prognosis group (PPG) subsequently did not receive protocol therapy but individual treatment courses, containing high-dose PRED (1,000 mg/m2) and cisplatinum (up to 40 mg/m2) as new elements, combined with standard components (ie, vincristine, asparaginase, cytarabine, etoposide, daunorubicin).

    Statistical Methods

    Differences between patient subsets were assessed by the Pearson 2 or the Fisher’s exact test for categoric variables and by the Mann-Whitney U test or the Kruskal-Wallis exact test for continuous variables. A two-tailed P value less than .05 was regarded as significant. Kaplan-Meier life-table analyses18 were used to estimate the probability of event-free survival (pEFS) or probability of overall survival (pOS), differences were assessed by the log-rank test. EFS time was calculated from the date of remission to the date of analysis or the date of an adverse event (ie, death in remission, relapse, and second malignancy). In case of nonresponse to therapy or death during induction therapy, EFS time was set to zero. To test the independence of factors predictive for EFS, multivariate Cox-Regression analysis and the Forward Wald tests have been applied, including SCT as a time-dependent covariate.

    RESULTS

    Total Group

    Treatment results of the total cohort of registered patients are given in Table 1. One-hundred-and-eighty out of 207 patients (87%) achieved a CR. Sixty-three out of 207 patients (30%) are in second complete continuous remission (CCR) at a median of 15.7 years (range, 13.7 to 16.6 years). Of the 180 children who achieved a second CR, 106 children suffered a second relapse. After their second relapse, 93 children subsequently died, and 13 children are alive in third CCR. Half of the subsequent relapses occurred within 14 months after first relapse diagnosis, the latest subsequent relapse was registered at 5.8 years. Most of the relapses (n = 88; 83%) occurred in the BM, whereas six relapses (6%) and 12 relapses (11%) were combined or isolated extramedullary, respectively. There was no association between the site of disease at first and subsequent relapse (P = .514) with respect to marrow involvement or specific extramedullary manifestation. Ten patients (5%) died in second CR because of treatment-related complications; four of these fatal events occurred after allogeneic SCT. The EFS probability at 10 years and 15 years is 0.30 ± 0.03 (Fig 2), and the OS probability is 0.37 ± 0.03 (Fig 3).

    Clinical Features of the Strategic Groups

    The sex of patients is similarly distributed in groups A and B, however, boys are overrepresented in group C (because of testicular relapses), and in the nonprotocol group (because of an association of male sex and T-lineage). Patients below 5 years of age at relapse are underrepresented, and those over 10 years of age are overrepresented in the strategic group B because of an association of age at relapse and the duration of first CR.

    Group A

    In group A (early BM relapse), 11 of the children (20%) did not respond to therapy, four children (7%) died during induction. Forty-one patients achieved a second CR, leading to a remission rate of 73%.

    Of the four toxic deaths in CR, two occurred 30 and 64 days after SCT, respectively. Two patients on chemotherapy died of Candida septicemia and sudden cardiac failure 44 and 138 days after treatment start, respectively. Thirteen patients underwent SCT in second CR, 10 patients received a graft from a suitable sibling donor and three patients received an autologous graft. Two transplanted children suffered a treatment-related death (both after allogeneic SCT), three children subsequently relapsed (two after allogeneic SCT, one after autologous SCT), and eight children remained disease-free in second CCR 14 years after SCT. Twenty-six out of 41 children of group A, who had achieved a second CR, suffered a subsequent relapse, 17 during the first year, seven during the second year, and two in the third year after treatment beginning. The pEFS at 10 years is 0.18 ± 0.05 (Fig 4), and the pOS is 0.20 ± 0.05 (Fig 5).

    Group B

    In group B (late BM relapse), 96 out of 101 patients (96%) achieved a second CR. One child did not respond to therapy, and four patients died during the first 28 days of therapy (two of massive hemorrhage, one of infection, and one of cardiac failure). Twelve patients underwent SCT from a HLA-matched related donor, 10 of them remained disease-free, and two children subsequently relapsed and died, one during the first year, the other 3.5 years after treatment start. Two children died in second CR of toxic side effects (ie, cerebral hemorrhage and multi-organ failure). Fifty patients (50%) in group B suffered a subsequent relapse, the pEFS at 10 years is 0.44 ± 0.05 (Fig 4), and the pOS is 0.52 ± 0.05 (Fig 5).

    Group C

    All 26 patients of group C (19 isolated CNS relapses, and 7 isolated testicular relapses) attained a second CR, and no treatment-related deaths occurred. Seventeen patients relapsed, fifteen after chemotherapy, two after autologous SCT, and nine children (35%) are in CCR. The pEFS is 0.35 ± 0.09 (Fig 4) and the pOS is 0.42 ± 0.10 (Fig 5).

    The pEFS and pOS of group A were significantly inferior to those of group B (P < .001) and group C (P = .01).

    Nonprotocol Therapy

    Regarding the group of 24 PPG patients treated with individual therapy, 17 patients (71%) achieved a second CR, five patients had progressive disease, and two patients died during induction therapy. Four patients died in second CR, the remaining 13 patients relapsed after chemotherapy and 12 of them subsequently died. Thus, only one patient of this group survived. With this cisplatin and high-dose PRED-based regimens neither the remission rate (71% v 72%), nor the pEFS (0.00 ± 0.00 v 0.18 ± 0.05) or the pOS (0.04 ± 0.04 v 0.20 ± 0.05) could be improved as compared with PPG patients treated according to the ALL-REZ BFM 87 protocol.

    Randomization of Induction Courses F-A and F-M

    In the strategic group A, 20 and 21 patients were randomly assigned to receive block F-A or F-M as induction block F, respectively. Furthermore, seven patients were allocated to arm F-A and eight patients to arm F-M without randomization. There was no difference between the two randomization groups with regard to remission rate, EFS, and OS.

    Prognostic Factors

    Several parameters present at diagnosis of relapse (ie, time and site of relapse, intensity of previous treatment, age, sex, white blood-cell count, immunophenotype) were analyzed for their impact on prognosis. In univariate analysis, an early time point of relapse (P < .001) and T-lineage immunophenotype (P < .001) proved to be significantly related to treatment failure (Table 1). Patients with early relapse (ie, within 18 months from diagnosis) or with a T-cell immunophenotype had an exceptionally unfavorable outcome and thus, were designated PPG. Patients of the PPG had a pEFS of 0.11 ± 0.04, whereas non-PPG patients had a pEFS of 0.38 ± 0.04 (P < .001; Table 1). In multivariate Cox regression analysis, time and site of relapse, immunologic subtype, and the performance of SCT (included as time-dependent covariate) were independent predictors of pEFS (Table 3). The other included factors, sex and age at relapse, did not significantly improve the model.

    Cranial Irradiation

    Fifty-five out of 100 patients with first isolated BM relapse without SCT did not receive cranial irradiation because of early adverse events occurring before irradiation could be performed in 34 patients, and parental refusal or center decision in six and 15 patients, respectively. In three nonprotocol patients, data on CNS-irradiation were not available; these patients were excluded from analysis. EFS was significantly inferior (P < .001) in the arbitrarily nonirradiated group (n = 21; pEFS = 0.05 ± 0.05; one patient in CCR) as compared with those patients who received cranial irradiation (n = 45; pEFS = 0.40 ± 0.07; 18 patients in CCR). Four subsequent relapses of the nonirradiated group (19%) occurred in the CNS as compared with two subsequent relapses (5%) in patients with cranial irradiation. No significant differences in either group were seen with regard to sex, duration of first CR, and immunophenotype.

    SCT

    Fifteen out of 58 patients (26%) with poor prognosis (group A and nonprotocol therapy), who achieved a second CR, have been transplanted from matched related stem-cell donors, whereas, in group B 12 out of 96 patients (13%) and in group C none of the patients received an allogeneic SCT. After allogeneic SCT, four patients (15%) suffered from therapy-related death, whereas six patients (4%) after chemotherapy/radiotherapy, and none of the eight patients after autologous SCT did so (P = not significant). The pEFS after allogeneic SCT was superior (0.59 ± 0.09) compared with the pEFS of patients who received chemotherapy/radiotherapy as postremission treatment (0.30 ± 0.04; P = .026; adapted for median time to transplant [109 days]; n = 138; censored observations = 44; pEFS = 0.32 ± 0.04; P = .130; Table 1). Autologous SCT was not included into the comparison because of low patient numbers.

    DISCUSSION

    The conceptional backbone of ALL-REZ BFM therapy is a series of short (ie, 5 to 7 days), intensive multiagent chemotherapy courses (block therapy), including most of the known substances with antileukemic efficacy, with an interval of 2 weeks between the blocks to allow for regeneration of BM-aplasia, then followed by local irradiation therapy when indicated, and conventional maintenance therapy. This block therapy concept proved to be feasible, effective, and relatively well-tolerated. Thus, it is incorporated into many other treatment regimens for relapsed ALL and high-risk primary ALL worldwide.19-21 However, other treatment strategies with a more continuous therapy have been reported, achieving comparable results.7,8,22 It remains unclear and should be a subject of prospective studies, whether short course intensive, or continuous less intensive chemotherapy constitute the more adequate and effective approach in treating childhood relapsed ALL or which subgroups of patients may benefit more from one or the other approach.

    The design of the ALL-REZ BFM 87 study reported here was only marginally different from the predecessor study ALL-REZ BFM 85,16 thereby allowing to us confirm its results in a larger patient group. With ALL-REZ BFM 87, we were able to reproduce the notable results of ALL-REZ BFM 85 with regard to second remission rate, pEFS, and survival. Furthermore, the stability of second remissions over a long period of time is demonstrated, with the latest subsequent relapse less than 6 years after relapse diagnosis, and with a negligible rate of second malignancies. Hence, 37% of the children, being alive and free of symptomatic disease after 15 years, can be considered as cured.

    A majority of patients (87%) achieved a second remission despite of intensive front-line therapy according to ALL-BFM and German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia protocols, which is comparable with published reports of other groups.8,23 However, long-term CR could be maintained in only 30% of the patients. The major adverse event for children in second CR was subsequent BM relapse. Even a risk-adapted intensification of treatment by prolonging the intensive treatment phase could not prevent a high rate of relapses in the high-risk group A, which resulted in a significantly inferior outcome as compared with the other strategic groups of the protocol. In comparison with that, the incidence of therapy-related deaths (5%) was rather acceptable in our cohort.

    Allogeneic SCT performed in second CR has repeatedly been reported to produce better survival rates than chemotherapy/radiotherapy alone.24-27 The rate of patients who underwent SCT in ALL-REZ BFM 87 is 20%, which is considerably lower compared with recent trials of our group (30% SCT), in which increasingly unrelated stem-cell donors are considered. This lower SCT-rate in ALL-REZ BFM 87 was mainly caused by the limited availability of a suitable sibling donor. As alternative treatment intensification, autologous SCT was performed in a minority of patients. Selection of patients for this procedure was not controlled, a fact that may bias the results of the different treatment arms. In the meantime, the results of autologous SCT proved not to be superior to chemotherapy.28,29 It remains now restricted to a subset of patients with extramedullary disease.

    In patients with BM relapse treated according to trial ALL-REZ BFM 87, SCT was associated with a superior EFS compared with chemotherapy/radiotherapy as postremission therapy alone. Furthermore, SCT proved to be independently associated with EFS when included into the Cox model as time-dependent covariate. Results of trial ALL-REZ BFM 87 however, show that 30% of patients achieve long-term CR without SCT. It remains a major task of ongoing and future trials to predict subsequent relapses more precisely, thus clarifying which patients benefit from postremission intensification by allogeneic SCT. In this context, not only the acute mortality and toxicity, but also the long-term sequelae of allogeneic SCT have to be taken into account.

    The important role of cranial irradiation in patients without obvious CNS-involvement has been demonstrated previously by the BFM Relapse Study Group. Retrospective analyses during the course of ALL-REZ BFM 87 showed that in these patients CNS-irradiation was effective in preventing CNS-relapses, and in increasing the survival rate by reducing the overall relapse rate.12 Therefore, cranial irradiation was introduced during the early course of this study, and centers were informed to perform CNS-radiation retroactively. This additional CNS-prevention could also explain the fact that patients of the strategic group B (late BM relapse) have a significantly better EFS probability in ALL-REZ BFM 87 (0.44 ± 0.05; n = 101) compared with ALL-REZ BFM 85 (0.28 ± 0.06; n = 53, P < .05).

    Analysis of the prognostic relevance of several clinical parameters revealed time point of relapse and immunophenotype as significant predictors of EFS. These parameters proved to be independent risk factors in multivariate analysis. Whereas the site of relapse was not significantly associated with prognosis in univariate analysis, it was suitable to improve the Cox model. Interestingly, combined BM relapse is associated with superior EFS as compared with isolated BM relapse. This finding may be explained by the theory that combined BM relapses originate from the involved extracompartment, in which the leukemic cells could survive the front-line chemotherapy because they were protected by the blood-brain/testis barrier. Therefore, they may be more sensitive to chemotherapy than clones originating directly from the BM.11

    The above mentioned, easily achievable clinical features are the classical, still most important predictors of outcome and are confirmed by many other study groups.6-8 Recently, new prognostic factors determined by molecular biologic methods have been established, especially TEL-AML1 and BCR-ABL.10,15 Another powerful parameter for risk prediction is the detection of minimal residual disease by polymerase chain reaction or flow cytometry.30,31 It will be a task of ongoing and future studies to clarify the value of these and other new molecular parameters and to integrate them together with the well-known and validated clinical factors into a revised model of risk prediction.

    In summary, we present robust data of the trial ALL-REZ BFM 87 after a long period of follow-up, showing that for a subgroup of patients, combined chemotherapy and radiotherapy yields durable second remissions. For the 27% of PPG-patients (ie, early BM-relapse or any relapse of T-cell ALL), no promising therapy regimens exist, a challenge to future research.

    Appendix

    City locations and principal investigators of the participating medical centers. Aachen (L. Lassay, R. Mertens), Augsburg (A. Gnekow, P. Heideman), Berlin (G. Henze, W. D?rffel), Bielefeld (V. Sch?ck), Bonn (U. Bode, R. Dickerhoff), Braunschweig (G. Mau), Bremen (L. Nahnsen, H.J. Spaar), Celle (H. Jacobi), Datteln (W. Andle, I. Meyer), Dortmund (H. Breu), Düsseldorf (U. G?bel, H. Jürgens), Erlangen (J.D. Beck), Essen (W. Havers, B. Stollmann), Frankfurt (B. Kornhuber, V. Gerein), Freiburg (A. Sutor), Giessen (U. Bertram, F. Lampert), G?ttingen (S. Eber, M. Lakomek), Graz (I. Slavc, C. Urban), Hamburg (G. Janka-Schaub, K. Winkler), Hannover (H. Riehm, A. Reiter), Heidelberg (R. Ludwig, K.M. Debatin), Homburg/Saar (N. Graf, J. Müller), Innsbruck (K. Dengg, F.M. Fink), Karlsruhe (W. Dupuis, G. Nessler), Kassel (H. Wehinger), Kiel (M. Rister, M. Suttorp), Koblenz (M. Rister), K?ln (F. Berthold, U. Puyn), Linz (K. Schmitt), Loeben (I. Mutz), Ludwigshafen (H.C. Dominick), Mainz (M. Dittrich, P. Gutjahr), Mannheim (O. Sauer), München (C. Bender-G?tze, R.J. Haas, P.K. Klose, S. Müller-Weihrich), Münster (G. Schellong, J. Ritter), Neunkirchen-Kohlhof (E. Feldmann), Nijmegen (J. B?kkerink), Nürnberg (H. Gr?be, A. Jobke), Rotterdam (K. H?hlen), Salzburg (H. Grienberger), Sankt Augustin (K. v. Schnakenburg), Schwarzach (H. Haas), Stuttgart (W. Tausch, J. Treuner), Tübingen (R. Dopfer, D. Niethammer), Ulm (G. Gaedicke, E. Kleihauer), Vechta (D. Franke), Wien (H. Gadner, A. Zoubek), Würzburg (W. Kreht, J. Kühl).

    Members of the BFM Relapse Study Steering Committee: G. Henze (chairman); J.D. Beck, U. Bode, W. Ebell, R. Fengler, G. Gaedicke, V. Gerein, G. Janka-Schaub, H. Jürgens, S. Müller-Weihrich, H. Riehm, J. Ritter, W. Tausch, H. Wehinger (full members); R. Dopfer, W. D?rffel, H. Gadner, A. Reiter, H. Schmid, F. Zintl (associated members).

    Reference laboratories: Cytogenetics: F. Lampert, J. Harbott (Gie?en); Cytology: R. Fengler, G. Henze (Berlin); Immunophenotyping: W.D. Ludwig (Berlin); Impulse cytophotometry: Hiddemann (Münster)

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    NOTES

    Supported by Deutsche Krebshilfe, Bonn, Germany.

    Both authors contributed equally to this work.

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

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《临床肿瘤学医学期刊》2005年11月第23卷第11期