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Therapeutic value of clofarabine in younger and middle aged (18 – 65 yrs) adults with newly diagnosed AML

Bob Löwenberg, Thomas Pabst, Johan Maertens, Yvette van Norden, Bart J. Biemond, Harry C. Schouten, Olivier Spertini, Edo Vellenga, Carlos Graux, Violaine Havelange, Georgine E. de Greef, Okke de Weerdt, Marie-Cecile J.C. Legdeur, Juergen Kuball, Marinus van Marwijk Kooy, Bjorn T. Gjertsen, Mojca Jongen-Lavrencic, Arjan A. van de Loosdrecht, Daniëlle van Lammeren-Venema, Beata Hodossy, Dimitri A. Breems, Yves Chalandon, Jakob Passweg, Peter J.M. Valk, Markus G. Manz and Gert J. Ossenkoppele

Key points

  • 1. Clofarabine integrated in standard induction therapy for newly diagnosed AML reduces relapse probability but does not improve survival

  • 2. Clofarabine improves survival in intermediate-risk AML categories ELN-1 and the AML genotype without NPM1 and FLT3-ITD gene mutations

Abstract

Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared two induction regimens in newly diagnosed patients aged 18-65 with AML/high risk MDS, i.e., idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. 402 and 393 evaluable patients were randomized to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% versus 75% after cycle I). Clofarabine added grade III-IV toxicities, and delayed hematological recovery. At a median follow up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS 35% ±3 (SE) at 4 years) and clofarabine treatments (38% ±3) but a markedly reduced relapse rate (44% ± 3 versus 35% ± 3) in favor of clofarabine and an increased death probability in remission (15% ±2 versus 22% ±3). In the subgroup analyses, clofarabine improved OS and EFS for European-Leukemia-Net ELN 2010 Intermediate-I prognostic risk AML (EFS 26 % ±4 versus 40% ±5 at 4 years, Cox-P=0.002) and for the intermediate risk genotype NPM1wild type/FLT3 without internal-tandem-duplications (EFS 18% ±5 versus 40% ±7, Cox- P<0.001). Clofarabine improves survival in subsets of intermediate-risk AML only.

  • Submitted October 25, 2016.
  • Accepted December 23, 2016.