Klin Padiatr 2015; 227(03): 116-122
DOI: 10.1055/s-0035-1548816
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Randomised Introduction of 2-CDA as Intensification during Consolidation for Children with High-risk AML – Results from Study AML-BFM 2004

Randomisierte Einführung von 2-CDA als Intensivierung im Rahmen der Konsolidierung für Kinder mit Hoch-Risiko AML – Ergebnisse der Studie AML-BFM 2004
U. Creutzig
1   Department of Pediatric Hematology and Oncology, Children’s Hospital, Hannover Medical School, Hannover, Germany
,
M. Dworzak
2   St. Anna Children’s Hospital and Children’s Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna, Austria
,
M. Zimmermann
1   Department of Pediatric Hematology and Oncology, Children’s Hospital, Hannover Medical School, Hannover, Germany
,
J.-P. Bourquin
3   Pediatric Hematology/Oncology, Zürich, University of Zurich, Switzerland
,
B. Gruhn
4   Department of Pediatrics, Jena University Hospital, Jena, Germany
,
G. Fleischhack
5   Paediatric Hematology and Oncology, Medical Center, University of Essen, Essen, Germany
,
N. Graf
6   Paediatric Haematology and Oncology, Children’s Hospital Medical Center, Homburg, Germany
,
T. Klingebiel
7   Pediatric Hematology, Oncology and Hemostaseology, University Children’s Hospital of Frankfurt/Main, Goethe-University Frankfurt/Main, Frankfurt, Germany
,
B. Kremens
5   Paediatric Hematology and Oncology, Medical Center, University of Essen, Essen, Germany
,
T. Lehrnbecher
7   Pediatric Hematology, Oncology and Hemostaseology, University Children’s Hospital of Frankfurt/Main, Goethe-University Frankfurt/Main, Frankfurt, Germany
,
C. von Neuhoff
5   Paediatric Hematology and Oncology, Medical Center, University of Essen, Essen, Germany
,
A. von Stackelberg
8   Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany
,
J. Stray
9   Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
,
D. Reinhardt
5   Paediatric Hematology and Oncology, Medical Center, University of Essen, Essen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
18 May 2015 (online)

Abstract

Background: The outcome in children and adolescents with high-risk (HR) acute myeloid leukemia (AML) is still unsatisfactory. Therefore, in study AML-BFM 2004 we aimed to improve outcome of HR-patients by adding moderately dosed 2-Chloro-2-Deoxyadenosine (2-CDA) to the respective consolidation treatment backbone without increasing toxicity. The aim was to improve prognosis especially in FAB M4/M5/MLL patients, who represent the largest subgroup of HR patients.

Patients and Methods: In total, 343 children and adolescents with HR-AML were randomized to receive or not 2-CDA (6 mg/m²/d, days 1, 3) in combination with cytarabine/idarubicine (AI=500 mg/m² cytarabine 5 days continuous infusion plus 7 mg/m²/d idarubicin, days 3 and 5).

Results: Results for patients of the AI/2-CDA arm (n=168) vs. the AI-arm (n=175) were similar: 5-year overall survival 68±4 vs. 72±4%, plogrank=0.38, event-free survival 53±4 vs. 49±4%, plogrank=0.77; cumulative incidence of relapse at 5 years: 35±4 vs. 37±4%, p(Gray)=0.89. Results in patients with MLL rearrangement or FAB M4/M5 were also similar in the treatment groups. In addition, toxicities did not differ between the two arms.

Conclusion: We conclude that additional, moderate dose 2-CDA does not improve prognosis in HR-patients when given during consolidation treatment. Its effect might be too low in this multidrug regimen, where the strongest effects are achieved during induction, or the chosen dose of 2-CDA might have been too low.

Zusammenfassung

Hintergrund: Die Ergebnisse bei Kindern und Jugendlichen mit akuter myeloischer Leukämie (AML) und hohem Risiko (HR) sind nach wie vor unbefriedigend. Daher war es unser Ziel in der Studie AML-BFM 2004, die Prognose der HR-Patienten durch zusätzliche mäßig dosierten 2-Chlor-2-Desoxyadenosin (2-CDA) Gaben in der Konsolidierung ohne erhöhte Toxizität zu verbessern. Hierbei wurde eine Verbesserung insbesondere bei den FAB M4/M5/MLL-Patienten, die die größte Untergruppe der HR-Patienten stellen, angestrebt.

Patienten und Methoden: Insgesamt wurden 343 Kinder und Jugendliche mit HR-AML randomisiert: In den AI/2-CDA Arm (2-CDA [6 mg/m²/Tag, Tag 1, 3] in Kombination mit Cytarabin/Idarubicin [AI=500 mg/m² Cytarabin 5 Tage Dauerinfusion plus 7 mg/m²/d Idarubicin, Tag 3 und 5] oder in den AI Arm ohne 2-CDA.

Ergebnisse: Die Ergebnisse waren für die Patienten des AI/2-CDA Arms (n=168) im Vergleich zum AI-Arm (n=175) ähnlich: 5-Jahres-Überlebensrate 68±4 vs. 72±4%, plogrank=0,38, ereignisfreies Überleben 53±4  vs. 49±4%, plogrank=0,77; kumulative Inzidenz von Rezidiven nach 5 Jahren: 35±4 vs. 37±4%, p(Gray)=0,89. Ergebnisse bei Patienten mit MLL Rearrangement oder FAB M4/M5 waren ebenfalls in den Behandlungsgruppen im gleichen Bereich. Darüber hinaus gab es keinen Unterschied in den Toxizitäten zwischen den beiden Armen.

Schlussfolgerung: Eine Verbesserung der Prognose ist bei HR-Patienten durch zusätzliche Gabe von moderat dosiertem 2-CDA im Rahmen der Konsolidierung nicht zu erkennen. Die 2-CDA Wirksamkeit kommt bei dem eingesetzten Multidrug-Regime, das die entscheidende Wirksamkeit während der Induktion zeigt, nicht zum Tragen. Die gewählte Dosis von 2-CDA dürfte auch zu niedrig gewesen sein.

Supplementary Material

 
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