Initial Results of a Randomized Phase II Study of Low Dose Decitabine (DAC) Versus Low Dose Azacitidine (AZA) in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes (MDS)

Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor survival (Leukemia. 2008;22:538-543). Hypomethylating agents (HMA) improve the outcomes of patients with higher-risk MDS. Recent Phase I/II studies suggested that HMA doses below current standards of care retain activity in MDS, potentially with a better toxicity profile (JCO. 2009;27:1850-1856). We hypothesized that lower doses of HMA may be active and well tolerated in patients with lower-risk MDS.

Aim: This is a phase II randomized trial to evaluate the efficacy and tolerability of low-dose regimens of either DAC or AZA in patients with low- or intermediate-1-risk MDS.

Materials and Methods: Eligible patients were adults older than 18 years with de novo or secondary IPSS low- or intermediate-1-risk MDS, including CMML, with normal organ function. Patients were randomized on a Bayesian design to receive DAC 20 mg/m² IV or AZA 75 mg/m² IV/SC per day for 3 consecutive days every 28 days. The primary efficacy end point is overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points are HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Chi-square test and independent t-test were performed to evaluate differences of patients’ characteristics. OS was estimated with the Kaplan-Meier method. A log-rank test was used for statistical analysis, and p<0.05 was considered statistically significant.

Results: Between 11/2012 and 4/2014, 68 patients were enrolled. Eleven patients have not been on-study long enough for response assessment. Fifty-seven patients are currently evaluable in this study; 28 patients received DAC, and 29 patients received AZA. Median duration of follow-up is 9 months (range, 0-18+). Median age at enrollment was 71 years (33-85). Median time from diagnosis to therapy was 1.5 months (range, 0.2-63.4). Baseline patient demographic and clinical characteristics did not differ significantly between groups. Of the 28 patients in the DAC arm, 13 (46%) had diploidy, and 2 (7%) had complex karyotypes; 3 (11%) were low-risk and 25 (89%) were intermediate-1-risk by IPSS. Of the 29 patients in the AZA arm, 17 (59%) had diploidy, and 1 (3%) had complex karyotype; 5 (17%) were low-risk and 24 (83%) were intermediate-1-risk by IPSS (2006). Six (21%) patients in the DAC arm and 7 (24%) in the AZA arm received growth factor support prior to therapy.

Overall, 19 (33%) patients achieved CR, 2 (4%) CRp, 6 (11%) mCR, and 5 (9%) HI. In the DAC arm, 15 (54%) achieved OIR, 10 (36%) CR, 1 (4%) CRp, 3 (11%) mCR, and 1 (4%) HI. In the AZA arm, 16 (56%) achieved OIR, 9 (31%) CR, 1 (3%) CRp, 3 (10%) mCR, and 3 (10%) HI. Median response duration is 13 months (range, 0-16+). In the DAC group, 1 (8%) out of 12 initially RBC-dependent patients became RBC independent, 3 of 5 RBC/platelet-dependent patients became RBC/platelet-independent, and 1 (7%) of 14 transfusion-independent patients became RBC-dependent. In the AZA group, 3 (27%) of 11 initially RBC-dependent patients became RBC-independent, and 1 (7%) of 14 transfusion-independent patients became dependent. The median number of courses is 7 (range, 2-17+). Treatment has been well tolerated, and only 3 (5%) patients had dose reduction due to grade 3-4 myelosuppression. No death is observed during therapy but 9 deaths in total (16%) were observed after HMA failure; 3 (10%) in AZA and 1 (3%) in DAC in patients who failed to respond and discontinued therapy before death; 2 (7%) in AZA and 3 (11%) in DAC in patients who progressed to higher grade of MDS and changed therapy before death. The 1-year survival rates for the DAC and AZA were 80% and 67%, respectively (p=0.478). Median OS has not been reached, and no difference was noted between groups. Analyzing survival by the MDA lower-risk scoring system (Leukemia. 2008;22:538-543), the median survival was not reached for patients with low-risk disease, not reached for patients with intermediate-risk disease, and 272 days for patients for high-risk disease. The 1-year survival rates were 100%, 82%, and 64% for patients with low-, intermediate-, and high-risk disease, respectively.

Conclusion: Low-dose HMA shows promising results in patients with low- or intermediate-1- risk MDS, with an OIR of 53%. The study continues to accrue patients, and results will continue to be updated as they are analyzed.