Treatment Results in Childhood AML, with Special Reference
to the German Studies BFM -78 and BFM -83 *
U. Creutzig 1, J. Ritter 1, M. Budde 2, H. Jürgens 3, H. Riehm 2, and G. Schellong 1    Hämatol. Bluttransf. Vol 31

* Supported by the Bundesminister für Forschung und Technologie, FRG.
1 Universitäts-Kinderklinik Münster, FRG
2 Universitäts-KinderklinikHannover , FRG
3 Universitäts-Kinderklinik Düsseldorf, FRG.

A. Introduction

The number of children with acute myelogenous leukemia (AML) who achieve remission and the number of long-term survivors have increased in the last 10 years owing to intensified chemotherapy and better supportive care. This report reviews nine pediatric studies, particularly the German AML studies BFM-78 and BFM-83. A total of 294 children with AML under 17 years of age entered the AML studies BFM-78 (n=151) and BFM-83 (n = 143) between December 1978 and January 1986. The second study is still open for patient entry. The treatment in the first study consisted of a seven-drug regimen over a period of 8-10 weeks, together with prophylactic cranial irradiation, and was followed by maintenance therapy with 6-thioguanine and cytosine arabinoside (Ara-C) for 2 years and additional Adriamycin during the Ist year [1]. In the BFM-83 study an 8-day induction with Ara-C, daunorubicin, and YP16 precedes the BFM-78 protocol. The initial patient data of the two studies are in general comparable age: median 9.11 and 9.3 years; sex: boys 54% and 52% ; WBC: median ( x 10³/µl) 24.0 and 28.5; initial CNS involvement: 9% and 7%, respectively. Extramedullary organ involvement (excluding liver and spleen enlargement) was seen more often in the BFM-83 study (32%); it accounted for only 18% of patients in the BFM-78 study. But the involvement of bone, orbits, and kidney (7% in the BFM-83 study) was not evaluated in the BFM- 78 study. The distribution of the F AB subtypes [2] shows a higher proportion of the F AB M5 type (28%) in the BFM-83 study (only 21% in BFM- 78). In both studies the myeloblastic subtypes Ml and M2 account for 20%-24% of patients, whereas the M3 and the M6 subtypes were rarely seen (2%-4%). The overall results are presented in Table 1. In the BFM- 78 study, 54 relapses (8 with CNS involvement) occurred after a median follow-up time of 5.3 years (range 3.37.0 years). The life table estimations for an event-free survival (EFS, total group) and an event-free interval (EFI, remission group) after 7.0 years are 38% (SO 4%) and 47% (SD 5%), respectively (Fig.1). In the BFM-83 study, 25 relapses occurred (4 with CNS involvement) after a median follow-up of 1.8 years (range 0.2-3.0 years). The life table estimations are EFS 48% (SD 5% ) and EFI62% (SD 6%) (Fig.l). Risk factor analysis shows that hyperleukocytosis (WBC > lOO x 10³/µl) is the main risk factor for early hemorrhage and/or leukostasis (p < 0.001, X² test), for nonresponse (p<0.05, X² test), and also for relapse (p= 0.08, log rank test). In addition, in the monocytic subtypes M4 and M5, extramedullary organ involvement was a risk factor for early hemorrhage and/or leukostasis (p<0.001) and also for relapse (p=0.07, log rank test). The Ml subtype has the best prognosis: EFS 55% (SD 7%) and EFI66% (SD 7%) after 7 years.

Table 1. Results of the AML studies BFM-78 and BFM-83, January 1986

Fig.1. Probability of event-free interval in AML studies BFM-78, and BFM-83. /, patients in CCR
(all patients of BFM- 78 study, last patient entered the BFM-83 study group).
CC R, continuous complete remission

B. Discussion

In most pediatric trials starting before 1976, the median duration of complete remission was short less than 12 months; after 3 or 4 years, life table estimation for EFI was about 30% and for survival 20% in the best studies [3]. Eight recent pediatric chemotherapy protocols with high remission rates and good results are presented in Table 2, together with one bone marrow transplantation (BMT) trial. Even though the induction/consolidation regimens with two to seven drugs differ considerably, they all include one of the anthracyclines and Ara-C. Vincristine and prednisone were also administered in the VAPA [4] and BFM [1] studies. The first St. Jude's study [5] combined Ara-C with 6-azauridine. In consolidation of the BFM studies, cyclophosphamide was given at least twice. In most studies, remission was induced by relatively short and intensive therapy with a seven-plus-three regimen (Ara-C plus daunorubicin), with or without thioguanine, which induced a complete myelosuppression and was followed by a therapy pause of approximately 3 weeks. In contrast, the BFM78 study used a prolonged induction/consolidation regimen for 8 weeks, which also caused severe bone marrow hypoplasia, but in most cases the necessary therapy pauses were short. A new strategy in intensive post-remission therapy called intensification was initiated with the V APA-10 protocol [4] and is now part of most of the new studies presented in Table 2. Lie et al. [7] reported excellent results with high-dose Ara-C as postremission therapy in a small group of children. The results of BMT, which is another way of intensification in remission, are very encouraging, especially in young patients [8]. In conclusion, new therapy strategies including intensive induction regimens together with consolidation and intensification or intensive maintenance with noncross-resistant drugs will improve the treatment results in childhood AML and increase the proportion of patients in long-term remission to 50%. The low incidence of CNS relapses in the BFM studies indicates that prophylactic CNS treatment early in remission can prevent CNS disease, and the increasing number of long-term survivors emphasizes the need for effective prevention of CNS relapse in pediatric patients. It still remains to be seen whether prophylactic cranial irradiation together with intrathecal methotrexate or Ara-C is necessary or whether systemic treatment with Ara-C infusion or especially HD-Ara-C would produce an effective liquor level. Although some results favor BMT, this therapy is currently limited to patients with HLA-compatible donors, and the long-term effects are unknown. Prospective comparisons ofBMT with chemotherapy intensification or maintenance are necessary.


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Additional participating members of the BFM-AML-Study Group
M. Neidhardt (Augsburg); G. Henze (Berlin); H.-J. Spaar (Bremen); M. Jacobi (Celle); w. Andler (Datteln); J .-D. Beck (Erlangen); B. Stollmann (Essen); B. Kornhuber (Frankfurt); A. Jobke (Freiburg); G. Prindull (Göttingen); F. Lampert (Gießen); W. Brandeis (Heidelberg); N. Graf (Hombilrg/Saar); H. Kabisch (Hamburg); G. Nessler (Karlsruhe); H. Wehinger (Kassel); M. Rister (Kiel); F. Berthold (K61n-Univ.); W. Sternschillte (K61n); 0. Sailer (Mannheim); C. Eschenbach (Marbilrg); P. Giltjahr (Mainz); K.-D. Tympner (München-Harlaching); Ch. Bender-G6tze (München-Univ.); St. Müller-Weihrich (M ünchen-Schwabing); R. J. Haas (München v. Hailnersches Spital); A. Reiter (Nürnberg); W. Ertelt (Stilttgart); D. Niethammer (Tübingen); G. Gaedicke (Ulm); Th. Luthardt (Worms)