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Journal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: pp. 4384-4393 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.191 Early Deaths and Treatment-Related Mortality in Children Undergoing Therapy for Acute Myeloid Leukemia: Analysis of the Multicenter Clinical Trials AML-BFM 93 and AML-BFM 98From the Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster; Department of Pediatric Hematology and Oncology, University Children's Hospital, Frankfurt; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany; St Anna Kinderspital and Children's Cancer Research Institute, Vienna, Austria; 2nd Medical Faculty, Charles University, Prague, Czech Republic Address reprint requests to Ursula Creutzig, MD, AML-BFM Trial Center, University Children's Hospital Muenster, Department of Pediatric Hematology and Oncology, Albert-Schweitzer-Str 33, D-48129 Muenster, Germany; e-mail: ursula{at}creutzig.de
PURPOSE: The rates of early death (ED) and treatment-related mortality (TRM) are unacceptably high in children undergoing intensive chemotherapy for acute myeloid leukemia (AML). Better strategies of supportive care might help to improve overall survival in these children. PATIENTS AND METHODS: In a retrospective study, we analyzed incidence, clinical features, and risk factors for lethal complications of 901 children enrolled onto the multicenter trials Acute Myeloid Leukemia-Berlin-Frankfurt-Muenster (AML-BFM) 93 and AML-BFM 98. RESULTS: One hundred four patients (11.5%) enrolled onto the clinical trials AML-BFM 93 and AML-BFM 98 died shortly after diagnosis or as a result of treatment-related complications. Thirty-two patients (3.5%) died before (six patients) or during (26 patients) the first 14 days of treatment, mainly as a result of bleeding or leukostasis. Low performance status, hyperleukocytosis, and French-American-British type M5 were the main risk factors for a lethal event before day 15. After day 15, the predominant causes of death were complications caused by infections, particularly bacterial and fungal infections. The incidence of lethal infections was highest during induction therapy and decreased thereafter. When comparing both clinical trials, significantly fewer patients died within the first 6 weeks in AML-BFM 98 than in AML-BFM 93 (14 [3.5%] of 430 patients v 35 [7.4%] of 471 patients; P = .01). CONCLUSION: To reduce the high incidence of ED and TRM in children with AML, early diagnosis and adequate treatment of complications are needed. Children with AML should be treated in specialized pediatric cancer centers only. Prophylactic and therapeutic regimens for better treatment management of bleeding disorders and infectious complications have to be assessed in future trials to ultimately improve overall survival in children with AML.
During the last two decades, the intensification of antileukemic treatment has improved the long-term survival of both children and adults with acute myeloid leukemia (AML).1-5 For example, the cumulative doses of cytarabine were successively increased, and more effective anthracyclines such as idarubicin were given in the Acute Myeloid Leukemia-Berlin-Frankfurt-Muenster (AML-BFM) clinical trials. Additionally, stem-cell transplantation (SCT) was introduced for patients at high risk for relapse.6 Concomitantly, the intensification of therapy resulted in an improved overall survival, which now ranges from 50% to 60% in children.4,7,8 However, intensification of therapy is associated with increased toxicity. Recently, a clinical trial in the United Kingdom reported on a treatment-related mortality (TRM) of 13.8% in children undergoing therapy for AML,9 which is comparable to the percentage of TRM in the clinical trial AML-BFM 937 and the TRM in a recent national phase III study in the United States.10 The high rate of treatment-related mortality prompted us to perform a retrospective analysis in a large cohort of children enrolled onto the multicenter clinical trials AML-BFM 93 and AML-BFM 98. The objectives of this study were to identify the incidence, the clinical features, and the risk factors for lethal complications in these patients. The results of this analysis may help improve supportive-care strategies in children undergoing therapy for AML and decrease TRM, thus, improving overall survival.
Patients A total of 901 patients with de novo AML who had been enrolled onto the multicenter clinical trials AML-BFM 93 (n = 471) and AML-BFM 98 (n = 430) were included in the analysis. The entry criteria included primary AML (diagnosis confirmed by the reference laboratory), diagnosis before November 2002, age between birth and 18 years, and written informed consent of the patient and/or parents. Children with Down syndrome and children with extramedullary sarcomas with less than 30% blasts in the bone marrow were excluded. The patients were treated in 91 hospitals (Germany, 66 patients; Austria, 12 patients; Switzerland, 7 patients) between January 1993 and October 2002. Six pediatric cancer centers in the Czech Republic participated in the clinical trial AML-BFM 98 only.
Diagnosis
Therapy
In the clinical trial AML-BFM 98, standard-risk patients (except patients with FAB type M3 and patients with Down syndrome) received the same chemotherapy as high-risk patients (Fig 1). After induction (AIE and HAM), patients were randomly allocated to the standard 6-week consolidation phase or to a regimen consisting of two blocks of chemotherapy: 500 mg/m2/d cytarabine, continuous infusion over 4 days, plus 7 mg/m2/d idarubicin on days 3 and 5 (AI); and 1 g/m2 cytarabine every 12 hours for 3 days, plus 10 mg/m2/d mitoxantrone on days 3 and 4 (haM). Subsequently, all patients received chemotherapy with high-dose cytarabine and etoposide (HAE). In addition, patients without initial CNS involvement were randomly allocated to CNS irradiation with 12 Gy or 18 Gy. Whereas granulocyte colony-stimulating factor (G-CSF) was individually administered to some patients of the AML-BFM 93 trial, one of the study objectives of the AML-BFM 98 trial was to evaluate the effect of G-CSF. Patients with less than 5% blasts in the bone marrow on day 15 were randomly assigned to receive G-CSF at a dosage of 5 µg/kg after the first two cycles of chemotherapy or not. The infusion time for the anthracyclines (AIE and ADE) during induction was 4 hours, and the infusion time for mitoxantrone was 30 minutes. In case of initial hyperleukocytosis, a prephase with low-dose cytarabine (40 mg/m2/d) or hydroxyurea (two doses of 20 mg/m2/d) was recommended. Recommendations for supportive care measures included trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii (recommended dosage: 5 mg/kg/d trimethoprim thrice weekly) and the administration of nonabsorbable antibiotics and antimycotics. Systemic antifungal prophylaxis was not recommended. The administration of penicillin after chemotherapeutic regimens that included high-dose cytarabine was recommended in AML-BFM 98. Notably, the supportive care measures depended on the institution where the patient was treated and were, therefore, not standardized.
Definitions and Statistics Early death. Early death (ED) was defined as death before or within the first 6 weeks (42 days) of treatment. ED was further subdivided into two types: ED before start of treatment or within the first 15 days of therapy, which mainly reflects lethal events due to leukostasis and bleeding; and ED in the period between days 16 and 42 of treatment, which mainly reflects deaths caused by complications from infections during aplasia after induction therapy. Nonresponders (NR). All patients surviving the first 42 days of treatment without achieving CR until the end of intensive chemotherapy were defined as NR. According to the CALGB criteria, patients with CR criteria lasting less than 4 weeks were also reported as NR. We recognized that some of the patients who died due to treatment-related complications before hematologic recovery might have achieved CR. Due to the high intensity of the two induction courses, aplasia lasted much longer than it had in previous trials, making it difficult to distinguish between treatment-related and leukemia-related deaths; therefore, these patients were included in our TRM analysis. TRM. All patients with continuous complete remission (CCR) who died after day 42 of treatment were considered for the evaluation of TRM, as well as patients who died after having undergone SCT in first CR. Additionally, all patients not responding to treatment who experienced a lethal complication between days 42 and 150, were included; whereas all nonresponders or patients with relapse who died after day 150 were excluded, since these paients died mainly due to progression of disease. Complications from infection. Complications from infection included fever requiring antibiotic therapy and/or clinical signs and symptoms associated with the isolation of a pathogen, or an infection identified by physical examination or imaging study.16 Infection episodes were categorized as clinically, radiologically, or microbiologically documented infections. For example, a pneumonia diagnosis was based on pathological chest x-ray or computed tomography scan accompanied by clinical symptoms of lower respiratory infection. Viral disease was recorded only when both symptoms of disease were observed and virus was detected in the organ (eg, cytomegalovirus pneumonia was defined as the combination of symptoms of pulmonary disease together with the detection of CMV in bronchoalveolar lavage fluid or in lung tissue). Fungal infections were defined as proven invasive infection (positive histopathologic findings or positive culture) or probable invasive infection (at least one host factor criterion, such as neutropenia, for > 10 days or persistent fever refractory to broad-spectrum antibacterial treatment in high-risk patients; and one microbiological criterion, such as a positive culture for Aspergillus from sputum or bronchoalveolar lavage fluid samples or a positive result for Aspergillus antigen in at least two blood samples, and one major (or two minor) clinical criterion such as halo-sign or air-crescent sign on pulmonary computed tomography imaging), according to criteria published recently.17 Data on complications from infections were obtained in the hospital where the patient was treated or by special study forms for treatment-related toxicity. Toxicity and performance. Toxicity and performance were assessed according to modified National Cancer Institute Common Toxicity Criteria.18
Statistics.
Univariate analysis was conducted by the Wilcoxon test for quantitative variables and Fisher's exact test for qualitative variables. When frequencies were sufficiently large, To evaluate the effect of the experience of hospitals with the treatment protocol, we compared the 11 centers representing 63 (15%) patients participating in an AML-BFM study for the first time with the 80 centers that had experience with previous AML-BFM trials. Statistical analyses were performed using SAS (SAS Institute, Cary, NC).
Overall Results The overall results of the 901 patients enrolled onto the multicenter clinical trials AML-BFM 93 (n = 471) and AML-BFM 98 (n = 430) are shown in Table 1. One hundred four (11.5%) of 901 patients died early or due to treatment-related complications. Compared to AML-BFM 93, the incidence of ED and TRM was lower in AML-BFM 98 (67 [14.2%] of 471 patients v 37 [8.6%] of 430 patients), but this difference did not reach statistical significance. If patients with FAB type M3 were excluded, ED and TRM were 62 (13.8%) of 448 and 34 (8.4%) of 403 in the clinical trials AML-BFM 93 and AML-BFM 98, respectively.
A total of 49 patients (5.4%) died within the first 6 weeks after diagnosis, six of them even before the start of treatment. ED in the AML-BFM 98 clinical trial was significantly lower than in the AML-BFM 93 trial (14 [3.3%] of 430 v 35 [7.4%] of 471; P = .01), which was mainly due to a reduction of ED before day 15 of therapy (7 [1.6%] of 430 v 25 [5.3%] of 471; P = .003). In contrast, ED  day 15 did not differ significantly between both clinical trials (7 [1.6%] of 430 v 10 [2.1%] of 471; Table 1). Among the patients surviving to day 42 and achieving remission, a total of 35 patients died due to therapy-related complications: 24 patients during intensive treatment (after day 42), two patients later, and nine patients from complications caused by SCT. Twenty patients did not achieve remission and died between days 43 and 150 (14 [3.0%] of 471 and six [1.4%] of 430 in AML-BFM 93 and AML-BFM 98, respectively). Another 49 nonresponders (31 and 18 patients in the trials AML-BFM 93 and AML-BFM 98, respectively) died after day 150, but these patients were excluded from further analysis of TRM, because these patients died mainly due to progression of disease. The percentage of nonresponders was similar in both clinical trials (36 [8.4%] of 430 patients in AML-BFM 98, and 49 [10.4%] of 471 in AML-BFM 93).
Early Death Before Day 15
Results in Patients With FAB Type M3 Six (12%) of 50 patients with FAB type M3 had lethal complications within the first 6 weeks of treatment. In four of these patients, ED occurred within 14 days after diagnosis (three patients with bleeding complications, one patient with sepsis). One patient died due to sepsis on day 16 and one due to all-trans-retinoic acid (ATRA) syndrome on day 38. Another two FAB type M3 patients died in CCR as a result of infections during intensive chemotherapy.
Treatment-Related Death After Day 15 Whereas bleeding and leukostasis were the main causes of death during the first two weeks after diagnosis, fatal infections were predominant after day 15 (Fig 2, Table 4). The incidence of fatal complications from infections was highest after induction therapy and HAM (n = 15 and n = 16, respectively) and decreased afterwards. Of the 20 patients who died without achieving remission between days 42 and 150, 16 (80%) died as a result of infections, particularly as a result of invasive fungal infections (n = 7).
Types of Infections Polymicrobial infection was seen in five patients (four patients with both invasive mold infection and bacteremia and one patient with both Candida infection and bacteremia). In 22 patients, fatal complications caused by infections occurred as a result of bacterial pathogens (gram-positive isolates, n = 7; gram-negative isolates, n = 14; and Chlamydia spp., n = 1). viridans group streptococci (VGS; n = 4) were predominant among gram-positive pathogens, whereas Pseudomonas aeruginosa (n = 7) and Klebsiella spp. (n = 4) accounted for most of the gram-negative isolates. Sixteen patients died of invasive fungal infection (invasive mold infection in 10 patients [proven in three, probable in seven patients], invasive Candida infection in four patients, simultaneous mold and Candida infection and infection due to Pneumocystis jiroveci in one patient each). Epstein-Barr virus (EBV) -associated hemophagocytosis was seen in one patient. Nineteen patients died of clinically/radiologically documented infections without having a pathogen identified. The incidence of bacterial infections and clinically documented infections was similar in the trials AML-BFM 93 and AML-BFM 98, whereas the incidence of invasive fungal disease was lower in AML-BFM 98 than in the previous trial, but this difference did not reach statistical significance (5 of 430 v 10 of 471; P = .26).
Cardiotoxicity
TRM After SCT
Experience
By increasing the intensity of cytotoxic treatment, the long-term survival of children suffering from AML has improved over the last decades.4,8,14 The intensive therapy, in turn, is associated with a high treatment-related toxicity. Better strategies for supportive care decreasing TRM could therefore have a significant impact on overall outcome in children with AML. Bleeding, leukostasis, and complications from infections had been identified by us and other authors as the main reasons for lethal events in children with AML.9 The risk of bleeding or leukostasis is particularly high during the first 14 days after diagnosis. In the first trials, AML-BFM 78 and AML-BFM 83, 32 (10%) out of a total of 333 patients died before or during the first 12 days after starting therapy as a result of bleeding and leukostasis. As already described by other reports,9,19 mortality was especially high in children with both FAB type M5 morphology and hyperleukocytosis (14 [70%] of 20) and in children with both FAB type M5 and organ involvement (12 [40%] of 30).20 The introduction of measures, such as the careful reduction of tumor load by the administration of hydroxyurea or low-dose cytarabine, exact fluid balance with careful hydration and the use of furosemid, the administration of allopurinol and the use of fresh-frozen plasma in case of disturbances in coagulation might have helped to decrease early mortality caused by bleeding or leukostasis by 4.9% in the clinical trial AML-BFM 93. Additionally, therapy with ATRA, which was introduced in 1994 in the AML-BFM trials, might help to avoid early lethal events caused by bleeding in children with FAB type M3 morphology. It was shown that disturbances of coagulation normalized earlier with ATRA than without ATRA.21 However, we cannot exclude the idea that simply an increase of experience treating patients with hyperleukocytosis is responsible for the decrease in ED. Patients with marked hyperleukocytosis, especially those with FAB type M5 and hyperleukocytosis, may benefit from exchange transfusion or leukapheresis,22,23 but evidence-based guidelines are lacking. Unfortunately, there were not enough data on coagulation parameters, such as plasma levels of plasminogen or split products, that we can draw any further conclusion in this retrospective analysis. Additionally, the effectiveness of exchange transfusion or leukapheresis might be limited by the lack of experience of staff, and technical problems in the individual centers, particularly regarding young children. Therefore, children with AML might benefit if they are transferred to specialized centers as soon as possible. Whereas complications caused by bleeding or leukostasis mainly occurred during the first 14 days, most of the fatal infections were seen later. Overall, a total of 62 (6.9%) patients died as a result of complications caused by infections, representing 60.0% of all treatment-related deaths, which is comparable to the report by Riley et al.9 In particular, patients who did not respond to treatment were at high risk of lethal infections. Invasive fungal infection is a major cause of death in children undergoing treatment for AML.9,10 Although most fungal infections are seen during prolonged neutropenia or after SCT, it is important to note that fungal infection can also occur early in treatment.24,25 In a multicenter phase III study in the United States (CCG 2961 study), the early application of 1 mg/kg of empiric amphotericin B for fever persisting longer than 72 hours helped to reduce infection-related mortality.10 In the ongoing AML-BFM study, the use of antifungal prophylaxis is recommended to reduce the high risk of invasive fungal infection in children with AML.26 Since a significant number of invasive fungal infections are diagnosed only by autopsy, the lower incidence of invasive fungal infections in AML-BFM 98 might be explained, at least in part, by the dramatic decrease of autopsies in Germany over the last decade.27,28 The cohort of children with AML will most likely not differ in this respect from the overall population. Unfortunately, we are not able to provide the exact number of autopsies performed in the trials AML-BFM 93 and AML-BFM 98. Whereas five of the 11 invasive fungal infections in AML-BFM 93 were diagnosed by autopsy, none of the five fungal infections in trial AML-BFM 98 was detected postmortem. However, it has to be noted that the incidence of invasive fungal infections might have been underestimated in both clinical trials because of insufficient diagnostic procedures.16 Therefore, the forthcoming clinical trial will prospectively evaluate new methods for early detection of invasive fungal infection. A significant number of children died of bacterial infections, particularly of infections with gram-negative pathogens (n = 14) and with VGS (n = 4), which was also reported by other authors.9,29 Infection due to VGS often occurs after chemotherapy with high-dose cytarabine,30,31 and has increased over the last few years, possibly due to intensification of therapy.29,30 Prophylaxis with penicillin G was shown to reduce morbidity and mortality due to streptococcal infections,32 but emerging resistance is a major concern.33 Empiric vancomycin for 24 to 48 hours in febrile neutropenic children with AML could be an alternative regimen.10 Both options are implemented in the forthcoming AML-BFM clinical trial. The use of G-CSF did not reduce TRM in our study (manuscript in preparation). Randomized data are not available in children undergoing treatment for AML, but a nonrandomized study showed that G-CSF neither reduced the incidence of infections nor reduced the number of fatal complications from infections.34 Recently, an extensive retrospective study has shown that a better long-term outcome in nonsurgical cancers is associated with larger hospital volume or specialized focus.35 The authors conclude that, for all forms of cancer, efforts to concentrate initial care would be appropriate. This is even more important for pediatric malignancies, since they have a low incidence. For example, in the MRC 10 trial, significantly fewer children with AML died of therapy-related toxicity in the second half of the study than in the first half (14% v 7%; P = .03), probably because of increasing experience of the medical staff.9 Similarly, early mortality was reduced in both trials AML-BFM 93 and AML-BFM 98 compared with previous AML-BFM clinical trials (13%, 12%, and 9%, in trials AML-BFM 78, 83, and 87, respectively, v 7.3% and 3.2% in trials AML-BFM 93 and AML-BFM 98; Ptrend < .001). An analysis of the overall survival of children enrolled onto the AML-BFM 93 trial in hospitals in former East Germany showed an improvement of treatment results over time as well.36 In contrast to other reports, cardiotoxicity was not a major problem in our clinical trial. This might be due, at least in part, to the careful use of anthracyclines with prolonged infusion time which can avoid peak-levels and may have a positive impact on avoiding early and late cardiotoxicity.37,38 Additionally, cumulative doses of anthracyclines were between 300 and 400 mg/m2 and thus lower than those of the MRC 10 trial in which a cardiotoxic death rate of 2.6% of all cases (19% of all toxic deaths) was reported.9 In conclusion, to reduce the high incidence of ED and TRM in children with AML, early diagnosis and adequate treatment of complications must be instituted. Therefore, children with AML should be treated exclusively in specialized pediatric cancer centers with experienced medical staff. There should be a high index of awareness of complications, and the threshold to readmit children undergoing treatment for AML should be low. Prophylactic and therapeutic regimens for better management of bleeding disorders and bacterial or fungal infections need to be assessed in future studies. The forthcoming AML-BFM clinical trial has clearly implemented central advice and guidelines to better control lethal complications, and thus, to improve overall survival in children undergoing intensive treatment for AML.
Principal investigators of Studies AML-BFM 93 and AML-BFM 98 in Germany: R. Mertens, Kinderklinik RWTH, Aachen; A. Gnekow, I. Kinderklinik des Klinikums, Augsburg; Th. Rupprecht, Kinderklinik GmbH, Bayreuth; G. Henze, CCVK-Kinderklinik, Berlin; W. Dörffel, Helios Klinikum Berlin, Klinikum Buch, II. Klinik f. Kinderheilkunde, Berlin-Buch; N. Jorch, Kinderklinik Gilead, Bielefeld; U. Bode/G. Fleischhack, Universitäts-Kinderklinik, Bonn; A. Pekrun, Prof.-Hess-Kinderklinik, Bremen; M. Kirschstein, Klinik für Kinder-und Jugendmedizin des AKH Celle, Celle; I. Krause, Städtische Kinderklinik Chemnitz; R. Frank, Kinderklinik im Klinikum Coburg, Coburg; E. Holfeld, Kinderklinik d. Carl-Thiem-Klinikums, Cottbus; W. Andler/Th. Wiesel, Vestische Kinderklinik, Datteln; C. Niekrens, Kinderklinik der Städtischen Kliniken, Delmenhorst; H. Breu, Kinderklinik der Städt. Kliniken, Dortmund; I. Lauterbach, Kinderklinik d. TU, Dresden; V. Scharfe, Städtische Kinderklinik, Dresden-Neustadt; U. Göbel, Universitäts-Kinderklinik, Düsseldorf; G. Weinmann, Universitäts-Kinderklinik, Erfurt; J.D. Beck, Universitäts-Kinderklinik, Erlangen; W. Havers Universitäts-Kinderklinik, Essen; T. Klingebiel Universitäts-Kinderklinik, Frankfurt; C.M. Niemeyer, Universitäts-Kinderklinik, Freiburg; A. Reiter/R. Blütters-Sawatzki, Universitäts-Kinderklinik, Gießen; M. Lakomek/Schweigerer, Universitäts-Kinderklinik, Göttingen; J.F. Beck/H. Weigel, Universitäts-Kinderklinik, Greifswald; E. Pretel, Kinderklinik, Gummersbach; G. Horneff/R. Schobeß, Universitäts-Kinderklinik, Halle; H. Kabisch/R. Schneppenheim, Universitäts-Kinderklinik, Hamburg; K. Welte, Zentrum f. Kinderheilkunde der Med. Hochschule, Hannover; A.E. Kulozik, Universitäts-Kinderklinik, Heidelberg; Ch. Tautz, Gemeinschaftskrankenhaus, Herdecke; N. Graf, Universitäts-Kinderklinik, Homburg/Saar; J. Hermann, Universitäts-Kinderklinik, Jena; W. Dupuis, Städtische Kinderklinik, Karlsruhe; M. Rodehüser, Städt. Kinderklinik, Kassel; A. Claviez, Klinikum d. Chr.-Albrechts-Univ. zu Kiel, Kiel; M. Rister, Kinderklinik Kemperhof, Koblenz; F. Berthold, Universitäts-Kinderklinik, Köln; W. Sternschulte, Städtisches Kinderkrankenhaus, Köln; S. Völpel, Städt. Krankenhäuser, Krefeld; D. Körholz, Universitäts-Kinderklinik, Leipzig; P. Bucsky, Universi-täts-Kinderklinik, Lübeck; H.Ch. Dominick/B. Selle, Kinderklinik St. Annastift, Ludwigshafen, U. Kluba, Universitäts-Kinderklinik, Magdeburg; P. Gutjahr, Universitäts-Kinderklinik, Mainz; M. Dürken, Städt. Kinderklinik, Mannheim; H. Christiansen, Universitäts-Kinderklinik, Marburg; P. Klose, Städt. Krankenhaus Harlaching, München; Ch. Bender-Götze/A. Borkhardt, Kinderklinik und Poliklinik im Dr v. Haunerschen Kinderspital (Klinikum der Universität München), München; St. Burdach/L. Stengel-Rutkowski, Kinderklinik d. Technischen Universität, München-Schwabing; H. Jürgens, Universitäts-Kinderklinik, Münster; W. Scheurlen/A. Jobke, Cnopf’sche Kinderklinik, Nürnberg; U. Schwarzer, Städtische Kinderklinik, Nürnberg; H. Müller, Zentrum f. Kinder- u. Jugendmed. im Klinikum Oldenburg, Oldenburg; J. Wolff, Klinik St. Hedwig, Regensburg; G. Eggers, Universitäts-Kinderklinik, Rostock; R. Schumacher, Kinderklinik, Schwerin; R. Dickerhoff, Johanniter Kinderklinik, St. Augustin; J. Treuner, Olgahospital, Stuttgart; W. Rauh, Krankenanstalt im Mutterhaus der Borromäerinnen, Trier; D. Niethammer, Universitäts-Kinderklinik, Tübingen; K.-M. Debatin, Universitäts-Kinderklinik, Ulm; H.-P. Krohn, Reinhard-Nieter Krankenhaus, Wilhelmshaven; P.-G. Schlegel/St. Rutkowski, Universitäts-Kinderklinik, Würzburg; K. Runge/B. Dohrn, Kinderklinik im Klinikum Barmen, Wuppertal. Principal investigators in Austria: B. Ausserer, A.ö. Krankenhaus, Dornbirn; G. Müller, Landeskrankenhaus Feldkirch, Feldkirch-Tisis; Ch. Urban, Universitätsklinik für Kinder- und Jugendheilkunde, Graz; F.-M. Fink/B. Meister, Univ.Klinik für Kinder- und Jugendheilkunde, Innsbruck; W. Kaulfersch, A.ö. Landeskrankenhaus, Klagenfurt; I. Mutz, A.ö. Landeskrankenhaus, Leoben; K. Schmitt, Landes-Kinderklinik, Linz; O. Stöllinger, Krankenhaus der Barmherzigen Schwestern, Linz; W. Sperl/N. Jones, St. Johanns Spital/Landeskrankenhaus, Salzburg; H. Haas, Kardinal Schwarzenberg'sches KH, Schwarzach im Pongau; I. Slavc, Universitätsklinik f. Kinder- und Jugendheilkunde, Wien; 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; Y. Jabali, University Hospital, Ceske Budejovice; K. Tousovska, University Hospital, Hradec Kralove; V. Mihal, University Hospital, Olomouc; B. Blazek, University Hospital, Ostrava; J. Stary, University Hospital Motol, Prague. Principal investigators in Switzerland: P. Imbach, Kinderklinik d. Kantonsspitals, Aarau; P. A. Avoledo, Universitäts-Kinder-spital, Basel; A. Feldges, Ostschweizerisches Kinderspital, St. Gallen; M. Nenadov-Beck/C. Dessing, CHUV-Kinderklinik, Lausanne; U. Caflisch, Kinderspital, Luzern; L. Nobile Buetti, Kinderklinik Hospital La Carita, Locarno; F. Niggli, Universitäts-Kinderklinik, Zürich.
The authors indicated no potential conflicts of interest.
We thank Elisabeth Kurzknabe and Jutta Meltzer for their excellent technical assistance, Jans-Enno Müller for his competent data management, Sylke Diekamp for her helpful assistance in data retrieval, Ursula Bernsmann for her valuable assistance in the management of the AML Trial Office in Münster, and all principal investigators (see Appendix).
Supported by the Deutsche Krebshilfe. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5% blasts in the bone marrow on day 15, FAB type M3 irrespective of the number of blasts on day 15; high-risk group, all other patients).
2 statistic was used. Logistic regression was used for multivariate analysis of risk factors for TRM. For testing trends in frequency tables, the Cochran-Armitage test was applied. Cumulative incidence functions for different causes of TRM were constructed with the method of Kalbfleisch and Prentice and compared with Gray's test. 
