DNA methyltransferase inhibitors

The nucleoside analogues azacitidine and decitabine are inhibitors of DNA methyltransferase. Both drugs require prolonged administration before benefits are seen. The median number of cycles required to see first hematologic response to azacitidine was 3; 90% of responders showed response by 6 cycles; and the median number of cycles of decitabine required to see first response was 2.2.[21] Azacitidine received FDA approval based on the results of a randomized trial that was not designed to study survival.[22]

A phase III randomized controlled trial (AZA PH GL 2003 CL 001 [NCT00071799]) of azacitidine versus other regimens, including low-dose cytarabine, AML-type remission induction chemotherapy, or best supportive care, was limited to patients with higher-risk MDS subtypes (IPSS intermediate-2 risk and high risk).[17] The median and 2-year overall survival (OS) favored the azacitidine arm, at 24 months versus 16 months (P = .0001) and 51% versus 26% (P < .0001), respectively.[17][Level of evidence A1] The FDA-approved azacitidine dose schedule used in this study (75 mg/m2 per day for 7 consecutive days) has proven inconvenient to some practitioners. A community-based study has suggested that alternate dosing schedules may provide similar hematologic benefits; however, the impact of such dosing schedules on survival is not known.[23]

While the azacitidine congener decitabine demonstrated similar activity in phase II trials, two randomized trials of decitabine versus supportive care failed to show a survival benefit.[21,24] Both decitabine studies used the FDA-approved dose schedule (15 mg/m2 every 8 hours for nine doses). In the European phase III study in higher-risk patients, median OS was similar for patients in both the decitabine and best supportive care arms, at 10.1 months versus 8.5 months, respectively (P = .38). A combined OS and delay in AML transformation end point was 8.8 months versus 6.1 months, respectively (P = .24).[25][Level of evidence A1]

Decitabine can be given as daily intravenous or subcutaneous infusions at doses that differ from the original labeled schedule, with hematologic response rates that appear comparable to the phase III study.[26,27]

Both of these drugs have been approved for refractory anemia, RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, and refractory anemia with excess blasts in transformation. However, the highest response rates and levels of evidence have been generated in trials in which patients with higher-risk MDS (IPSS risk groups of intermediate-2 or high) were treated.[28] In lower-risk patients, response rates appear similar to those in higher-risk patients, although the survival benefit is unknown. The use of these drugs in low-risk patients may preclude their subsequent use upon disease progression.

Combinations of azacitidine with lenalidomide [29] and vorinostat [30] were compared with single-agent azacitidine in a national randomized phase II trial (S1117 [NCT01522976]).