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Journal of Clinical Oncology, Vol 24, No 27 (September 20), 2006: pp. 4499-4506 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.5037 Less Toxicity by Optimizing Chemotherapy, but Not by Addition of Granulocyte Colony-Stimulating Factor in Children and Adolescents With Acute Myeloid Leukemia: Results of AML-BFM 98
From the Department of Hematology/Oncology, University Children's Hospital, Muenster; Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover; Department of Pediatric Hematology and Oncology, University of Frankfurt, Frankfurt; Department of Pediatric Hematology and Oncology, University Children's Hospital, Homburg; Department of Pediatric Hematology and Oncology, University Children's Hospital, Jena; Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg; Department of Pediatric Hematology and Oncology, University Children's Hospital, Giessen, Germany; St Anna Children's Hospital and Children's Cancer Research Institute, Vienna, Austria; and the Department of Pediatric Hematology/Oncology, University Hospital Motol, Prague, Czech Republic Address reprint requests to Ursula Creutzig, MD, PhD, Universitätsklinikum Münster, Klinik und Poliklinik für Kinderund Jugendmedizin, Pädiatrische Hämatologie und Onkologie, Albert-Schweitzer-Str 33, D-48129 Münster, Germany; e-mail: ursula{at}creutzig.de
PURPOSE: To improve prognosis in children with acute myeloid leukemia (AML) by randomized comparisons of (1) two short consolidation cycles versus the Berlin-Frankfurt-Muenster (BFM) -type biphasic 6-week consolidation and (2) the prophylactic administration of granulocyte colony-stimulating factor (G-CSF) versus no G-CSF. Further, therapy for standard risk patients was intensified by addition of a second induction, HAM (high-dose cytarabine and mitoxantrone). PATIENTS AND METHODS: Four hundred seventy-three patients younger than 18 years with de novo AML were enrolled in trial AML-BFM 98. Patients received five courses of intensive chemotherapy, cranial irradiation, and 1-year maintenance therapy. RESULTS: Four hundred eighteen patients (88%) achieved remission. Compared with trial AML-BFM 93, early deaths decreased from 7.4 to 3.2% (P = .005), and 5-year overall survival increased from 58% to 62% (log-rank P = .03). Both types of consolidation therapy led to similar outcome (event-free survival, 51% v 50%), but in the two-cycle arm, treatment duration was shorter (median duration, 15 days), and treatment related mortality was lower (five v nine patients). G-CSF shortened neutropenia, but did not reduce the rate of severe infections. Intensification of induction therapy did not improve prognosis of standard-risk patients (event-free survival, 62% v 67%). CONCLUSION: Overall results were improved by neither the administration of G-CSF nor by cycle therapy; however, the latter was easier to perform. Compared with study AML-BFM 93, therapy intensification with HAM in standard-risk patients did not result in improved prognosis. Future treatment designs have to balance intensification of treatment with higher toxicity, improve supportive care, and to consider alternative treatment strategies.
Long-term survival for children with acute myeloid leukemia (AML) has considerably improved to 50% to 60% during the last 20 years.1-3 This was mainly due to intensification of chemotherapy, including stem-cell transplantation (SCT). Even though a high proportion of patients did benefit from treatment, prognosis remained poor in many others. To further improve outcome in patients with poor prognosis, but at the same time avoid increasing toxicity in patients with favorable prognostic factors, we applied a risk-adapted strategy (based on the results of studies AML-Berlin-Frankfurt-Muenster (BFM) 83 and 874 in study AML-BFM 93 and in the here-presented trial 98. In study AML-BFM 93, induction with AIE (cytarabine, idarubicin, etoposide) induced a significantly better blast cell reduction in the bone marrow on day 15 than the standard ADE (cytarabine, daunorubicin, etoposide) regimen.5 In addition, therapy intensification with HAM (high-dose cytarabine and mitoxantrone), administered to high-risk (HR) patients only, resulted in a significantly better probability of survival (pOS) and event-free survival (pEFS) compared with a similar cohort of the previous study AML-BFM 87.6 Based on these results, we further intensified induction within a pilot study using an increased anthracycline dose. However, this led to intolerable toxicities with a prolonged duration of aplasia and severe mucositis.7 In contrast, the HAM course had been proven to be tolerable and was therefore administered in study AML-BFM 98 not only to HR but also to standard-risk (SR) patients with the aim to improve prognosis by intensification of therapy. We also compared the 6-week consolidation treatment with seven different drugs, as traditionally given in the AML-BFM studies (standard treatment), with two short therapy cycles (intensified treatment) as generally applied in other pediatric or adult AML trials.2,3 In addition, the impact of prophylactic use of granulocyte colony-stimulating factor (G-CSF) was tested in study AML-BFM 98.
Eligibility Entry criteria were as follows: age 0 to 18 years; newly diagnosed AML between July 1, 1998, and June 30, 2003; and written informed consent. Patients with myelosarcoma (< 30% blasts),8 secondary AML or myelodysplastic syndrome were excluded. Patients with AML and Down syndrome were eligible, but were excluded from this analysis. The French-American-British (FAB) classification was used for the initial diagnosis of AML.9,10 Initial smears were routinely examined at the University Children's Hospital Muenster (Germany) and were centrally reviewed by a panel of hematologists. The diagnoses of the FAB M0 and M7 subtypes required confirmation by immunologic methods.10,11 Day 15 bone marrow aspirates were also centrally reviewed.
Aims and Study Design Study questions (Fig 1): (1) to evaluate by random assignment whether two short chemotherapy cycles (two-cycle) compared with the BFM-type 6-week consolidation (CONS; standard treatment, administered for all patients in study 93),6 could improve prognosis (the cumulative dose of anthracyclines was similar in both arms); (2) to evaluate by random assignment whether the use of G-CSF (5 µg/kg/d) on day 15 after the start of the first and second therapy course could reduce the incidence of serious infections (defined as National Cancer Institute Common Toxicity Criteria version 3.0 grades 3 and 4; http://ctep.cancer.gov/reporting/ctcnew.html). Patients with more than 5% blasts in bone marrow on day 15 or FAB M3 were excluded because of potential adverse events.12
An additional goal was to improve prognosis (ie, pOS and pEFS) in SR patients. Therefore, the HAM course was administered to all patients (except M3 patients); thus, SR and HR patients received the same number of intensification blocks and the only stratified treatment was SCT in first complete remission (CR; discussed in Treatment). FAB M3 patients were included when comparing overall results with the previous study and in the random assignment of consolidation treatment. Because of their favorable outcome, they were not assigned to the intensification with HAM as were other SR patients, and they were not treated with G-CSF, because G-CSF in addition to all-trans retinoic acid (ATRA) is not recommended. 12
Treatment
Definition and Statistics Random assignments were performed centrally using the permuted block method. Patients were stratified according to risk groups. First random assignment: According to results from previous AML-BFM studies, the 5-year pEFS was estimated to be 55% for patients receiving 6-week CONS. To detect an increase in pEFS of 15% for the two-cycle consolidation group, 170 patients per group had to be randomly assigned (power, 80%;  , 5%; two-sided test). Second random assignment: 135 patients per group had to be randomly assigned to detect a decrease of severe infections from 30% in the control group to 15% in the G-CSF–treated group (power, 80%; , 5%; two-sided test). A third, late randomization (cranial irradiation; test of equivalence of 12 v 18 Gy) is continued in the current study AML-BFM 2004 and will be reported later. No interactions between the treatment arms were anticipated for this 2x2x2 factorial design. CR was defined according to the Cancer and Leukemia Group B (CALGB) criteria13 and had to be achieved by the end of intensive treatment (HAE course). Early death (ED) was defined as death before or within the first 6 weeks of treatment. EFS was calculated from date of diagnosis to last follow-up or first event (ED, resistant leukemia, relapse, secondary malignancy, or death resulting from any cause). Failure to achieve remission was considered event on day 0. Overall survival (OS) was calculated from date of diagnosis to death, and disease-free survival (DFS) from date of remission to first event. Rates were calculated according to Kaplan-Meier and compared by log-rank test. SEs were obtained using Greenwoods formula. The effect of SCT on survival was tested using the Mantel-Byar method.14 Follow-up was as of March 2005. Toxicities were evaluated according to modified National Cancer Institute Common Toxicity Criteria version 3.0. Computations were performed using SAS (Statistical Analysis System Version 9.1; SAS Institute, Cary, NC).
Patient Characteristics In total, 473 non-Down patients (and 66 Down syndrome patients, whose results are published elsewhere15) with de novo AML were enrolled in study AML-BFM 98. Median follow-up of patients alive was 3.4 years (range, 0.8 to 6.4 years). The patient characteristics were similar to those of study AML-BFM 93 (n = 471; Table 1).
Overall Treatment Results Treatment results are summarized in Table 2 and in Figure 3. The 5-year pOS in the 473 patients of study AML-BFM 98 was 62% ± 3%, and thus significantly better than in the previous study AML-BFM 93 (pOS 58% ± 2%, log-rank P = .03). Compared with AML-BFM 93, the remission rate increased in study AML-BFM 98 (82% v 88%; P = .01), whereas the 5-year pEFS and probability of DFS (pDFS) were in the same range (pEFS 50% ± 2% v 49% ± 3%; log-rank P = .77; and pDFS 61% ± 3% v 57% ± 3%; log-rank P = .32).
Results During Induction Compared with AML-BFM 93, the ED rate decreased in study AML-BFM 98 (7% versus 3%, P = .005; Table 2). Blast cell reduction in bone marrow on day 15 was similar to that of patients treated according to the idarubicin arm in study AML-BFM 93. In study 98, in which all patients were treated with idarubicin during induction, 65 (16.7%) of 389 patients had more than 5% blasts on day 15 (FAB M3 patients excluded) compared with 25 (17%) of 144 patients in the idarubicin arm of study AML-BFM 93. In contrast, 46 (31%) of 149 patients treated with daunorubicin in study 93 had more than 5% blasts on day 15 (  2 P = .01). The rate of nonresponders was similar in both trials (10% v 9%; P = .44). In study AML-BFM 98, CR rate and pEFS were significantly better in children with a bone marrow blast count of 5% or lower on day 15 than in those with blasts more than 5% (CR, 93.8% v 76.9%; P < .001; pEFS 54% ± 3% v 33% ± 6%, log-rank P < .0001; FAB M3 patients excluded; Table 3).
Results of Random Assignments First random assignment. Three hundred ninety (84%) of 462 patients eligible for random assignment (defined as those surviving > 33 days) were randomly assigned after the first induction course (two-cycle, n = 199; 6-week CONS, n = 191). Seventy-two patients were not randomly assigned (mainly due to parents' or physicians' choice). Although allocated to the two-cycle arm, nine patients actually received the 6-week CONS and, similarly, seven children allocated to the CONS arm actually received the two-cycle regimen. However, patients were analyzed as randomly assigned on an intent-to-treat basis. Patient characteristics in both treatment arms were similar except for a higher percentage of patients with t(15;17) in the CONS arm (13 v 4 patients; P = .02; data not shown). The two treatment strategies did not differ in pOS, pEFS, and pDFS when analyzing the total group and the subgroups of SR or HR patients (intent-to-treat-analyses; Fig 4). Similar results were obtained by analyzing the children as actually treated. However, differences between the two-cycle therapy and the 6-week CONS were seen for treatment duration and toxicity (Table 4). The total duration of the intensive chemotherapy was in median 15 days shorter in the two-cycle arm than in the CONS arm (P = .0001). Although not statistically significant, less toxic deaths occurred in the two-cycle arm (five v nine patients; P = .3) and were mainly due to bacterial infection during aplasia.
Second random assignment. One hundred seven (23%) of 473 patients were not eligible for random assignment to G-CSF versus no G-CSF because of ED within the first 15 days after starting treatment, M3 subtype, or more than 5% blasts on day 15. In total, 272 (74%) of 366 patients eligible for the second random assignment were randomly assigned (G-CSF, n = 134; no G-CSF, n = 138). Except for a higher percentage of females in the control group (54% v 36%; P = .002), patient characteristics were similar in both arms. The duration of neutropenia (defined as < 500/µL) was significantly shorter in the G-CSF arm (after AIE, median, 18.0 v 23.0 days; P = .02; and after HAM, 11.0 v 16.0 days; P = .0005; Table 5), whereas the duration of thrombocytopenia (< 20,000/µL) was similar in both groups. No impact of G-CSF was found on the incidence of grade 3 and 4 infections. Five-year pEFS did not differ significantly between the groups with and without G-CSF (51% ± 5% v 55% ± 5%; log-rank P = .42). Similar results were obtained by performing the intent-to treat analysis and analyzing the children according to the treatment actually received.
Results of Subgroups Table 3 shows pEFS and pOS according to different risk parameters in studies AML-BFM 93 and 98. Compared to the previous study, AML-BFM 98 did not show significant differences in pEFS and pOS in the respective subgroups:
Standard risk group (FAB M3 excluded).
Compared with AML-BFM 93, SR patients received an additional HAM course during induction in study AML-BFM 98. This did not, however, result in a higher CR rate (93% v 89%,
High-risk group. Results in HR patients were similar to those of the previous study (Table 3). Five-year pOS of HR patients with or without SCT in first CR was also similar (69% ± 14% v 64% ± 4%; Mantel-Byar P = .25; for the calculation of the Kaplan-Meier estimate of the group without SCT, patients with EFS < 0.44 years [median time to SCT] were excluded). Cytogenetics. In study 98, the 5-year pEFS of the 120 patients with favorable karyotypes [defined as t(8;21), t(15;17) or inv16] was significantly better than that of the 302 patients with unfavorable or normal karyotypes (76% ± 5% v 40% ± 3%; log-rank P = .0001). Five-year OS in patients with favorable karyotypes improved considerably compared to study 93 (91% ± 3%, v 74% ± 5%; log-rank P = .003).
The overall results of the clinical trial AML-BFM 98 showed a significantly better 5-year overall survival than the preceding study AML-BFM 93, whereas pEFS and pDFS did not improve. Therapy intensification with HAM in SR patients did not result in improved prognosis in this patient group. In addition, shortened therapy cycles or the administration of G-CSF did not improve overall results. On the other hand, there are important insights for future treatment designs, in which (a) intensification of treatment has to be well balanced with expected higher toxicity, (b) improvement of supportive care is of critical interest,16 and (c) alternative treatment strategies have to be considered, in particular for subgroups of AML patients. Study AML-BFM 98 confirms the results of AML-BFM 93, in which there was a significantly better blast cell reduction in the day-15 bone marrow in patients treated with idarubicin compared with those receiving daunorubicin.5 Although there are no day-15 data from other studies comparing both anthracyclines, one randomized trial in adults with AML found a significantly lower number of induction failures after 40 days in the idarubicin arm.17 Compared with previous AML-BFM trials, the ED rate could further be reduced in AML-BFM 98 [13%, 12%, 9%, and 7.3% for trials AML-BFM 78, 83, 87 and 93, respectively, v 3.2% in trial AML-BFM 98, P trend < .001)]. This was mainly a result of improved supportive care and better experience.16 Beside intensity of treatment, type and order of therapy elements have an impact on therapy success.18 A comparison between the results of the randomized two-cycle consolidation versus the 6-week CONS showed similar overall outcome, but the total time of the intensive treatment phase was 15 days shorter, and there was a trend to less toxic deaths in the two-cycle arm (five v nine patients). These results might be explained by several reasons: (1) in children with AML, the prolonged administration of steroids in the 6-week CONS is profoundly immunosuppressive, without having a clear benefit regarding cytotoxic effects on AML blasts19; (2) the frequent and prolonged periods of aplasia are associated with a high risk of bacterial and fungal infections, which often necessitate to interrupt or even to stop this treatment phase. Therefore, much experience is needed in the CONS to decide whether the highly toxic treatment should be continued or stopped, which, in turn, may increase the risk of relapse. In contrast, the two-cycle consolidation has rather clear criteria for stopping or continuing treatment. These considerations were relevant to the decision to abandon CONS and to continue the two-cycle consolidation in the ongoing study AML-BFM 2004. The main objective of the G-CSF randomization in study AML-BFM 98 was to evaluate the impact of G-CSF on the duration of neutropenia and the incidence of severe infections. G-CSF significantly shortened the duration of neutropenia, but, surprisingly, did not influence the incidence of severe infectious complications or the 5-year pEFS. The only study on G-CSF in pediatric AML patients so far was nonrandomized and compared two consecutive cohorts of patients.20 The authors report that G-CSF decreased neutropenia duration, hospital stay and the time to continue therapy. However, G-CSF had no impact on the incidence of severe infections and outcome. Corroborating the results of four recent trials,21-24 a review of 11 adult AML studies found mainly a reduced duration of neutropenia, whereas the risk of infectious complications was reduced in only a minority of the trials. Only two studies observed an impact of G-CSF on survival, but this was restricted to high-risk patients only.25 Our results, however, are in contrast to a meta-analysis of randomized controlled trials that evaluated the effect of prophylactic hematopoietic growth factors in children undergoing intensive therapy for different types of cancer.26 That analysis demonstrated that the prophylactic use of G-CSF or granulocyte macrophage colony-stimulating factor led to a 20% reduction in febrile neutropenia in those patients with an original risk of febrile neutropenia of 40% or higher. On the other hand, in vitro data show that G-CSF can stimulate proliferation in AML blasts.27 Because there was no evidence of beneficial effects in our study concerning serious infections, the administration of G-CSF will not be routinely recommended in future AML-BFM studies. However, it remains unclear whether there is a subgroup of pediatric AML patients who might benefit from the use of G-CSF. In previous AML-BFM studies, we have shown that the stratification variables such as "blast cell reduction on day 15," or the stratification in SR and HR groups defined by combined risk criteria are of prognostic significance.4 In the 1980s, prognosis in SR patients was improved by intensification of initial chemotherapy.1 Similarly, in the last 10 years, outcome in HR patients has been improved using more intensive therapy (eg, high-dose cytarabine courses in study AML-BFM 93).6 Consequently, SR patients also received HAM intensification in study 98. However, prognosis in SR patients remained similar to that in the previous studies AML-BFM 93, 87, and 83, indicating that it may be extremely difficult to improve prognosis in this subgroup. Similar observations have been reported by the Medical Research Council (MRC) trials. Compared to chemotherapy alone, allogeneic SCT in first CR did not result in a survival advantage in the "MRC-good-risk group," as defined by favorable cytogenetics.3,28 Interestingly, preliminary analysis of HR patients treated according to AML-BFM 98 showed that these patients did not benefit from a matched sibling donor SCT in first CR. New therapeutic approaches such as molecular targeted therapy might be an option to increase survival in specific patient subgroups (ie, characterized by FLT3, RAS or KIT mutations).29 The estimated probability of long-term survival of children with AML who achieve remission is now in the range of 65% to 70%. Our results show that survival in SR patients could not be improved by intensification of chemotherapy with HAM. Similarly, short-cycle chemotherapy and the prophylactic use of G-CSF had no impact on overall prognosis. As improvement of prognosis cannot be achieved by intensification of treatment alone, the ongoing study AML-BFM 2004 assesses, in addition to intensification in HR patients, whether intensified supportive care strategies will reduce treatment related morbidity and mortality and thereby improve survival. Furthermore, alternative treatment strategies are urgently needed, because the results show that the dogma "the more, the better" might not be true in children undergoing therapy for AML.
Principal investigators of Studies AML-BFM 98 in Germany: R. Mertens, Kinderklinik RWTH, Aachen; A. Gnekow, I. Kinderklinik des KZVA, Augsburg; Th. Rupprecht, Universitäts-Kinderklinik GmbH, Bayreuth; G. Henze/R. Fengler, Charité Campus Virchow-Klinikum, Berlin; A.-K. Liebeskind, Helios Klinikum Berlin-Buch, Berlin; N. Jorch, Ev. Krankenhaus Bielefeld gGmbH, Bielefeld; U. Bode/G. Fleischhack, Universitäts-Kinderklinik, Bonn; H.G. Koch/W.Eberl, Städt. Klinikum, Braunschweig; A. Pekrun, Prof.-Hess-Kinderklinik, Bremen; I. Krause, Klinikum Chemnitz gGmbH, Chemnitz; E. Holfeld, Carl-Thiem-Klinikum, Cottbus; W. Andler/Th. Wiesel, Vestische Kinderklinik, Datteln; H. Olschewski, Kinderklinik der Städt. Kliniken, Dortmund; M. Suttorp/ I. Lauterbach, Universitäts-Kinderklinik Carl-Gustav-Carus, Dresden; U. Göbel, Universitäts-Kinderklinik, Düsseldorf; A. Sauerbrey/G. Weinmann, Helios Klinikum Erfurt GmbH, Erfurt; J.D. Beck, Universitäts-Kinderklinik, Erlangen; B. Kremens, Universitäts-Kinderklinik, Essen; Th. Klingebiel/Th. Lehrnbecher, Klinikum d. J. W. Goethe-Universität, Frankfurt; C.M. Niemeyer, Universitäts-Kinderklinik Freiburg; A. Reiter/R. Blütters-Sawatzki, Universitäts-Kinderklinik, Gießen; M. Lakomek/L. Schweigerer, Georg-August-Universität, Göttingen; J.F. Beck/H. Weigel, Universitäts-Kinderklinik, Greifswald; D. Körholz/R.Schobeß, Martin-Luther-Universität Halle-Wittenberg, Halle; R. Schneppenheim/H. Kabisch, Universitätsklinikum Hamburg-Eppendorf, Hamburg; K. Welte, Zentrum f. Kinderheilkunde der Med. Hochschule, Hannover; A. E. Kulozik, Universitäts-Kinderklinik, Heidelberg; N. Graf, Universitäts-Kinderklinik, Homburg/Saar; J. Hermann, FSU Jena, Klinik f. Kinder- und Jugendmedizin, Jena; J. Kühr/A. Leipold, Städtische Kinderklinik, Karlsruhe; M. Rodehüser, Städt. Kinderklinik, Kassel; M. Schrappe/A. Claviez, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel; M. Rister, Städt. Klinikum Kemperhof, Koblenz; F. Berthold, Universitäts-Kinderklinik, Köln; W. Sternschulte, Städt. Kinderkrankenhaus Riehl, Köln; S. Völpel, Städt. Krankenhäuser, Krefeld; U. Bierbach, Universitäts-Kinderklinik, Leipzig; S. Selle, Kinderklinik St. Annastift, Ludwigshafen; P. Bucsky, Universitäts-Kinderklinik, Lübeck; U. Mittler/U. Kluba, Otto-v. Guericke-Universität, Magdeburg; P. Gutjahr, Klinikum d. Joh. Gutenberg-Universität, Mainz; M. Dürken, Universitäts-Kinderklinik, Mannheim; H. Christiansen, Klinikum d. Philipps-Universität, Marburg; A. Borkhardt, Kinderklinik und Poliklinik im Dr v. Haunerschen Kinderspital (Klinikum der Universität München), München; St. Burdach/A. Wawer, Kinder- und Poliklinik des Klinikums rechts der Isar der Technischen Universität München Kinderklinik Schwabing, München; R. Roos/T. Papousek, Städt. Krankenhaus Harlaching, München; H. Jürgens/L. Ritter, Universitäts-Kinderklinik, Münster; W. Scheurlen/A. Jobke, Cnopf'sche Kinderklinik, Nürnberg; H. Gröbe/U. Schwarzer, Klinikum Nürnberg, Nürnberg; H. Müller/R. Kolb, Klinikum Oldenburg gGmbH, Oldenburg; F.J. Helmig/O. Peters, Klinik St. Hedwig, Regensburg; G. Eggers, Universitäts-Kinderklinik, Rostock; R. Dickerhoff, Asklepios Klinik St. Augustin GmbH, St. Augustin; St. Bielack, Olgahospital, Stuttgart; W. Rauh, Krankenanstalt, Mutterhaus der Borromäerinnen e.V., Trier; R. Handgretinger/H. Scheel-Walter, Universitäts-Kinderklinik Tübingen; K.-M. Debatin, Universitäts-Kinderklinik, Ulm; M. Albani/G. Beron, Dr Horst-Schmidt-Kinderklinik, Wiesbaden; T. Liebner, Reinhardt-Nieter-Krankenhaus, Wilhelmshaven; H. Sopnik, Stadtkrankenhaus, Worms; P.-G. Schlegel/St. Rutkowski, Universitäts-Kinderklinik, Würzburg; K. Sinha/B. Dohrn, Klinikum Barmen, Wuppertal Principal investigators in Austria: Ch. Urban, Universitätsklinik für Kinder- und Jugendheilkunde, Graz; F.-M. Fink/ B. Meister, Univ.Klinik für Kinder- und Jugendheilkunde, Innsbruck; K. Schmitt, Landes-Kinderklinik, Linz; O. Stöllinger, Krankenhaus der Barmherzigen Schwestern, Linz; N. Jones, St. Johanns Spital / Landeskrankenhaus, Salzburg; H. Gadner/M. Dworzak, Zentrum für Kinder- u. Jugendheilkunde im St. Anna Kinderspital, Wien Principal investigators in the Czech Republic: H.Hrstkova/J. Sterba, University Hospital, Brno; K.Tousovska, University Hospital, Hradec Kralove; J.Stary, University Hospital Motol, Prague Principal investigators in Switzerland: P. Imbach, Kantonsspital Aarau, Aarau; M. Paulussen, Univ.-Kinderspital Beider Basel, Basel; J. Greiner, Ostschweizerisches Kinderspital, St Gallen; M. Beck-Popovic, CHUV, Lausanne; L. Nobile Buetti, Ospedale Regionale di Locarno, Locarno; U. Caflisch, Kinderspital, Luzern; F. Niggli/J.-P. Bourquin, Universitäts-Kinderklinik, Zürich
The authors indicated no potential conflicts of interest.
We are especially grateful to Elisabeth Kurzknabe for skillful technical assistance, J.-E. Müller for competent data management, and Ursula Bernsmann for the valuable assistance in the management of the AML studies. This article is dedicated to the 80th birthday of Günther Schellong, MD, PhD, who inspired us by his continuous pursuit of knowledge and dedication to academic life.
Supported by the Deutsche Krebshilfe e.V. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
