A Phase II Study Of The Efficacy and Safety Of An Intensified Schedule Of Azacitidine (AZA) In Intermediate-2 and High Risk MDS Patients

Although azacitidine (AZA) improves survival over conventional treatments in higher risk MDS (Lancet Oncol, 2009), median overall survival (OS) with AZA is only about 2 years, the CR+PR rate about 30%, and further improvements are needed. Gene hypomethylation appears to be a major mechanism of action of AZA but, with the typical 7 days of administration every 28 days, reversal of gene hypomethylation is seen at the end of each cycle (Braiteh F, Clin Cancer Res 2008), suggesting that increasing the number of treatment days could improve AZA results. This trial tested the hypothesis that an AZA regimen with more days of drug administration (ie using the standard daily dose of 75 mg/m², but during 5 days every 14 days ) could increase the response rate, and that this improvement could translate into better OS.

Patients (pts) aged 18-75 years with ECOG performance status (PS) of 0–2 and no major comorbidities preventing administration of an intensified regimen of AZA, with IPSS int-2 or high MDS, CMML with WBC < 13,000/mm3 and marrow blasts > 10% , and AML with 20-30% marrow blasts (ie EU label for AZA) who had received no prior treatment for their MDS/AML except ESAs could be included. Treatment consisted of AZA 75mg/m²/d for 5 days every 14 days for 4 cycles (AZA-14, cycles 1-4). Patients achieving CR or PR then received 4 cycles of AZA 75mg/m²/d during 5 days every 21 days (AZA-21, cycles 5 to 8) followed by classical cycles of AZA 75mg/m²/d for 7 days every 28 days, to be continued until progression/relapse or toxicity arose. This schedule corresponded to a 20% increase in the number of days of AZA during the first 8 weeks of treatment. Patients not obtaining CR or PR after the initial 4 cycles of AZA-14 received 4 additional cycles of AZA 14 (cycles 5 to 8). Patients not obtaining CR, PR or HI after 8 cycles of AZA-14 were taken off-study. The primary endpoint was response after 4 and 8 cycles (IWG 2006 criteria). We present here the 1^st interim analysis of the trial based on the first 22 patients/26 inclusions. Median [IQR] are reported unless specified.

One patient was excluded for consent withdrawal. 21 patients (M/F: 14/7, median age 66) were enrolled between 2011 and 2013, including 2 RCMD, 2 RAEB1, 10 RAEB2 and 5 AML (with 20 to 30% marrow blasts). Karyotype (IPSS) was favorable in 9 pts, intermediate in 4 patients and unfavorable in 8 pts. Median marrow blast was 13% (range 9.5-15), baseline platelet count was 71 G/l (37-204) including 33% with platelet<50 G/L, baseline Hb level was 9.6 g/dl (8.9-10.2), and baseline ANC was 1.2 G/l (0.6-2.3), including 38% with less than 0.8 G/L. IPSS was int-2 in 13 patients and high in 8 patients. With a median follow-up of 8.6 months, 184 cycles were administered (median 8 /patient, including 13 patients who received 6 or more cycles). Cycle 2 was performed at a median of 14 (14-14) days after cycle 1 and had to be delayed beyond d15 in only 1 patient, due to pleural effusion. Cycles 3 and 4, scheduled at d28 and d42, were slightly delayed in many pts (and were administered at a median of d34 and d50 from AZA onset). 1 pt terminated the study before cycle 4 due to CNS bleeding. 6 pts had died and 24 grade 3-4 SAEs were reported in 7 pts, including transient bilirubin increase in 2 pts, transient renal failure in 1pt, gut toxicity in 2 pts and CNS bleeding in 1 pt.

20 patients were evaluable for response after 4 cycles: 1 achieved CR, 5 PR , 5 marrow CR, , 8 stable disease without HI, and 1 progression (overall response rate ORR 55%). After 8 cycles, 1 PR patient at 4 cycles achieved CR and 5 additional responses were observed (3 marrow CR and 2 CR) leading to an ORR of 14/20 (70%). With a median follow up of 8.6 months, 1year overall survival was 69%.

In this population of relatively “fit” Higher risk MDS, an intensified schedule of AZA seems feasible without obvious increase in toxicity compared to the classical 7 day schedule of azacitidine. Cycles were delayed in a limited proportion of patients and no extra toxicities were observed. Both the ORR of 70% and the 69% overall survival at 1 year are encouraging.

Guerci-Bresler:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Fenaux:CELGENE: Research Funding.