Decitabine for Treatment of Myelodysplastic Syndromes in Chinese Patients: An Open-Label, Phase-3b Study

Abstract

Introduction: The objective of this study was to evaluate the efficacy and safety of decitabine in Chinese patients with myelodysplastic syndrome (MDS).

Methods: Patients (≥18 years) who had a de novo or secondary MDS diagnosis according to French-American-British classification and an International Prognostic Scoring System score ≥0.5 were enrolled and randomized (1:1) to one of two decitabine regimens: 3-day treatment (3-h intravenous infusion of 15 mg/m(2) given every 8 h for three consecutive days/cycle/6 weeks) or 5-day treatment (1-h intravenous infusion of 20 mg/m(2) once daily on days 1-5/cycle/4 weeks). After a minimum of 30 patients were assigned to 3-day schedule, the remaining were assigned to the 5-day schedule. The primary efficacy endpoint was the overall response rate (ORR). Secondary outcome measures included hematologic improvement (HI), cytogenetic response rate, the time to acute myeloid leukemia (AML) progression, and overall survival (OS).

Results: In total, 132 of 135 enrolled patients (3-day treatment, n = 36; 5-day treatment, n = 99) discontinued treatment (major reasons included patient withdrawal/lack of efficacy, n = 48; adverse events, n = 23; and disease progression, n = 22). During the study, 35 of 132 (26.5%) patients from the intent-to-treat (ITT) group achieved significant (P < 0.001) ORR [3-day group (n = 10, 29.4%), P = 0.003; 5-day group (n = 25, 25.5%), P < 0.001]. The HI rate was similar between the 3-day (47.1%) and 5-day groups (48.0%). Cytogenetic response was achieved in 20 of the 30 (66.7%) patients who had a baseline cytogenetic abnormality. Fifty-three (40.2%) AML transformations or deaths occurred and the median AML-free survival time was 23.8 months for all patients from the ITT set; 24-month OS rate was 48.9%. Adverse events of myelosuppression-related disorders (85.6%) and infections (43.2%) were commonly reported.

Conclusion: Decitabine treatment was efficacious in Chinese patients with MDS with its safety profile comparable to the global studies of decitabine conducted to date.

Funding: Xian-Janssen Pharmaceutical Ltd. China (a company of Johnson & Johnson).

Trial registration: ClinicalTrials.gov identifier, NCT01751867.

Keywords: Chinese population; Decitabine; Hematology; Myelodysplastic syndrome (MDS); Oncology; Phase 3b.

Figures

Fig. 1

Study design and patient disposition. aAfter reaching a minimum of 30 patients in the intent-to-treat analysis set for the 3-day treatment group, all remaining patients were enrolled into the 5-day treatment group. bAll patients were treated for ≥4 cycles; treatment continued for a maximum of 2 years as long as patients continued to benefit. cOther reasons: primarily included patient voluntary withdrawal from the study, and withdraw from the study due to economic reasons or lack of efficacy. Decitabine for injection was supplied as a sterile lyophilized powder (50 mg decitabine), in a single dose vial to be aseptically reconstituted prior use. ITT intent to treat, IV intravenous, PK pharmacokinetics

Fig. 2

Time to the first and best response—combining both treatment groups (ITT analysis set). Only patients with remission were included in the analysis. CR complete remission, HI hematologic improvement, ITT intent to treat, mCR marrow complete remission, PR partial remission

Fig. 3

Kaplan–Meier survival curves showing time to AML transformation or death after combining both treatment groups by IPSS classification (ITT analysis set). Hazard ratio is from nonstratified proportional hazards model. P value is from a nonstratified log-rank test. AML acute myeloid leukemia, CI confidence interval, IPSS International Prognostic Scoring System, ITT intent to treat

Fig. 4

Kaplan–Meier survival curves showing survival time after combining both treatment groups (intent-to-treat analysis set)

Fig. 5

Kaplan–Meier curves of the overall survival rate according to IPSS classification (intent-to-treat analysis set). P value is from a nonstratified log-rank test. Hazard ratio is from nonstratified proportional hazards model. CI confidence interval, IPSS International Prognostic Scoring System

Fig. 6

Mean (standard deviation) decitabine plasma concentration on day 3 of cycle 1 with 3-day dosing regimen (pharmacokinetic analysis set). Decitabine 15 mg/m2 intravenous infusion was administered over 3 h every 8 h for three consecutive days

Fig. 7

Mean (standard deviation) decitabine plasma concentration on day 5 of cycle 1 with 5-day dosing regimen (pharmacokinetic analysis set). Decitabine 20 mg/m2 intravenous infusion was administered over 1 h, once daily for five consecutive days