Oral Clofarabine in the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome.
Authors: Faderl Stefan , Garcia-Manero Guillermo , Estrov Zeev , Ravandi Farhad , Borthakur Gautam , Cortes Jorge , O'Brien Susan , Gandhi Varsha , Plunkett William , Byrd Anna L. , Kwari Monica , Kantarjian Hagop 
Published: October 2019

Abstract
Abstract 118

Clofarabine (CLO) is a second generation deoxyadenosine nucleoside analog with activity in patients (pts) with acute myeloid leukemia (AML). Early reports also suggestedactivity of iv CLO in myelodysplastic syndrome (MDS), but the role of CLO in MDS therapy remains largely undefined. Due to the molecular characteristics of CLO it can also be administered as an oral formulation with a bioavailability of around 50%. As an oral agent has obvious advantages over parenteral administrations, we designed a phase 2 study to evaluate the activity and safety of oral CLO in patients with MDS. Pts were eligible if they had MDS and ≥ 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 (2 RA, 11 RAEB-1, 11 RAEB-2, 2 RAEB-t, 5 CMML-1, 1 CMML-2) were treated. Twenty-two pts (69%) had intermediate-2 or high-risk disease by IPSS. Median age was 70 yrs (range 53–86). Overall, ≥ 27 pts (84%) were older than 60 yrs. Thirteen pts (41%) had a history of a prior malignancy and 20 pts (66%) failed prior hypomethylator therapy (6 pts azacitidine, 12 pts decitabine, 2 pts both). Cytogenetics were intermediate and poor in 9 (28%) and 10 (31%) pts, respectively. The starting dose of CLO was 40 mg/m2 orally daily × 5 days every 4–6 weeks (6 pts), which was decreased due to toxicities to 30 mg/m2 orally daily × 5 days (19 pts), and eventually 20 mg/m2 orally daily × 5 days (7 pts). Twenty-eight pts (88%) received treatment in an outpatient facility and almost all pts (94%) received anti-infectious prophylaxis. Responses of 31 evaluable pts are summarized in the Table:
Among 20 pts who failed prior hypomethylator therapy responses were CR in 2 (10%), HI in 2 (10%), and CB in 2 (10%). The median number of cycles to response was 1 (range 1–3). Of 10 pts who received further consolidation cycles, the median number was 1 (range 1–8+). No pts died within 6 wks of induction. Acute renal failure occurred in 4 pts (1 pt 40 mg/m2, 3 pts 30 mg/m2) in the context of myelosuppresssion-associated infectious complications; 4 pts died. Common adverse events were nausea/vomiting, rashes, reversible transaminase elevations and hyperbilirubinemia, and fatigue and were mainly ≤ grade 2. The most frequent ≥ grade 3 toxicity were reversible elevations of transaminases. Myelosuppression was ubiquitous, but prolonged myelosuppression (> 42 days) was rare in responding pts. Infectious episodes occurred in 16 pts and were more frequent in pts receiving CLO at 40 or 30 mg/m2. Oral CLO has an ORR of 46% in pts with higher-risk MDS. Responses are lower in pts failing prior hypomethylator therapy. The optimal dose and schedule to balance activity and toxicity remain to be defined.

Disclosures:
Faderl: Genzyme: Consultancy, Research Funding. Off Label Use: Clofarabine in MDS. Kantarjian:Genzyme: Consultancy, Research Funding.