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

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%, p_logrank=0.38, event-free survival 53±4 vs. 49±4%, p_logrank=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%, p_logrank=0,38, ereignisfreies Überleben 53±4  vs. 49±4%, p_logrank=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.

Key words

acute myeloid leukemia - 2-Chloro-2-Deoxyadenosine - children - consolidation

Schlüsselwörter

akute myeloische Leukämie - 2-Chloro-2-Deoxyadenosine - Kinder - Konsolidierung

• References

• 1 Abrahamsson J, Forestier E, Heldrup J et al. Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol 2011; 29: 310-315
• 2 Bloomfield CD, Lawrence D, Byrd JC et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 1998; 58: 4173-4179
• 3 Cheson BD, Cassileth PA, Head DR et al. Report of the National Cancer Institute-sponsored workshop on definitions and response in acute myeloid leukemia. J Clin Oncol 1990; 8: 813-819
• 4 Creutzig U, Zimmermann M, Bourquin JP et al. Additional treatment with 2-Chloro-2-Deoxyadenosine (2-CDA) during consolidation in children with high risk acute myeloid leukemia does not improve survival. Leukemia 2015; in press
• 5 Creutzig U, Ritter J, Schellong G. Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in the study AML-BFM-83 as compared with study AML-BFM-78. Blood 1990; 75: 1932-1940
• 6 Creutzig U, Zimmermann M, Bourquin JP et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004. Blood 2013; 122: 37-43
• 7 Creutzig U, Zimmermann M, Bourquin JP et al. CNS irradiation in pediatric acute myleoid leukemia: Equal results by 12 or 18 Gy in studies AML-BFM98 and 2004. Pediatr Blood Cancer 2011; 57: 986-992
• 8 Fernandez HF, Sun Z, Yao X et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009; 361: 1249-1259
• 9 Gale RE, Hills R, Pizzey AR et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 2005; 106: 3768-3776
• 10 Gandhi V, Estey E, Keating MJ et al. Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: pharmacokinetic, pharmacodynamic, and molecular interactions. Blood 1996; 87: 256-264
• 11 Gibson BE, Webb DK, Howman AJ et al. Results of a randomized trial in children with Acute Myeloid Leukaemia: Medical Research Council AML12 trial. Br J Haematol 2011; 155: 366-376
• 12 Griffig J, Koob R, Blakley RL. Mechanisms of inhibition of DNA synthesis by 2-chlorodeoxyadenosine in human lymphoblastic cells. Cancer Res 1989; 49: 6923-6928
• 13 Holowiecki J, Grosicki S, Giebel S et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol 2012; 30: 2441-2448
• 14 Holowiecki J, Grosicki S, Robak T et al. Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 2004; 18: 989-997
• 15 Hubeek I, Peters GJ, Broekhuizen R et al. In vitro sensitivity and cross-resistance to deoxynucleoside analogs in childhood acute leukemia. Haematologica 2006; 91: 17-23
• 16 Kalbfleisch J, Prentice R. The Statistical Analysis of Failure Time Data. New York, NY: Wiley; 2002
• 17 Kaspers GJ. Pediatric acute myeloid leukemia. ExpertRevAnticancer Ther 2012; 12: 405-413
• 18 Kaspers GJ, Zimmermann M, Reinhardt D et al. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol 2013; 31: 599-607
• 19 Klusmann JH, Reinhardt D, Zimmermann M et al. The role of matched sibling donor allogeneic stem cell transplantation in pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study. Haematologica 2012; 97: 21-29
• 20 Krance RA, Hurwitz CA, Head DR et al. Experience with 2-chlorodeoxyadenosine in previously untreated children with newly diagnosed acute myeloid leukemia and myelodysplastic diseases. J Clin Oncol 2001; 19: 2804-2811
• 21 Lange BJ, Smith FO, Feusner J et al. Outcomes in CCG-2961, a children’s oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children’s oncology group. Blood 2008; 111: 1044-1053
• 22 Robak P, Robak T. Older and new purine nucleoside analogs for patients with acute leukemias. Cancer Treat Rev 2013; 39: 851-861
• 23 Santana VM, Mirro Jr J, Harwood FC et al. A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. J Clin Oncol 1991; 9: 416-422
• 24 Santana VM, Mirro Jr J, Kearns C et al. 2-Chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J Clin Oncol 1992; 10: 364-370
• 25 Seto S, Carrera CJ, Kubota M et al. Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest 1985; 75: 377-383
• 26 Tsukimoto I, Tawa A, Horibe K et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: the AML99 trial from the Japanese Childhood AML Cooperative Study Group. J Clin Oncol 2009; 27: 4007-4013
• 27 von Neuhoff C, Reinhardt D, Sander A et al. Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol 2010; 28: 2682-2689