Cytogenetic responses to the hypomethylating agent, decitabine (DAC), in a phase III trial of DAC vs supportive care (SC) in patients (pts) with myelodysplastic syndromes (MDS)

Abstract

6501 Background: Clonal cytogenetic abnormalities are detected in 40%-70% of cases of de novo MDS and 95% of cases of therapy-related MDS, and the incidence increases with poor risk. DAC is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. In this analysis, we asked whether the hypomethylating agent DAC leads to cytogenetic response in MDS. Methods: We report cytogenetic response data from a Phase III randomized, open-label trial of DAC vs SC in 170 MDS pts. Eligibility requirements included confirmed MDS (de novo or secondary) fitting any of the recognized French-American-British classifications and an International Prognostic Scoring System (IPSS) score of 0.5 or more as determined by complete blood count, cytogenetics, and bone marrow assessment. Cytogenetics was assessed as a secondary endpoint, whereas primary endpoints were response rate (CR+PR) and time to AML or death. For pts with clonal abnormalities at baseline, follow-up cytogenetic evaluations at study end were available for 26 pts in the DAC arm and 21 pts in the SC alone arm. Results: As previously reported, overall response rate according to International Working Group MDS criteria was 17% (15/89) for DAC vs 0% for SC (p<0.001). Responses occurred in all IPSS groups and were also seen in pts with 5q and 7 deletions. Response rate was 13% (2/16) in pts with 5q deletions and 21% (4/19) in pts with 7 deletions. In pts without 5q or 7 deletions, response rates were 16% (11/67) and 14% (9/64), respectively. Complete cytogenetic responses were observed in 35% (9/26) of DAC pts vs 10% (2/21) of SC pts (p=0.08, Fisher’s exact). Also, 1 pt receiving DAC had a minor cytogenetic response. 10/10 DAC pts with cytogenetic response had clinical benefit (6 CR, 2 PR, 1 hematologic improvement, and 1 with normalization of marrow blast count). The primary toxicity was myelosuppression. Conclusion: DAC induces a substantial rate of cytogenetic responses in pts with MDS, suggesting that the clinical improvements induced by this agent are related to elimination of the neoplastic clone rather than to pure differentiation effects. [Table: see text]