A Randomized Study of Low Dose Oral Clofarabine 10 Mg Versus 20 Mg (flat dose) Daily × 5 for Patients with Higher-Risk Myelodysplastic Syndrome (MDS)
Authors: Faderl Stefan , Garcia-Manero Guillermo , Ravandi Farhad , Cortes Jorge E. , Estrov Zeev , Borthakur Gautam , O'Brien Susan M. , Kadia Tapan M. , Konopleva Marina , Daver Naval , Brandt Mark , Schroeder Heather , Kantarjian Hagop M. 
Published: October 2019

Abstract
Abstract 3851
Clofarabine (CLO) is a nucleoside analog with activity in myeloid malignancies. We have previously reported an overall response rate (ORR) of 43% (CR rate 25%) in patients (pts) with higher-risk MDS treated with oral CLO at doses between 20 mg/m2 and 40 mg/m2 daily × 5 (S Faderl et al. J Clin Oncol 2010, 28: 2755). However, myelosuppression and infectious complications were frequent. We therefore developed a trial based on a Bayesian randomization design of CLO 10 mg vs 20 mg (flat dose) orally daily × 5 days with the objective to maintain reasonable efficacy and minimize toxicities. Cycles were repeated every 4 to 8 weeks for up to a total of 12. Pts were eligible if they had MDS with ≥ 5% blasts (including RAEB-t by FAB) or IPSS intermediate-2 and high-risk, and CMML. Hematopoietic growth factor support prior to and during the study was permitted. Thirty-two pts (19 RAEB [59%], 7 RAEB-t [22%], 2 MDS/MPN [6%], 4 CMML [13%]) were randomized. Patient characteristics were similar between the groups and are summarized in Table 1.
Table 1: Patient Characteristics Characteristic 10 mg 20 mg N 16 16 Median age, yrs (range) 67.5 (43–87) 72.5 (54–84) Median WBC, ×109/L (range) 4 (1.2–121.3) 4.8 (0.4–47) Median blood blasts, % (range) 0.5 (0–25) 3.5 (0–32) Median marrow blasts, % (range) 12 (4–28) 12 (2–24) Secondary MDS, N (%) 9 (56) 4 (25) Median N prior therapies (range) 1 (0–3) 1 (0–4) Prior hypomethylator therapy, N 14 (88%) 13 (81%) Cytogenetics 5 (31) 6 (38) Diploid, N (%) 4 (25) 4 (25) -5/5q- and/or -7/7q- 4 (25) 2 (13) IM/not done
Seven pts (22%) responded: 3 CR and 4 CR without platelet recovery (CRp). Four pts (25%) in the 10 mg group and 3 pts (19%) in the 20 mg group responded (differences not significant). Median remission duration was 6.5 months for all pts (6.5 months [10 mg]; 4.4 months [20 mg], p=.942). The median number of cycles was 2 in each treatment group with a range of 1–4 (10 mg) and 1–12 treatment cycles (20 mg), respectively. One pt in each group died. Median survival for the whole group was 8.5 months (8.2 months [10 mg]; 8.5 months [20 mg], p=.9). Clofarabine at both 10 mg and 20 mg orally daily × 5 has a comparable CR/CRp rate as do higher doses. Myelosuppression does still occur but prolonged myelosuppression has been rare.
Even lower doses including at different schedules may still warrant further study.

Disclosures:
Faderl: Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Clofarabine in MDS. O'Brien:Avila: Research Funding; Bayer: Consultancy; Bristol-Myers Squibb: Research Funding; Gilead Sciences: Consultancy, Research Funding; Celgene: Consultancy; Cephalon: Consultancy; CII Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Research Funding; Genzyme: Consultancy; GlaxoSmithKline: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Seattle Genetics, Inc.: Consultancy; Sigma Tau Pharmaceuticals: Consultancy; Talon: Research Funding; The Medal Group: Speakers Bureau. Kantarjian:Genzyme: Research Funding.