- © 2010 by American Society of Clinical Oncology
Vinblastine in Children and Adolescents With High-Risk Anaplastic Large-Cell Lymphoma: Results of the Randomized ALCL99-Vinblastine Trial
- Marie-Cécile Le Deley,
- Angelo Rosolen,
- Denise M. Williams,
- Keizo Horibe,
- Grazyna Wrobel,
- Andishe Attarbaschi,
- Jozsef Zsiros,
- Anne Uyttebroeck,
- Ildiko M. Marky,
- Laurence Lamant,
- Wilhelm Woessmann,
- Marta Pillon,
- Rachel Hobson,
- Audrey Mauguen,
- Alfred Reiter and
- Laurence Brugières
- From the Institut Gustave-Roussy, Villejuif; Université Paris-Sud, Le Kremlin-Bicêtre; Centre Hospitalier Universitaire Toulouse, Hôpital Purpan; L'Institut National de la Santé et de la Recherche Médicale U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; University Hospital, Padova, Italy; Cambridge University Hospital National Health Service Trust, Cambridge; Children's Cancer and Leukaemia Group Data Centre, Leicester, United Kingdom; Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan; Children Oncology and Hematology, Medical University, Wroclaw, Poland; St Anna Children's Hospital, Vienna, Austria; Emma Kinderziekenhuis, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; University Hospital, Leuven, Belgium; Göteborg University, Göteborg, Sweden; and Non-Hodgkin's Lymphoma–Berlin-Frankfurt-Muenster Study Centre, Justus-Liebig-University, Giessen, Germany.
- Corresponding author: Marie-Cécile Le Deley, MD, PhD, Biostatistics and Epidemiology Unit, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: marie-cecile.ledeley{at}igr.fr.
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Presented in part at the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA, and the Third International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin's Lymphoma, June 11-13, 2009, Frankfurt, Germany.
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A.Re. and L.B. contributed equally to this work.
Abstract
Purpose The impact of adding vinblastine to a 4-month chemotherapy regimen, based on the Non-Hodgkin's Lymphoma Berlin-Frankfurt-Münster 90 protocol, in childhood high-risk anaplastic large-cell lymphoma (ALCL) was assessed.
Patients and Methods Children and adolescents with high-risk ALCL, defined by mediastinal, lung, liver, spleen, or skin involvement, were eligible for the trial. After a prephase and one chemotherapy course, patients were randomly assigned to receive either five further chemotherapy courses without vinblastine or the same regimen with one vinblastine injection (6 mg/m2) during each course followed by weekly vinblastine to complete a total of 1 year of treatment. The primary end point was event-free survival (EFS), analyzed on the intent-to-treat population.
Results Between November 1999 and June 2006, 110 patients were randomly assigned to receive vinblastine, and 107 were randomly assigned not to receive vinblastine. Median follow-up was 4.8 years. Patients in the vinblastine arm had a significantly reduced risk of events during the first year (hazard ratio [HR] = 0.31; 95% CI, 0.15 to 0.67; P = .002) followed by an increased risk thereafter (HR = 4.98; 95% CI, 1.65 to 15.0; P = .003). Consequently, EFS at 1 year differed significantly (91% in the vinblastine group v 74% in the no-vinblastine group), with no difference at 2 years (73% and 70%, respectively). Overall EFS curves did not differ significantly (HR = 0.91; 95% CI, 0.55 to 1.5; P = .71). Thirty-one percent of weekly doses of vinblastine were reduced as a result of hematologic toxicity, although vinblastine was discontinued for toxicity in only three patients.
Conclusion Adding vinblastine during induction and as maintenance for a total treatment duration of 1 year significantly delayed the occurrence of relapses but did not reduce the risk of failure.
INTRODUCTION
There is still no consensus regarding the standard treatment for anaplastic large-cell lymphoma (ALCL). Most European pediatric oncology groups have used short-pulse chemotherapy regimens based on mature B-cell non-Hodgkin's lymphoma (NHL) strategies, including high-dose methotrexate (MTX), cyclophosphamide, vincristine, doxorubicin, and corticosteroids with a duration of 4 to 6 months.1–4 In North America, patients with ALCL receive prolonged repeated-pulse chemotherapy.5,6 The failure rate at 2 years remains at 30% for most of these regimens.1–10
In a retrospective multivariate analysis of European ALCL studies including 225 patients treated between 1986 and 1995, the following three factors were found to be significantly associated with a high risk of disease failure: mediastinal involvement, visceral involvement (defined as lung, liver, or spleen involvement), and skin lesions. Patients with at least one risk factor, accounting for 64% of the population, had a 5-year progression-free survival rate of 61%, compared with a rate of 89% in standard-risk patients.11
Vinblastine seemed to be a promising candidate to reduce the risk of failure because, when given as a single agent, it has been shown to induce complete remission in patients with relapsed ALCL even after high-dose chemotherapy or multiple relapses.12,13 Surprisingly, in a small series of heavily pretreated patients with relapsed ALCL who then received vinblastine alone for a median duration of 14 months, 30% of patients were alive without subsequent relapse 5 years later.13 The good safety profile of vinblastine is known from the experience in Langerhans cell histiocytosis.14 The aim of the ALCL99-vinblastine trial was to evaluate the role of vinblastine in reducing the risk of failure in patients with high-risk ALCL defined by the involvement of mediastinum, visceral organs, or skin.
PATIENTS AND METHODS
Study Design
The ALCL99-vinblastine trial was a large international randomized trial based on the NHL Berlin-Frankfurt-Münster (NHL-BFM) 90 protocol,3 which compared six induction courses of chemotherapy (no-vinblastine arm) with the same treatment plus a vinblastine injection (6 mg/m2) during the five latter induction courses and then weekly for a total treatment duration of 1 year (vinblastine arm).
The ALCL99-vinblastine study was part of a factorial design trial including another trial comparing the efficacy and safety of two MTX doses and administration schedules during the six induction courses of chemotherapy (MTX trial).15
Eligibility Criteria
This trial was conducted in 12 countries, via 10 national or cooperative groups including most European pediatric lymphoma study groups and a Japanese group. Eligible candidates were younger than 22 years old with biopsy-proven ALCL classified as high-risk disease (mediastinal, lung, liver, or spleen involvement or biopsy-proven skin lesion). Patients with isolated skin disease or involvement of the CNS were not eligible for the trial. Additional exclusion criteria were progressive disease after the first chemotherapy course, previous treatment, evidence of congenital immunodeficiency, AIDS, previous organ transplantation, or previous malignancy. Written informed consent was mandatory. The local ethics committees approved the protocol in line with the legislation in each country.
The diagnosis of ALCL was based on morphologic and immunophenotypic criteria16 and, whenever possible, on molecular definition (evidence of anaplastic lymphoma kinase fusion genes). A review by the national pathologist was requested before random assignment for all patients negative for anaplastic lymphoma kinase 1 (ALK1) immunostaining or patients expressing B-cell markers. Additionally, all patients were to be reviewed by an international panel of pathologists blinded to treatment allocation.
Pretreatment Evaluation
Patients underwent a physical examination, chest-abdominal computed tomography and skeletal scintigraphy, bone marrow aspiration and biopsies, CSF cytospin examination, and biopsy of skin lesions. Patients were staged according to the St Jude and Ann Arbor staging systems.17,18
Treatment
Chemotherapy was based on the NHL-BFM90 protocol.3 All patients received a 5-day prephase followed by six alternating induction courses (courses A and B), given every 21 days (Table 1). The MTX dose and administration schedule were randomly allocated before the first course (MTX trial).15
Chemotherapy Doses and Schedule in Each Induction Course
Before the second course, high-risk patients were randomly assigned to receive (or not) one vinblastine injection (6 mg/m2; maximum, 10 mg per injection) during courses 2 to 6 and then weekly as maintenance treatment, for a total treatment duration of 1 year (vinblastine arm) compared with a 4-month treatment duration in the no-vinblastine arm. During maintenance, vinblastine was withheld for grade 4 neutropenia or grade 3 or 4 thrombocytopenia, and the dose was reduced to 4 mg/m2 in case of two episodes of grade 4 neutropenia or grade 3 or 4 thrombocytopenia. The dose was reduced to 3 mg/m2 if symptomatic peripheral neuropathy occurred.
Response Criteria
Tumor response was evaluated after each course. A complete remission was defined as the disappearance of the disease for at least 4 weeks, and an unconfirmed complete remission was defined as a reduction in tumor size exceeding 70%.19 Follow-up was performed every 2 to 4 months for the first 3 years, every 6 months during years 4 and 5, and then yearly. Relapses required confirmation by biopsy.
Random Assignment
Overall, 175 centers participated in the trial. The random assignment was performed after the first induction course to allow for a pathology review for patients not fulfilling the classical criteria for diagnosis. Random assignment was balanced and stratified according to country and to the treatment allocated by the first random assignment for the MTX trial (factorial design).15 Five different data centers managed the random assignment. A centralized randomization software was used in all five data centers except in Italy, with a minimization program (France) or stratified random assignment with permuted blocks of size four (Japan, BFM, and Sweden). In the Italian data center, predefined stratified balanced random assignment lists were used to allocate treatments.
Blinding to therapy could not be achieved because of the obvious differences in the treatments, but a central review of all events was performed at the end of the study by the principal investigator blinded to the allocated treatment. Questionable events were reviewed by the whole study committee.
Statistical Considerations
The primary end point was event-free survival (EFS), which was defined as the time from random assignment to the time of the first failure (progression, relapse, second malignancy, or death) or to the last follow-up visit for patients in first complete remission. Secondary end points were overall survival (OS), complete remission, and acute toxicity. OS rates were estimated from the date of random assignment to death, whatever the cause, or the date of the last follow-up visit for patients last seen alive. Toxicity, including neurologic toxicity, was assessed after each course during induction therapy and weekly during maintenance treatment using the National Cancer Institute Common Toxicity Criteria (version 2.0).
Survival rates (EFS and OS) were estimated using the Kaplan-Meier method with Rothman's 95% CIs. Median follow-up was estimated using Schemper's method. The hazard ratios (HRs) for events (EFS) and deaths (OS) were estimated using Cox models adjusted on country and on treatment allocated by the first random assignment (MTX1/MTX3).
The trial was designed to demonstrate an improvement from 62%11 to 80% in the 2-year EFS probability (HR = 0.47). A total of 59 events and 204 patients were required to reach a power of 80% with a type I error of 5% (two-sided log-rank test).
Three planned interim analyses were performed after observing 25%, 50%, and 75% of events, using Fleming's plan and discussed with the independent data monitoring committee. The present analysis is the final analysis, performed with a two-sided P = .0412.
The main analysis of EFS was performed on the intent-to-treat population. A prespecified secondary analysis was performed after exclusion of patients for whom the diagnosis of ALCL had been rejected after review. Prespecified analyses were performed to study variations in the treatment effect according to the treatment allocated by the first random assignment and according to country. Exploratory analyses were performed on patients receiving vinblastine maintenance treatment to investigate the effect of actual dose-intensity and overall treatment duration on the risk of failure. This former analysis was performed on patients who had received at least 50 weeks of treatment. All reported P values for heterogeneity are two-sided.
Vinblastine dose-intensity was computed taking into account the injections given from the start to the end of maintenance treatment, truncated at 52 weeks. Data were entered and checked with the PIGAS software19a and analyzed with the SAS software version 9.1 (SAS Institute, Cary, NC).
RESULTS
Patients
Between November 1999 and May 2006, 529 patients were screened for study entry (Fig 1). Overall, 217 (85%) of 254 potentially eligible patients were included (107 in the no vinblastine arm and 110 in the vinblastine arm). All patients, except one, were observed for at least 2 years from random assignment (median, 4.8 years; maximum, 8.4 years). Patient characteristics are listed in Table 2.
Participant flow. (*) One of the six patients for whom the diagnosis of anaplastic large-cell lymphoma (ALCL) was rejected is also included among the four non–high-risk patients (isolated skin lesions, diagnosis reviewed as CD30-positive cutaneous lymphoproliferation).
Patient Demographic and Clinical Characteristics by Treatment Arm
A central histopathology review was performed for 207 of 217 patients. The diagnosis of ALCL was rejected in seven patients (Hodgkin's lymphoma, n = 1; ALK-negative peripheral T-cell NHL not otherwise specified, n = 3; ALK-negative B-cell NHL, n = 1; ALK-positive immunoblastic B-cell NHL, n = 1; CD30-positive cutaneous lymphoproliferation, n = 1). All 210 other patients were CD30-positive, 200 (95%) were positive for ALK1, and 187 (89%) expressed at least one T-cell marker. The distribution of subtypes according to the WHO classification, available for 195 patients (93%), was as follows: common type (n = 107), mixed (n = 58), small cell (n = 14), lymphohistiocytic (n = 7), Hodgkin's like (n = 6), and giant cell (n = 3).
Treatment
A major protocol violation was observed in four patients. Three patients in the vinblastine arm did not receive any of the planned vinblastine injections, and one patient in the no-vinblastine arm received the whole maintenance treatment.
Ten of the 110 patients in the vinblastine arm did not receive any maintenance treatment as a result of progression or death (n = 5), protocol violation (n = 3), or other reasons (n = 2). The median duration of treatment was 53 weeks (range, 21 to 86 weeks). Treatment duration was less than 50 weeks for 10 patients as a result of progression (n = 3), toxicity (n = 3), protocol violation (n = 1), and miscellaneous reasons (n = 3); duration was between 50 and 54 weeks as planned in the protocol for 53 patients, between 54 and 70 weeks for 20 patients, and greater than 70 weeks for 17 patients. Prolonged treatment durations were a result of misinterpretation of the term total duration of treatment versus the duration of maintenance. The average vinblastine dose was 4.7 mg/m2/wk during maintenance treatment. Overall, 33 of 100 patients received at least 90% of the planned weekly dose of vinblastine (5.4 mg/m2/wk). As detailed later, dose reductions were mainly a result of hematologic toxicity.
Outcome
Overall, 205 evaluable patients achieved complete remission or unconfirmed complete remission before the end of induction treatment. An event was reported in 66 of 217 patients (10 progressions during treatment, 55 relapses, and one death as a result of toxicity of induction treatment). Seventeen patients died after progression or relapse, including six deaths related to the toxicity of second-line treatment. Two-year EFS and OS rates were 71% (95% CI, 75% to 77%) and 94% (95% CI, 89% to 96%), respectively, for the whole trial population. The outcome results by treatment arm are listed in Table 3.
Outcome by Treatment Arm
The overall number of events was well balanced, but the median interval from random assignment to progression/relapse differed greatly between the two arms (13.1 months in the vinblastine arm v 6.5 months in the no-vinblastine arm; Wilcoxon test, P < .001). Time to relapse from the last chemotherapy injection did not differ significantly between the vinblastine and no-vinblastine arms (median, 1.6 v 2.7 months, respectively; P = .07). During the first year, we observed a significantly lower risk of events in the vinblastine arm compared with the no-vinblastine arm (HR = 0.31; 95% CI, 0.15 to 0.67; P = .002), whereas the risk was significantly increased after the first year (HR = 4.98; 95% CI, 1.65 to 15.0; P = .003). This led to a 17% difference in 1-year EFS (90.9% in vinblastine arm v 73.8% in no-vinblastine arm), whereas there was no significant difference at 2 years (72.5% v 70.1%, respectively; difference = +2.4%; 95% CI, −10% to 15%; Fig 2A). Throughout the whole follow-up period, there was no significant difference in EFS between the randomized groups (HR = 0.91; 95% CI, 0.55 to 1.5; P = .71). The effect of vinblastine on EFS did not differ according to the country (P = .28). No significant interaction was detected between the effect of vinblastine and the dose of MTX (factorial design, interaction test, P = .83). Considering the 100 patients who started vinblastine maintenance treatment, there was a nonsignificant reduction in the risk of failure in the 33 patients who received at least 90% of the planned weekly dose of vinblastine compared with the patients with lower dose-intensity (HR = 0.60; 95% CI, 0.25 to 1.41; P = .24). With a similar follow-up after the end of treatment in both groups, patients with a treatment duration greater than 70 weeks had a nonsignificant reduction in the number of treatment failures compared with patients with a shorter duration of treatment (three [18%] of 17 patients v 23 [32%] 73 patients, respectively; Fisher's exact test, P = .38). There was no significant effect of vinblastine on OS (HR = 1.28; 95% CI, 0.49 to 3.38; P = .60; Fig 2B). Results were similar after exclusion of the seven patients for whom the diagnosis of ALCL was rejected after central pathology review.
(A) Event-free survival (EFS) by treatment group. (B) Overall survival (OS) by treatment group. VLB, vinblastine.
Toxicity
During the induction courses, there was no significant difference in the incidence of toxicity between the vinblastine and no-vinblastine arms except for grade 4 anemia (8% of the vinblastine arm v 5% of the no-vinblastine arm; P = .05) and grade 3 or 4 stomatitis (13% v 9%, respectively; P = .05). One patient in the vinblastine arm experienced grade 3 peripheral neuropathy during induction treatment.
Only three patients stopped vinblastine maintenance as a result of toxicity, but the dose of vinblastine was reduced in 793 (31%) of 2,563 courses. Hematologic toxicity was the main reason for dose reduction. Of the 2,164 evaluated maintenance courses, grade 3 and grade 4 neutropenia were reported after 634 courses (29%) and 253 courses (12%), respectively. All but 11 patients experienced at least one episode of grade 3 or 4 neutropenia. Sixteen patients received at least one RBC transfusion during maintenance. No platelet transfusion was required. During maintenance treatment, four patients experienced grade 3 peripheral neuropathy, which was transient in two patients but led to the premature stopping of treatment in one patient and to a significant dose reduction in the other.
DISCUSSION
This trial demonstrated that adding vinblastine to standard chemotherapy for a total treatment duration of 1 year in children with high-risk ALCL significantly delayed the occurrence of relapse but did not reduce the risk of failure, resulting in no benefit in the 2-year EFS or overall EFS curves.
We were able to reproduce the results of the NHL-BFM90 study3 in this large study involving 12 different countries, with a 2-year EFS probability of 71% in the whole trial population. This result was better than expected in the control arm. In addition, despite the rarity of the disease, the number of patients recruited in the study allowed comparison of the two treatment groups in a randomized trial with an acceptable power.
The external validity of this study is robust; in all participating groups, patients with childhood ALCL diagnosed between 1999 and 2006 were screened for trial entry eligibility, and there was a subsequent 85% random assignment rate. Furthermore, the slides of 95% of patients were centrally reviewed, and the diagnosis of ALCL was rejected in only seven patients.
Maintenance treatment with weekly vinblastine proved feasible. Although hematologic toxicity occurred frequently, few patients stopped maintenance treatment as a result of toxicity, and the mean dose-intensity was 78% of the planned weekly dose.
The trial demonstrated a significant reduction in the risk of relapse during vinblastine maintenance treatment, leading to a 6-month postponement of the median time to relapse. This confirmed that weekly vinblastine is an important agent in this disease as suggested by data on patients experiencing relapse12,13,20 and by in vitro data.21 However, we cannot exclude the possibility that comparable results might be obtained by different maintenance treatments because several patients reported in the literature have achieved remission with prolonged treatment with other drugs such as oral MTX or etoposide.12,22 However, in a mouse model, vinblastine has recently been shown to have a dual therapeutic effect, combining direct induction of tumor cell death and maturation of dendritic cells, thereby leading to an increased host immunity against tumor antigens.22–24 This latter effect might be important in ALCL in which increasing evidence supports an important role of the immune system.25–31 The design of the present study was probably not optimal to test the clinical impact of immunologic properties of vinblastine.
Several patients experienced relapse after the end of maintenance, so overall, the proportion of patients who experienced relapse was similar in both treatment arms, suggesting that weekly vinblastine maintenance after chemotherapy for up to 1 year was unable to eradicate minimal residual disease. Although we observed a reduction in the risk of failure in patients who were able to tolerate 90% of the planned weekly dose and in patients with duration of treatment longer than 70 weeks, these results were not statistically significant, and no firm conclusion can be drawn from these exploratory analyses.
The OS of the whole trial population is excellent, with a 5-year OS rate of 92%, with no significant difference between both randomized groups. These findings suggest that the residual tumor cells do not acquire resistance to chemotherapy. The chemotherapy sensitivity of ALCL after relapse is quite unique when compared with other malignancies, especially other aggressive lymphomas. Considering that prolonged treatment with single-drug vinblastine can induce long-term survival after relapse,12,13,20 we cannot rule out the possibility that a longer treatment could be more effective in eradicating residual tumor cells than the 1-year therapy tested in this trial.
In conclusion, we have shown that the addition of vinblastine to standard chemotherapy for a total duration of 1 year significantly delayed the occurrence of relapse but did not reduce the risk of failure, resulting in no benefit in terms of 2-year EFS and overall EFS.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Marie-Cécile Le Deley, Angelo Rosolen, Denise M. Williams, Alfred Reiter, Laurence Brugières
Provision of study materials or patients: Angelo Rosolen, Denise M. Williams, Keizo Horibe, Grazyna Wrobel, Andishe Attarbaschi, Jozsef Zsiros, Anne Uyttebroeck, Ildiko M. Marky, Laurence Lamant, Wilhelm Woessmann, Marta Pillon, Alfred Reiter, Laurence Brugières
Collection and assembly of data: Marie-Cécile Le Deley, Marta Pillon, Rachel Hobson, Laurence Brugières
Data analysis and interpretation: Marie-Cécile Le Deley, Angelo Rosolen, Denise M. Williams, Keizo Horibe, Grazyna Wrobel, Andishe Attarbaschi, Jozsef Zsiros, Anne Uyttebroeck, Ildiko M. Marky, Laurence Lamant, Wilhelm Woessmann, Audrey Mauguen, Alfred Reiter, Laurence Brugières
Manuscript writing: Marie-Cécile Le Deley, Angelo Rosolen, Denise M. Williams, Keizo Horibe, Grazyna Wrobel, Andishe Attarbaschi, Jozsef Zsiros, Anne Uyttebroeck, Ildiko M. Marky, Laurence Lamant, Wilhelm Woessmann, Marta Pillon, Rachel Hobson, Audrey Mauguen, Alfred Reiter, Laurence Brugières
Final approval of manuscript: Marie-Cécile Le Deley, Angelo Rosolen, Denise M. Williams, Keizo Horibe, Grazyna Wrobel, Andishe Attarbaschi, Jozsef Zsiros, Anne Uyttebroeck, Ildiko M. Marky, Laurence Lamant, Wilhelm Woessmann, Marta Pillon, Rachel Hobson, Audrey Mauguen, Alfred Reiter, Laurence Brugières
Acknowledgment
We are indebted to all children and parents; Nathalie Bouvet and all data managers; the independent data monitoring committee (Maria-Grazia Valsecchi, Julia Brown, Hervé Tilly, John Sandlund); Xavier Paoletti and Catherine Patte for their reviews; Lorna Saint-Ange for editing; and all pathologists and investigators (see Appendix).
Written on behalf of the European Intergroup for Childhood Non-Hodgkin Lymphoma, the Société Française de Lutte contre les Cancers et Leucémies de l'Enfant, the Associazione Italiana di Ematologia ed Oncologia Pediatrica Lymphoma Committee, the UK Children's Cancer and Leukaemia Group, the Japanese Pediatric Leukemia/Lymphoma Study Group, the Polish Pediatric Leukemia/Lymphoma Study Group, the Dutch Childhood Oncology Group, the Belgian Society of Pediatric Hematology and Oncology, the Nordic Society for Pediatric Hematology and Oncology, and the Non-Hodgkin's Lymphoma Berlin-Frankfurt-Muenster Group.
Supported by the Association Cent Pour Sang la Vie, Institut Gustave-Roussy, Cancer Research UK, the Forschungshilfe Station Peiper, the Associazione Italiana Contro le Leucemie, Fondazione Citta della Speranza, and Ministry of Health, Labor and Welfare (Japan).
Appendix
List of Data Managers Involved in the Trial
D. Lemmens, Data Centre, University Hospital, Leuven, Belgium; U. Meyer and Dr B. Burkhardt, Berlin-Frankfurt-Münster (BFM) Data Center, Giessen, Germany; Ilaria Zecchini, Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) Data Center, Padova, Italy; Y. Okabe and Dr T. Takimoto, Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Data Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan; L. Scheffers, Dutch Childhood Oncology Group (DCOG) Data Center, The Hague, the Netherlands; Dr K. Mellgren, Göteborg University, Goteborg, Sweden; for data management and study coordination assistance.
List of Pathologists and Biologists Involved in the Trial
Dr I. Simonitsch, St Anna Kinderspital, Vienna, Austria; Pr G. Delsol, Hôpital Purpan, Toulouse, France; Pr H. Stein, Berlin; Pr H-L. Hansmann, Frankfurt; G. Buck, Dr W. Klapper, Giessen; Pr J. Harbott, Giessen; Dr I. Oschlies, Pr R. Parwaresch, Pr R. Siebert, Kiel; Pr R. Parwaresch, Kiel; Dr A. Feller, Luebeck; Pr P. Moeller, Ulm; Pr H. Mueller-Hermelink, Wuerzburg, Germany; Dr E. d'Amore, Padova, Italy; Dr K. Oshima, Kurume University, Kurume; Dr A. Nakagawa and Dr J. Fujimoto, National Center for Child Medical Health and Development, Tokyo, Japan; Dr J. Maldyk, Warsaw Medical University, Warsaw, Poland; Dr A. Porwit, Karolinska Hospital, Stockholm, Sweden; Dr M. Fraga, Hospital Xeral de Galicia, Santiago de Compostella, Spain; Dr K. McCarthy, Gloucestershire Royal Hospital, Gloucester, United Kingdom; for pathology review or cytogenetics assessment.
List of All Investigators Who Participated in the Trial
BFM-Austria: Pr C. Urban, Universitätskinderklinik, Graz; Pr B. Meister, Universitätskinderklinik, Insbruck; Pr K. Schmitt, Landeskinderkrankenhaus, Linz; Pr G. Mann, Pr A. Attarbaschi, St Anna Children's Hospital, Vienna; Belgium: Dr C. Vermylen, Clinique Universitaire–St Luc, Bruxelles; Dr C. Devalck, Hopital Reine Fabiola, Bruxelles; Dr G. Laureys, University Hospital, Gent; Dr M.F. Dresse, Hospital La Citadelle, Liege; Dr N. Francotte, CH Clinique Esperance, Montegnee; France: Dr B. Pautard, Centre Hospitalier Régional Universitaire (CHRU) Nord, Amiens; Dr X. Rialland, CHRU d'Angers, Angers; Pr Y. Perel, Groupe Hospitalier Pellegrin, Bordeaux; Dr P. Boutard, Centre Hospitalier Universitaire (CHU), Caen; Pr F. Demeocq, Hôtel Dieu CHU, Clermont-Ferrand; Dr G. Couillault, Hôpital d'Enfants, Dijon; Pr D. Plantaz, CHU A. Michalon, Grenoble; Dr B. Nelken, Hôpital J. de Flandre – CHU Huriez, Lille; Dr C. Piguet, CHU Dupuytren, Limoges; Dr C. Bergeron, Centre Léon Bérard, Lyon; Dr Y. Bertrand, Hôpital Debrousse, Lyon; Dr G. Michel, Hôpital d'Enfants de la Timone, Marseille; Dr C. Schmitt, Hôpital d'Enfants – CHU, Nancy; Dr F. Mechinaud, Hôtel Dieu de Nantes, Nantes; Dr N. Sirvent, Hôpital de l'Archet 2, Nice; Dr H. Pacquement, Institut Curie, Paris; Pr. A. Baruchel, Hôpital Saint Louis, Paris; Dr K. Yacouben, Hôpital Robert Debré, Paris; Pr G. Leverger, Hôpital Trousseau, Paris; Dr F. Millot, Hôpital Jean Bernard La Mileterie, Poitiers; Dr C. Behar, Hôpital Américain, Reims; Dr V. Gandemer, CHR Sud, Rennes; Pr J. Vannier, Hôpital Charles Nicolle, Rouen; Pr P. Lutz, Hôpital Hautepierre, Strasbourg; Dr A. Robert, Hôpital des Enfants – CHU de Toulouse, Toulouse; Dr O. Lejars, Hôpital de Clocheville – CHU, Tours; BFM-Czech Republic/Germany/Switzerland: Dr R. Mertens, Universitätskinderklinik Aachen; Dr Th. Kühne, Baseler Kinderspital, Basel; Pr G. Henze, Charite Campus Virchow-Klinikum, Berlin; Dr W. Doerffel, Helios Klinikum Berlin-Buch; Dr N. Jorch, Evangelisches Krankenhaus Bielefeld GmbH, Bielefeld; Pr U. Bode, Universitäts-Kinderklinik, Bonn; Dr W. Eberl, Städtisches Krankenhaus, Braunschweig; Pr A. Pekrun, Kliniken der Freien Hansestadt, Bremen; Dr U. Krause, Klinikum Chemnitz GmbH, Chemnitz; Dr E. Holfeld, Carl-Thiem-Klinikum, Cottbus; Dr H. Breu, Staedtisches Klinikum, Kinderklinik, Dortmund; Pr M. Suttorp, Universitäts-Kinderklinik Dresden; Pr U. Göbel, Universitäts-Kinderklinik, Düsseldorf; Pr J. Sauerbrey, Helios Klinikum Erfurt; Pr J. Beck, Universität-Kinderklinik, Erlangen; Pr B. Kremens, Universitäts-Kinderklinik Essen; Pr T. Klingebiel, Universitäts-Kinderklinik Frankfurt; Pr C. Niemeyer, Universitäts-Kinderklinik, Freiburg; Pr L. Lakomek, Universitäts-Kinderklinik, Goettingen; Pr S. Burdach, Universitäts-Kinderklinik Halle; Pr G. Janka-Schaub, Universitäts-Kinderklinik Hamburg; Pr K. Welte, Medizinische Hochschule Hannover; Pr A. Kulozik, Universitäts-Kinderklinik, Heidelberg; Dr A. Laengler, Kinderklinik Herdecke; Pr N. Graf, Universitäts-Kinderklinik Homburg/Saar; Pr F. Zintl, Universitäts-Kinderklinik Jena; Dr L. Städt, Klinikum Karlsruhe GmbH, Karlsruhe; Pr M. Schrappe, Universitäts-Kinderklinik Kiel; Pr M. Rister, Städtisches Krankenhaus Kemperhof, Koblenz; Dr W. Sternschulte, Städtisches Kinderkrankenhaus, Koeln; Pr F. Berthold, Universitäts-Kinderklinik Koeln; Pr D. Körholz, Universitäts-Kinderklinik Leipzig, Leipzig; Pr P. Bucsky, Universitäts-Kinderklinik Luebeck; Dr U. Caflisch, Kinderklinik Luzern; Pr U. Mittler, Universitäts-Kinderklinik Magdeburg; Pr P. Gutjahr, Universitäts-Kinderklinik Mainz; Pr H. Christiansen, Universitäts-Kinderklinik Marburg; Pr B. Erdlenbruch, Kinderklinik des Klinikum Minden, Minden; Pr H. Jürgens, Universitäts-Kinderklinik, Muenster; Pr A. Borkhardt, von Haunersches Kinderspital der LMU, München; Pr O. Schofer, Kinderklinik Kohlhof, Neunkirchen; Dr A. Jobke, Cnopf'sche Kinderklinik, Nuernberg; Dr H. Müller, Zentrum für Kinder und Jugendmedizin, Oldenburg; Dr E. Kabickowa, University Hospital Prag; Dr O. Peters, Klinik St Hedwig, Regensburg; Dr R. Geib, Winterbergkliniken Saarbruecken; Dr J. Greiner, St Gallen; Dr R. Dickerhoff, Kinderklinik St Augustin; Pr J. Treuner/Pr S. Bielack, Olga-Hospital Stuttgart; Pr D. Niethammer, Universitäts-Kinderklinik, Tuebingen; Pr K.-M. Debatin, Universitäts-Kinderklinik, Ulm; Pr M. Albani, Dr.-Horst-Schmidt-Kliniken, Wiesbaden; Pr P.-G. Schlegel, Universitäts-Kinderklinik, Wuerzburg; Dr F. Niggli, Universitäts-Kinderklinik Zuerich; Italy: Dr A. Lombardi, Ospedale Pediatrico Bambino Gesù, Roma; Dr F. Spreafico, Istituto Nazionale Tumori, Milano; Dr P. Pierani, Azienda Ospedaliera G. Salesi, Ancona; Dr N. Santoro, Policlinico Consorziale, Bari; Dr R. Burnelli, Ospedale S. Orsola – Malpighi, Bologna; Dr K. Tettoni, Dr A. D'Ippolito, Spedali Civili, Brescia; Dr R. Mura, Ospedale Regionale per le Microcitemie, Cagliari; Dr L. Lo Nigro, Policlinico Universitario, Catania; Dr C. Consarino, Ospedale Civile A. Pugliese, Catanzaro; Dr D. Sperlì, Azienda Ospedaliera di Cosenza, Cosenza; Dr A. Lippi, Azienda Ospedaliera A. Meyer, Firenze; Dr A. Garaventa, Istituto G. Gaslini, Genova; Dr M. Cellini, Policlinico Universitario, Modena; Dr V. Conter, Ospedale S. Gerardo, Monza; Dr S. Buffardi, Ospedale Pausilipon, Napoli; Pr F. Casale, Università degli Studi di Napoli, Napoli; Dr M. Nardi, Università degli Studi di Pisa, Pisa; Dr D. Del Principe, Università Tor Vergata, Roma; Dr M.L. Moleti, Università La Sapienza, Roma; Dr R. De Santis, Clinica Pediatrica, San Giovanni Rotondo; Dr M. Piglione, Ospedale Infantile Regina Margherita, Torino; Dr G.A. Zanazzo, Ospedale Infantile Burlo Garofalo, Trieste; Dr M. Aricò, Dr P. D'Angelo, Ospedale dei Bambini, Palermo; Dr E. Giraldi, Ospedali Riuniti, Bergamo; Dr I. Capolsini, Clinica Pediatrica, Perugia; Japan : Dr M. Tsurusawa, Aichi Medical University, Aichi; Dr K. Kato, Japanese Red Cross Nagoya First Hospital, Aichi; Dr A. Kikuta, Fukushima Medical University Hospital, Fukushima; Dr A. Takao, Gifu Municipal Hospital, Gifu; Dr M. Kobayashi, Hiroshima University Hospital, Hiroshima; Dr K. Hamamoto, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima; Dr S. Lizuka, National Hospital Organization Hokkaido Cancer Center, Hokkaido; Dr N. Suzuki, Sapporo Medical University Hospital, Hokkaido; Dr M. Kaneda, Hokkaido University Medical Hospital, Hokkaido; Dr A. Hayakawa, Kobe University Hospital, Hyogo; Dr I. Usami, Kobe City Medical Center General Hospital, Hyogo; Dr K. Matsubara, Nishi-Kobe Medical Center, Hyogo; Dr T. Fukushima, Tsukuba University Hospital, Ibaraki; Dr K. Kawakami, Kagoshima City Hospital, Kagoshima; Dr K. Kato, Tokai University School of Medicine Hospital, Kanagawa; Dr Y. Komada, Mie University Hospital, Mie; Dr K. Koike, Shinshu University Hospital, Nagano; Dr K. Asami, Niigata Cancer Center Hospital, Niigata; Dr K. Kawasaki, Kawasaki Medical School Hospital, Okayama; Dr J. Hara, Osaka City General Hospital, Osaka; Dr A. Tawa, Osaka National Hospital, Osaka; Dr N. Sakata, Kinki University School of Medicine, Osaka; Dr A. Kikuchi, Saitama Children's Medical Center, Saitama; Dr R. Kanai, Shimane University Hospital, Shimane; Dr J. Mimaya, Shizuoka Children's Hospital, Shizuoka; Dr K. Sugita, Dokkyo Medical University Hospital, Tochigi; Dr M. Kumagai, National Center for Child Medical Health and Development, Tokyo; Dr M. Saito, Juntendo University Hospital, Tokyo; Dr A. Ohara, Toho University Omori Medical Center, Tokyo; Dr T. Kaneko, Tokyo Metropolitan Kiyose Children's Hospital, Tokyo; Dr F. Bessho, Kyorin University Hospital, Tokyo; Dr S. Kounami, Wakayama Medical University, Wakayama; Dr N. Hotta, Yamaguchi University Hospital, Yamaguchi; Dr M. Tsuchida, Ibaragi Children's Hospital; K. Isoyama, Showa University Fujigaoka Hospital; Y. Hayashi, Gunma Children's Medical Center; S. Sunami, Narita Red Cross Hospital; Y. Okimot, Chiba Children's Hospital; R. Hosoya, St Luke's International Hospital; E. Ishii, Nagano Children's Hospital; Y. Miyajima, Anjo Kosei Hospital; S. Kojima, Nagoya University Hospital; N. Kondo, Gifu University Hospital; S. Okada, Hamamatsu University Hospital; M. Mayumi, Fukui University Hospital; H. Ohta, Osaka University Hospital; T. Nakahata, Kyoto University Hospital; T. Imai, Otsu Red Cross Hospital; K. Kawakami, Kagoshima City Hospital; M. Okada, Nagasaki University Hospital; the Netherlands : Dr E.T. Korthof, Leiden University Medical Center, Leiden; Pr N. Hoogerbrugge, University Medical Center, Nijmegen; Dr A. Beishuizen, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam; Poland: Dr A. Kołtan, Clinic of Pediatrics, Hematology and Oncology, Ludwik Rydygiers's Medical Academy, Bydgoszcz; Dr Olejnik, Center of Pediatrics and Oncology in Chorzów, Chorzow; Dr L. Maciejka-Kapuscinska, Clinic of Pediatrics, Hematology, Oncology and Endocrinology, Institute of Pediatrics Medical Academy in Gdansk, Gdansk; Dr A. Dluzniewska, Department of Pediatric Oncology and Hematology Polish-American Institute of Pediatrics Jagiellonian University Medical College, Krakow; Dr M. Stolarska Clinic of Children Diseases, Institute of Pediatrics, Medical Academy in Łódź, Department of Oncology and Hematology, Łódź; Dr J. Stefaniak, Department of Hematology and Oncology, Children's Hospital, Medical Academy, Lublin; Dr K. Stefanska, Department of Pediatric Oncology, Hematology and Transplantology, Karol Marcinkowski University of Medical Sciences, Poznan; Dr B. Sopylo, Clinic of Pediatrics, Hematology and Oncology, Medical Academy, Warsaw; Pr A. Chybicka and Dr B. Kazanowska, Department of Bone Marrow Transplantation, Children Hematology and Oncology, Medical Academy, Wroclaw; Dr H. Bubala, Department of Oncology, Hematology and Chemotherapy, Clinic of Pediatrics, Silesian Medical Academy, Zabrze; Sweden: Pr O. Bjork, Karolinska Hospital, Stockholm; United Kingdom: Dr A. McCarthy, Royal Belfast Hospital for children, Belfast; Dr B. Morland, Birmingham Children's Hospital, Birmingham; Dr A. Foot, Bristol Royal Hospital, Bristol; Dr M. English, Llandough Hospital, Cardiff; Dr F. Breatnach, Our Lady's Hospital for Sick Children, Dublin; Dr E. Chalmers, Royal Hospital for Sick Children, Glasgow; Dr S. Picton, St James University Hospital, Leeds; Dr H.P. McDowell, Alder Hey Children's Hospital, Liverpool; Dr J. Kingston, St Bartholomew's Hospital, London; Dr M. Michelagnoli, The Middlesex Hospital, London; Dr B. Brennan, Royal Manchester Children's Hospital, Manchester; Pr Pearson, Sir James Spence Inst. Child Health, Newcastle; Dr D.A. Walker, University Hospital, Nottingham; Dr K. Wheeler, John Radcliffe Hospital, Oxford; Dr M. Gerrard, Sheffield Children's Hospital, Sheffield; Dr J.A. Kohler, Southampton General Hospital, Southampton; Pr K. Prichard-Jones, Royal Marsden National Health Service Trust, Sutton.
Footnotes
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Information regarding grant support for this study can be found in the online version of this article, at JCO.org.
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Clinical trial information can be found for the following: NCT00006455.
- Received February 26, 2010.
- Accepted May 17, 2010.
