Randomized Open-Label Phase II Study of Decitabine in Patients with Low- or Intermediate-1 Risk Myelodysplastic Syndromes,
Authors: Garcia-Manero Guillermo , Jabbour Elias , Borthakur Gautam , Faderl Stefan , Estrov Zeev , Godley Lucy , Gabrail Nashat Y. , Berdeja Jesus G. , Nadeem Ahmed , Stein Karen , Noble Yvonne , Kassalow Laurent , Kantarjian Hagop M. 
Published: October 2019

Abstract
Abstract 3812

Background:
Decitabine (DAC) is a hypomethylating agent indicated for the treatment of myelodysplastic syndromes (MDS). We hypothesized that low-dose subcutaneous (SC) schedules of DAC may be active and safe in patients with lower risk MDS.

Methods:
This randomized, open-label, multicenter phase II study evaluated 2 DAC regimens in patients with low- or intermediate-1 risk MDS: 20 mg/m2/day SC for 3 consecutive days every 28 days (Arm A) or 20 mg/m2/day SC every 7 days (on days 1, 8, and 15) for 21 days, followed by 7 days without DAC (Arm B). The aim was to determine clinical activity, safety, and tolerability of the 2 regimens. The primary objective was overall improvement rate (OIR), defined as complete remission (CR), partial remission (PR), marrow CR (mCR), or hematologic improvement (HI), measured at the end of each cycle using patient's best response according to International Working Group (IWG) 2006 criteria. Secondary objectives included safety, HI, transfusion independence, cytogenetic response, and overall survival (OS). The tertiary objective was change in DNA methylation. Treatment on study was for ≤1 year, but patients who had clinical benefit could continue DAC off protocol. Target enrollment was 80 patients. Categorical and continuous variables were compared using Fisher's exact test and 1-way ANOVA, respectively; survival was analyzed with Kaplan-Meier, Cox regression, and log-rank methods.

Results:
Sixty-seven patients were randomized at 5 sites when the trial terminated early after achievement of protocol-defined superiority. On Oct 12, 2009, the posterior probability of at least 95% was met that OIR to Arm A was superior to Arm B. Thus enrollment in Arm B was terminated on Oct 16, 2009. Arm A was terminated on Dec 2, 2009, based on sponsor review and confirmation of achievement of protocol-defined superiority.
The mITT population comprised 65 patients (Arm A, n=43; Arm B, n=22). Overall mean age (SD) was 68 y (13), 69% men; 89% had de novo MDS, and median time since diagnosis was 3.6 months (range, 0, 118). 94% had ECOG performance status (PS) 0–1, 29% had IPSS low-risk classification, and 69% had normal baseline cytogenetics. Arms were balanced apart from having more men in Arm B (P =.01). Patients received a median 7.0 (range, 1, 13) cycles of therapy in Arm A and 5.5 (2, 16) in Arm B. At study end, OIR was 10/43 (23%; 7 CR, 3 HI) and 5/22 (23%; 1 mCR, 1 PR, 3 HI) for Arms A and B, respectively (95% CI of difference: -21.1, 22.1). For transfusion status, of patients who were RBC dependent at baseline, 6/17 (35%) in Arm A and 4/8 (50%) in Arm B became independent on study. Corresponding data for platelets were 3/4 (75%) and 1/4 (25%), respectively. Approximately 40% of patients in each arm who were RBC/platelet dependent at baseline became independent on study. Of patients who were RBC independent at baseline, 24/26 (92%) in Arm A and 11/14 (79%) in Arm B remained independent on study. Corresponding data for platelets were 34/39 (87%) and 17/18 (94%), respectively, and for patients who were RBC/platelet independent, 22/25 (88%) and 9/12 (75%), respectively. IPSS, age, time from MDS diagnosis, type of MDS, prior MDS therapy, baseline cytogenetics, and ECOG PS were similar and did not affect OIR, HI, or transfusion status. There were no cytogenetic responses. At 500 days follow-up, median OS had not been reached (Figure); there were 8 deaths (19%) in Arm A and 6 (27%) in Arm B (hazard ratio 1.5; 95% CI: 0.5, 4.5). Induction of hypomethylation was seen in patients in both arms.
All patients experienced ≥1 treatment-emergent AE. The most frequent at least possibly drug-related AEs for Arms A and B, respectively, were neutropenia (28% vs 36%), anemia (23% vs 18%), thrombocytopenia (16% vs 32%), fatigue (19% vs 9%), and leukopenia (9% vs 27%). Drug-related AEs of grade ≥3 were mainly hematologic and reported in 17 patients (40%) in Arm A and 10 patients (46%) in Arm B. There were no deaths within the first 8 weeks on study. One patient (neutropenic sepsis) in Arm A and 2 patients (1 each of anemia and MDS) in Arm B died as a result of an AE; none were reported to be drug related.

Conclusions:
DAC 20 mg/m2/day SC is active and well tolerated in lower-risk MDS. The OIR was similar in both arms, but a 3-day regimen appears more favorable than a 3x per week regimen based on all efficacy and safety results and the statistical decision to terminate the study early based on Arm A superiority. Further studies with these regimens are warranted.

Disclosures:
Off Label Use: Dacogen is a nucleoside metabolic inhibitor indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Borthakur:Eisai: Research Funding. Faderl:Eisai: Research Funding. Stein:Eisai: Employment. Noble:Eisai: Employment. Kassalow:Eisai: Employment. Kantarjian:Eisai: Research Funding.