Response to Azacytidine (AZA) in MDS or AML with Del 5q : Current Results of the French ATU Program

Background: AZA significantly improves survival over conventional treatment in higher risk MDS, especially in case of −7/del 7q (ASH 2007, abst n°817). Del 5q is the most frequent cytogenetic abn in MDS. Lower risk MDS with del 5q respond dramatically to lenalidomide (LEN), but the response rate to LEN is lower in higher risk MDS and AML with del 5q, that still have a poor outcome (ASH 2007, abst n°820). We analyzed response to AZA in those pts.

Methods: A multicenter patient named treatment program of AZA (75mg/m2/d for 7 days every 28 days) for higher risk MDS and AML (ATU program) was started in France in 2004. The first 195 pts having completed ≥ 1 cycle included 38 pts with del 5q treated in 16 centers, who are analyzed here.

Results: Median age was 66y (range 45–82). M/F : 20/18, WHO at inclusion : AML in 14 pts (de novo : 8, post-MDS : 5, post-MPD : 1 ; first-line : 9, relapsing/refractory after intensive chemo : 5), MDS in 24 pts (RCMD-RS : 1; RAEB1 : 4; RAEB2 : 15; RAEBt : 1; CMML : 1; unclass : 2). Del 5q was isolated in 3/38 cases, and with 1 and > 1 additional abn in 4 and 31 cases resp.(31 complex karyotypes). 22/38 pts had concomitant −7/del 7q. In MDS pts, IPSS was int-2 in 5 and high in 19 pts, resp. 6 pts had received LEN without response. Pts received a median of 3 cycles of AZA (range 1–17). The overall response rate (ORR, including CR+ PR+ marrow CR) of pts with del 5q was 11% (4% PR, 7% marrow CR, but no CR). An additional 4% of MDS achieved only HI-E. ORR of del 5q pts was lower than that of pts without del 5q (11% vs 30%, p=0.04). In del 5q pts, the ORR was similar in pts with and without concomitant −7/del 7q (6 vs 13%, p=.56). On the other hand, the ORR was 19% in −7/del7q pts (n=48) and tended to be lower in the presence than in the absence of concomitant del 5q (7% vs 27% resp., p=.09). In the overall group of pts with complex karyotype (n=46), the ORR was 18%, and also tended to be negatively affected by presence of del 5q (9% vs 27%, p=0.2). After adjustment on risk factors in the ATU cohort (including WHO diagnosis and age), del 5q pts still had a poorer ORR (HR=0.26 [0.07–0.91], p=0.035). Median survival after onset of AZA was 9 months in pts with del 5q vs 15 months in pts without del 5q (p=.007), and this difference was confirmed after adjustment on age and WHO diagnosis (HR=050 [0.28–0.89], p=0.019). In pts with complex karyotype, there was a trend for lower OS in case of del 5q (median 10 m vs 7 m, p=0.25).

Conclusion: Those findings suggest that higher risk MDS and AML with del 5q have poorer response rates and survival to AZA as single agent than other high risk MDS and AML, possibly also including pts with complex karyotype without del 5q. Novel therapeutic strategies, combining for example AZA and other drugs, may be required in those pts.