Patients with higher-risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) have a dismal prognosis; median survival in this patient population has been reported as ≤1.2 years, as cited in a 1997 study by Greenberg and colleagues. There is only one randomized study of azacitidine (AZA) in MDS showing a median survival of 24.5 months for AZA vs 15.1 months for conventional care regimens (HR, 0.58; CI, 0.43 to 0.77; log-rank P = .0001) [Fenaux P et al. Lancet Oncology. 2009].

Histone deacetylase inhibitors such as vorinostat (VOR) act synergistically with hypomethylating agents like AZA. A phase 1/2 study of VOR added to AZA in MDS in 33 evaluable patients showed a response of 70%, a complete response (CR) rate of 42%, and a median duration of response (DOR) of 16 months [Silverman LR et al. ASH 2013 (abstr 386)]. Lenalidomide (LEN) added to AZA in a phase 2 study in MDS (n = 36) resulted in an overall response rate (ORR) of 72%, a CR rate of 44%, and a DOR of > 17 months [Sekeres MA et al. Blood. 2012]. AZA and LEN have nonoverlapping mechanisms of action.

Mikkael Sekeres, MD, Cleveland Clinic, Cleveland, Ohio, USA, reported on the Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia study [Sekeres MA et al. ASH 2014 (abstr LBA-5)]. Groups participating in the study included the Southwest Oncology Group, Alliance, the Eastern Cooperative Oncology Group, and the National Cancer Institute of Canada.

Patients with higher-risk MDS or CMML were randomly assigned to AZA 75 mg/m²/day days 1 to 7 (n = 92), AZA plus LEN 10 mg/day for 21 days (n = 93), or AZA plus VOR 300 mg BID days 3 to 9 (n = 91). The primary objective was 20% improvement of ORR. Secondary objectives were improvements in overall survival (OS), relapse-free survival, and leukemia-free survival.

The 3 study arms were similar in patient characteristics. The mean age was 70 years; about 18% of patients had CMML, and about 7% had therapy-related MDS. Grade 3 or higher toxicities for the safety population (n = 260) are summarized in Table 1.

Responses are summarized in Table 2.

There were no differences in ORR or other response criteria comparing AZA plus LEN or AZA plus VOR to AZA monotherapy. Dr Sekeres said that some subgroups may have benefitted from AZA-based combinations, as the hematologic improvement rates for neutrophils were higher for patients receiving the AZA plus LEN combination (P = .05), as were response rates for CMML patients compared to AZA monotherapy, although the limited number in this subgroup precluded adequate power to show a significant difference (59% vs 33%, P = .15). Analyses by cytogenetic subgroups are pending. A strong signal for improved disease-free survival (DFS) was seen for the AZA plus VOR combination compared to AZA monotherapy (median 13 months vs 7 months, P = .11).

An open question is whether combination therapies in MDS are too toxic or whether toxicities need to be managed better. In this study, the investigators thought the toxicities were more severe than was reported by patients. It is possible that DOR and OS may be better end points for large MDS trials. In this trial, time to response was not assessed.