Median number of cycles required to see first hematologic response to 5-azacitidine was 3; 90% of responders showed response by 6 cycles; the median number of cycles of decitabine required to see first response was 2.2.
Preliminary results were reported from a phase III randomized controlled trial of decitabine versus best supportive care in higher-risk MDS patients. The median OS and a combined OS and delay in AML transformation endpoint were similar for patients in both the decitabine and best supportive care arms, at 10.1 months versus 8.5 months, respectively, for OS (P = .38) and 8.8 months versus 6.1 months, respectively, for the combined endpoint (P = .24).[Level of evidence: 1iiA]
Phase I and II studies have suggested that decitabine can be given as daily intravenous or subcutaneous infusions at doses that differ from the labeled schedule, which requires a minimum 3-day hospitalization; hematologic response rates are at least as good as in the phase III study.[27,28]
Administration of both nucleosides has been associated with reversal of methylation of cytosines in the promoter regions of silenced genes; however, it is not clear whether the clinical activity of these drugs requires methylation reversal.[29,30,31] While the mechanism of the clinical activity of 5-azacitidine and decitabine are not fully known, these two nucleosides demonstrated the highest single-agent response rates in this group of disorders. Both of these drugs have been approved for refractory anemia, RARS (if accompanied by neutropenia, or thrombocytopenia, or requiring transfusions), RAEB, and refractory anemia with excess blasts in transformation. Trials studying the combinations of both azacytosine nucleosides with histone deacetylase inhibitors have been completed, including the NCT00326170 study; some are ongoing, including the Eastern Cooperative Oncology Group's ECOG-E1905 trial.[31,33,34]
Lenalidomide (CC-5013), a congener of thalidomide, induced erythroid responses in approximately 50% of MDS patients in a phase I and II study, including transfusion independence in 20 out of 32 patients. Patients with MDS that was characterized by interstitial deletions of chromosome 5q31.1 (5q-) appeared particularly sensitive, with responses in 10 out of 12 patients compared with 13 out of 23 patients with a normal karyotype. In a phase II study of 148 low-risk and intermediate-risk I patients with 5q- chromosomal abnormalities (alone, or associated with other abnormalities), lenalidomide-induced transfusion independence in 67%, with a median time to response of 4 to 5 weeks. The median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. Of 62 evaluable patients, 38 patients developed complete cytogenetic remission. Lenalidomide administration is limited by dose-limiting neutropenia and thrombocytopenia.[Level of evidence: 3iiiDiv]
Antithymocyte globulin (ATG) has shown activity in MDS patients in several small series. The National Heart Lung and Blood Institute conducted a phase II trial including 25 MDS patients with less than 20% blasts. Of all the patients studied, 11 or 44% responded and became transfusion-independent after ATG (three complete responses, six partial responses, and two minimal responses). Multivariate analysis identified HLA-DR-15 (phenotype) expression, briefer period of red cell transfusion dependence, and younger age as predictors of response to ATG.