Time-dependent decision analysis: Stable disease in azacitidine (AZA)-treated patients (pts) with higher-risk MDS.

Abstract

6503 Background: In higher-risk MDS, 80% of first responses by IWG 2000 criteria (hematologic improvement or better; HI+) to AZA are achieved with a median of 6 treatment (Tx) cycles (Silverman, 2008). In the AZA-001 trial, an overall survival (OS) benefit with AZA vs conventional care regimens (CCR) was observed with a median of 9 AZA Tx cycles (Fenaux, 2009); CR was not necessary for prolonged OS. These findings provide little guidance for management of pts with a best response of stable disease without HI (SD) after 6 AZA cycles. We evaluated the impact of SD on OS in AZA- and CCR-Tx pts in AZA-001. Methods: OS was estimated using Cox proportional hazard models stratified by FAB and IPSS with a factor for Tx. Time-varying covariates of SD and HI+, and terms for Tx-by-response interactions were added. The best model was chosen using the Akaike Information Criterion and statistical significance of the covariates. Landmark analyses of pt response at 3, 6, and 9 mo and estimating OS (Kaplan Meier) were used to confirm results. Results: For 358 pts (179 AZA, 179 CCR) median followup was 21.1 mo. Pts in both Tx groups with SD as best response had significant OS benefit (HR = 0.09, 95%CI: 0.06, 0.15, p < 0.0001) compared with pts who progressed. Pts with HI+ had significant OS benefit with AZA vs CCR (HR = 0.05, 95%CI: 0.01, 0.43; p = 0.006). Pts with SD at 6 mo in the AZA (n = 49) and CCR (n = 41) groups had similar IPSS scores at baseline, but different hematologic indices: 52 vs. 29% had abnormal cytogenetics; 59 vs. 23% had 3 cytopenias; lower median platelet (plt) count, 96 vs. 159 x 109/L; and 10% vs. 0% required plt transfusions. With continued Tx, 21% of AZA pts with SD at 3 mo achieved HI+ at 6 mo vs. 14% of CCR pts, and 14% of AZA pts with SD at 6 mo achieved HI+ at 9 mo vs. 0% of CCR pts. Conclusions: Regardless of treatment, pts with SD as best response had significant OS benefit vs pts who progressed. With continued Tx, more AZA pts with SD go on to achieve HI+ than CCR pts. Any IWG response (HI+) with AZA confers significant OS advantage vs HI+ with CCR. Since AZA-Tx pts with SD at 6 mo may achieve HI+ by 9 mo, decision to continue AZA Tx in SD pts should be individualized. Benefit of continuing AZA in pts with SD at 6 mo would be best studied in a randomized discontinuation trial. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene Celgene Amgen, Celgene, Cepahlon, Johnson & Johnson, Roche Amgen, Celgene, Roche Celgene