Use of Clofarabine in the Treatment of Relapsed or Refractory Acute Myeloid Leukemia in Adults: The French Experience
Authors: Sibon David , Berceanu Ana , Ghez David , Foissac Frantz , Kammoun Leila , Braun Thorsten , Caillot Denis , Ojeda-Uribe Mario , Guieze Romain , Berthon Céline , Sanhes Laurence , Gruson Bérengère , Bouscary Didier , Recher Christian , Stalnikiewicz Laure , Rousselot Philippe , Raffoux Emmanuel , Prebet Thomas , Salles Bruno , de Botton Stéphane , Marcais Ambroise , Suarez Felipe , Hermine Olivier 
Published: October 2019

Abstract 2623

Introduction.

Relapsed or refractory acute myeloid leukemia (AML) patients (pts) have a dismal outcome and conventional chemotherapy offers almost no chance of cure. Consequently, allogeneic transplantation (alloSCT) has been widely used for these patients, but outcome is limited by a high relapse rate. There is no generally established standard for reinduction of remission. Clofarabine is a second-generation purine nucleoside analogue mainly evaluated in older adults with untreated AML, but there are limited data in relapsed/refractory AML. The aim of the present study was to establish the role of clofarabine in a large series of adults with relapsed/refractory AML.

Methods.

Eighteen French centers participated in this retrospective study. Eligibility criteria were as follows: confirmed diagnosis of AML, pts >18 years (yrs) old at clofarabine treatment, and clofarabine used outside of a clinical trial. Relapses after alloSCT were included, but use of clofarabine as part of the conditioning regimen of alloSCT was not included. Data were collected regarding patient demographics, leukemia characteristics, previous treatments and the use of clofarabine including the regimen used and the outcome following treatment.

Results.

Between January 2007 and June 2011, 100 pts were treated with clofarabine for relapsed/refractory AML. At first diagnosis of AML, median age was 58 yrs, male:female ratio was 60:40, 86% of pts had performance status 0–1, 57% had white blood cells < 10000/mm3, 37% had secondary AML (prior myelodysplastic syndrome 54%), 39% had unfavorable cytogenetics, 58% had intermediate cytogenetics and 3% had favorable cytogenetics, 14/55 had NPM1 mutation, 19/69 had FLT3 internal tandem duplication. At clofarabine treatment, median age was 59 yrs (range 18–77), 42 pts were in first relapse, 35 in relapse >1, and 23 had primary refractory AML. Anthracycline was previously used in 92 pts. Twenty three relapses occurred after alloSCT. Clofarabine was used as single agent (n=22) or in combination with low-dose cytarabine (LDAC, 20–40 mg/m2/d for 4–14 days, n=18) or intermediate-dose cytarabine (IDAC, 1000–2000 mg/m2/d for 3–5 days, n=56) or other drugs (n=4). The dose of clofarabine at cycle 1 was 20 mg/m2/d (n=26), 30 mg/m2/d (n=32), 40 mg/m2/d (n=40) or other (n=2) for a median number of 5 days (mean 4.9, range 3–5). Among all pts, 30 achieved complete remission (CR), and 9 achieved CR with incomplete recovery (CRi), for an overall response rate of 39%. Six pts died during cycle 1, all of infection. Responding pts received a median number of 2 cycles (mean 2.1, range 1–6). Thirteen pts underwent subsequent alloSCT and four pts proceeded to donor lymphocyte infusion. No predictive factor of response was found in univariate analysis among age (cut-off at 60 yrs), sex, de novo vs secondary AML, cytogenetics (unfavorable vs intermediate), molecular genetics, line of treatment (first relapse vs relapse>1 vs refractory AML), relapse after alloSCT vs other relapse (for patients < 65 yrs with equally distributed cytogenetics), regimen (monotherapy vs LDAC vs IDAC) or dose of clofarabine (20 vs 30 vs 40 mg/m2/d). The median disease-free survival (DFS) was 17 months (mo). No factor significantly influenced DFS in univariate analysis, even though DFS tended to be better in relapse after alloSCT than in other relapse (for patients < 65 yrs with equally distributed cytogenetics) with 1-yr DFS being 100% vs 60% (p=0.1). Median overall survival (OS) was 19 mo for responding pts (CR+CRi) vs 3 mo in treatment failure (p<0.0001). In univariate analysis, median OS was better in male than in female (6.8 mo vs 4.1 mo, p=0.03), and in intermediate vs unfavorable cytogenetics (5.4 mo vs 4.1 mo, p=0.04); median OS tended to be better in relapse after alloSCT than in other relapse (for patients < 65 yrs with equally distributed cytogenetics) with median OS being 21 mo vs 4 mo (p=0.09). In multivariate analysis, cytogenetics was the only prognostic factor for OS (p=0.02).

Conclusion.

This study suggests that clofarabine-based salvage regimen is safe and can be effective in the treatment of relapsed/refractory AML. Durable remissions were achieved, especially in AML relapsed after alloSCT, allowing pts the option of (second) transplantation with the potential of long term cure.

Disclosures:

Off Label Use: clofarabine is approved for relapsed ALL in children.