Decitabine therapy in patients with AML or MDS and chromosome 5, 7, or 8 abnormalities.

Abstract

6555 Background: Though cytogenetic abnormalities have a major prognostic impact in MDS and related myeloid malignancies, the IPSS and other classification systems have been derived using patients (pts) who received supportive care only. However, most pts receive 1 or more forms of treatment and prognostic scoring is likely to be affected by modern therapies. Regardless of their role in IPSS and related schemes, high-risk cytogenetic lesions likely convey a risk of refractoriness to most therapies, but specific modalities may be more or less effective in pts with certain chromosomal abnormalities, as shown, for example, with del5q and lenalidomide. DNA methyltransferase inhibitors, now FDA-approved for use in MDS, lead to responses in a significant minority of pts but predictive markers of response are not yet known. Specific chromosomal lesions could constitute such markers, as suggested by recent reports that del7/7q pts may show favorable response rate to hypomethylating agents. Methods: To identify prospective chromosomal markers of responsiveness or refractoriness to hypomethylating agents, we retrospectively evaluated by combined regression analysis 3 clinical trials of decitabine in 243 pts with advanced-stage MDS or AML; 104 pts had cytogenetic abnormalities of chromosomes 5, 7, and/or 8. Results: Of 62 pts with del5q who received decitabine, no difference in objective response rate (ORR) was found compared to 181 pts without this lesion (21% vs. 18%, p = 0.57). Consistent with the known poor prognostic impact of del5q in AML/MDS this defect was associated with poor overall survival (OS) (274 d vs. 489 d, p < 0.0001). Of 66 pts with del7/7q who received decitabine, no difference in ORR was observed compared to 177 pts without del7/7q (20% vs. 18%, p = 0.77) but carriers of this defect showed decreased OS (319 d vs. 485 d, p = 0.0002). For 64 pts with chromosome 8 abnormalities, there was no difference in ORR to decitabine vs. 179 pts without (22% vs. 17%, p = 0.42) and no difference in OS (289 d vs. 442 d, p = 0.07). Conclusions: We conclude that recurrent chromosomal abnormalities including del5q, del7/7q and tri-8 do not constitute selective markers of responsiveness to decitabine and hypomethylating therapy does not alter their impact on OS. No significant financial relationships to disclose.