Comparative Effectiveness of Azacitidine Versus Decitabine for the Treatment of Myelodysplastic Syndromes

Azacitidine (5-AzaC) and decitabine (DAC) are two hypomethylating agents commonly used in treatment of Myelodysplastic Syndromes (MDS). The comparative effectiveness of 5-AzaC versus DAC is not known. Both agents have been tested against supportive care in controlled settings, but not head-to-head. The most comprehensive assessment of the efficacy of 5-AzaC versus DAC was done by Kumar et al. (Haematologica95: 340-2) by performing an indirect meta-analysis using data from controlled trials, RCTs. The real world effectiveness of the 5-Aza-C versus DAC has not been evaluated. In response, we have performed a comparative effectiveness study of 5-AzaC versus DAC for treatment of MDS.

All MDS patients treated with 5-AzaC or DAC at Moffitt Cancer Center from December 1999 to December 2009 were included in the analysis. Benefits and harms associated with 5-AzaC and DAC were assessed. The primary outcome was overall survival, OS. The secondary outcomes were progression free survival (PFS), defined as progression to Acute Myeloid Leukemia (AML), response rate evaluated according to IWG 2006 criteria, reduction in IV antibiotic use and transfusion dependence. For harms assessment, we extracted data on grade 3/4 toxicities and treatment related mortalities (TRM). OS and PFS were estimated using the Kaplan-Meier method and difference between treatments was calculated using the log-rank test. Cox proportional hazard model was used to estimate hazard ratios. Competing risk regression was applied in estimating PFS for time to AML or death, since the occurrence of AML may be unobservable due to patients' death. Covariate matching analysis (CMA) was applied for the outcomes of OS and PFS to estimate differences in treatment due to the non-random nature of the data. Each patient was matched to four other patients on prognostically significant covariates of age, MDS type, IPSS score, and FAB class. Differences in treatment effects for dichotomous outcomes were assessed using Mann-Whitney test.

One hundred seventy four MDS patients met the inclusion criteria (121 patients treated with 5-AzaC and 53 with DAC). Patient characteristics are summarized in table below. The unadjusted results showed a statistically significant OS benefit with 5-AzaC versus DAC (hazard ratio (HR) was 1.496 (95% Confidence Interval (CI), 1.005 to 2.226; p=0.047). However, the CMA showed a statistically non-significant gain of 1.088 months of survival with use of 5-AzaC versus DAC (95% CI, -4.219 to 6.395; p=0.688). For PFS, a statistically significant benefit was associated with 5-AzaC versus DAC (unadjusted HR=1.471 (95% CI 1.000 to 2.165; p=0.049). Nevertheless, CMA results showed a statistically non-significant gain of 1.060 months of PFS with use of 5-AzaC versus DAC (95% CI, -4.391 to 6.512; p=0.703). The overall response rate (20.0% vs 6.3%; p=0.029) and hematological response rate (24.4% vs 6.0%; p=0.006) was significantly better with 5-AzaC versus DAC. However, differences in cytogenetic response rate (23.4% vs 33.3%; p=0.398), bone marrow blast response rate (43.3% vs 54.5%; p=0.370), reduction of IV antibiotic drug use (9.5% vs 12.0%; p=0.780), and RBC (15.3% vs 12.2%; p=0.609) or platelet (5.0% vs 9.8%; p=0.291) transfusion requirements were statistically non-significant with 5-AzaC versus DAC. There was a statistically non-significant difference in occurrence of grade 3/4 toxicity (24.6% vs 37.6%; p=0.094) or TRM (1.0% vs 0.0%; p=.512) between patients treated with 5-AzaC versus DAC.

Results from first retrospective population based study assessing the effectiveness of 5-AzaC versus DAC for treatment of MDS showed no significant difference in OS and PFS. However, 5-AzaC was associated with higher overall response rates compared with DAC with no significant difference in harms associated with the two treatments. Due to the limitations of retrospective analysis, these results warrant a prospective direct comparison of 5-AzaC versus DAC in a RCT.

Lancet:Eisai: Consultancy; Celgene: Honoraria.