Results of a Randomized, Open-Label, Phase IIIb Study of 2 Schedules of Decitabine in Higher-Risk Myelodysplastic Syndrome Patients

To evaluate the efficacy and safety of 3-day and 5-day treatment schedules of decitabine (nucleoside analogue) in Chinese patients with Myelodysplastic Syndrome (MDS).

In this open-label, multi-center, phase 3b study, consenting men and women (n=132) above 18 years of age with de novo or secondary MDS fitting any of the recognized French-American-British classifications, with score on International Prognostic Scoring System (IPSS) ≥ 0.5 within 30 days before randomization, and having Eastern Cooperative Oncology Group performance (ECOG) status of 0–2, were enrolled. Patients were randomized (1:1) to either 3-day treatment schedule (15 mg/m²/day decitabine administered by continuous intravenous infusion within a 3-hour period, repeated every 8 hours for 3 consecutive days/cycle; cycles repeated every 6 weeks) or to 5-day treatment schedule (20 mg/m² decitabine administered by a 1-hour infusion once-daily, on days 1 through 5/cycle; cycles repeated every 4 weeks), until minimum of 30 patients were included in the 3-day treatment group. All remaining patients were enrolled for the 5-day treatment. Patients were treated for ≥4 treatment cycles and for a maximum of 2 years, as long as the patient continued to benefit (absence of overt progression of disease or unacceptable toxicity). The primary efficacy endpoint was overall response rate (ORR) that included complete remission, bone marrow complete remission and partial remission, according to the International Working Group (IWG) 2006 response criteria. The secondary endpoints included hematological improvement, time to acute myeloid leukemia (AML) progression or death, and overall survival (OS). Safety and pharmacokinetics of decitabine were evaluated. Assuming a 10% dropout rate, with 132 enrolled patients, the study had 90% power at a 5% significance level to detect a >10% ORR.

Thirty-four patients were included in the 3-day treatment group and 98 patients were included in the 5-day treatment group. Overall, 78 (59.5%) patients prematurely discontinued the study (16 [12.2%] patients discontinued due to disease progression). The demographic and baseline characteristics were comparable between the 2 treatment groups. In the overall population, the median age was 53.9 years (range: 18.5 – 84.0), 59% were men, all had de novo MDS, the mean (SD) time since diagnosis of MDS was 4.2 (9.38) months, 41.4% patients were IPSS Intermediate-1 (0.5–1.0), 43% were IPSS Intermediate −2 (1.5–2.0) and 15.6% were IPSS high risk (≥2.5) and the majority (68.9% of patients) had ECOG score of 1. Median number of treatment cycles was 3 for each of the treatment groups. Based on the single sample proportion comparison with given value (10%), the significant ORR was achieved in the overall population (22.9%; 95% CI: 16.0, 31.1; p<0.001) as well as in the 3-day treatment group (26.5%; 95% CI: 12.9, 44.4) and 5-day treatment group (21.6%; 95% CI: 13.9, 31.2). The hematological improvement (CR+PR+HI) rate (% [95% CI]) for overall population, 3-day treatment group and 5-day treatment group was 39.7 (31.3, 48.6), 44.1 (27.2, 62.1) and 38.1 (28.5, 48.6) respectively. AML transformations or deaths occurred in 21 (16.0%) patients overall, and in 5 (14.7%) and 16 (16.5%) patients in the 3-day and 5-day treatment group respectively. For the overall population, the maximum estimated time to AML transformations or death was 27.8 months (3-day treatment: 17.9 months, 5-day treatment: 27.8 months). For the overall population, the 12-month OS was 80.6 % and 24-month OS was 60.7%. At steady state, the mean (SD) maximum plasma concentration and mean (SD) area under plasma concentration-time curve (AUC_0-∞) was 54.44 (20.07) ng/mL and 118.93 (50.55) ng.hr/mL, respectively for the 3-day treatment group (n=7) and 222.35 (53.74) ng/mL and 180.43 (43.78) ng.hr/mL, respectively for the 5-day treatment group (n=17). Overall, at least one treatment-emergent adverse event (TEAE) occurred in 97 (74%) patients (32 [94.1%] patients in the 3-day treatment group and in 65 [67%] patients in the 5-day treatment group); TEAEs were related to study drug in 31 (91.2%) patients in the 3-day treatment group and 60 (61.9%) patients in the 5-day treatment group.

Decitabine was found to be efficacious and safe for treatment of MDS. Results of this study were consistent with similar decitabine studies conducted previously.

No relevant conflicts of interest to declare.