Treatment of High Risk MDS and AML Post-MDS with Azacytidine (AZA): Preliminary Results of the French ATU Program.
Authors: Fabre Claire , Chermat Fatsiha , Legros Laurence , Park Sophie , Dreyfus François , Isnard Françoise , Nowak Florence , Marfaing Anne , de Botton Stéphane , Noel Marie-Pierre , Fruchart Christophe , Prebet Thomas , Vey Norbert , Dartigeas Caroline , Fenaux Pierre 
Published: October 2019

Abstract
Background : Following FDA approval of AZA for MDS and activation of a phase III trial randomizing AZA to conventional treatment in higher risk MDS, a compassionate program for the use of AZA (ATU nominative) was started in France for MDS with exclusion criteria for this trial.
Patients (pts) : IPSS int-2 and high-risk MDS (and some int-1) with contra-indication to the trial (ie therapy related (t-MDS) or already treated by cytoreductive agents or having progressed to AML or patient refusal), received AZA 75 mg/m/d (d 1–7) (SC) every 4 weeks.
Results : From Sept 2004 to May 2006, 90 pts from 31 centres were included, of whom 77 had completed at least one course of AZA : M/F: 52/25, median age 71 y [42–88]. WHO at inclusion : 15 RAEB1, 30 RAEB2, 14 AML post-MDS, 7 CMML, 3 RA, 3 RAS, 2 RCMD, 3 unclassified MDS. 22 pts had previously received intensive Anth-AraC, 9 low dose AraC, 16 EPO and 13 other treatments (alkylators, Arsenic, androgens, Thal) and 1 had t-MDS. 32 (42%), 16 (21%) and 29 (37%) pts had fav, int and unfav karyotype, resp. 37 pts (48%) were IPSS high, 26 pts (34%) int-2 and 14 pts (18%) int-1. Pts received a median of 4 cycles [range 1–16]. Response was generally assessed after 4 cycles, unless pts progressed before. Thus, 16 pts were not yet evaluable for response. Of the remaining 61 pts, 10 (16%) achieved CR (IWG criteria), 15 (25%) achieved PR and 13 (21%) achieved HI (Overall response rate OR=62%). 23 pts (38%) were considered failure of whom 4 died before evaluation and 10 of them were considered failure because early evaluation after only 2 cycles showed stable disease only, and AZA was then stopped. OR was 73%, 57%, 67% and 36% for RAEB1, RAEB2, CMML and AML post-MDS resp (p<0.1); 75%, 56% and 59% for fav, int and unfav karyotype, resp (p=NS). 4/6 pts with monosomy 7 responded (1 CR+3 PR), 2/4 pts with + 8 (1 PR+1 HI) and 13/23 pts with complex karyotype (5 CR+6 PR+2 HI). OR was 56%, 77% and 56% for IPSS high, int-2 and int-1 pts, resp (p=NS) and 50%, 76% in pts previously treated or not by cytoreductive agents resp (p<0.05). Median survival from inclusion was 7 months [range 3–17]. AZA induced myelosuppression lead to dose reduction in 17% pts and hospitalization in 13% pts but was not responsible for any death. Other side effects included frequent local reactions (reversible with local NSAID) (32%), grade I-II gastro-intestinal disorders (39%), unexpected cardiac arythmias (3%).
Conclusion : AZA, in this population with overall unfavorable features, gave response rates at least similar to those of CALGB studies, that may have been higher if treatment had not been stopped in some of the pts stable after 2 courses. Pts with unfavorable karyotype (− 7, complex) or + 8 had about 50% response rates. Accrual in this program is continuing. Data on response duration will be presented.