Clofarabine Plus Low-Dose Cytarabine For The Treatment Of Patients Withhigher-Risk Myelodysplastic Syndrome (MDS) Who Have Been Relapsing After, Or Are Refractory To, Hypomethylator Agent Therapy

Treatment with hypomethylating agents (HMA) such as azacitidine and decitabine has changed the overall outcome of patients with MDS. Failure to responed to or relapse from treatment with HMA carries a poor outcome and no approved therapy for these patients exists. Clofarabine is a second generation nucleoside analog with single agent activity in MDS.

This is a phase II trial to evaluate the safety and activity of the combination of clofarabine and low dose cytarabine in the treatment of patients with high risk MDS who failed prior HMA therapy.

Eligible were adults older than 18 years with MDS who have had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine. Patients were required to have an ECOG performance status of </=2 at the time of study entry. Responses were defined according to IWG 2006 criteria. Induction therapy consisted of clofarabine 15 mg/m² IV daily X 5 days (days 1-5) and cytarabine 20 mg SC twice daily X 7 days (days 1-7). Patients could receive up to 3 induction cycles as long as they tolerated the therapy and had stable disease. Responding patients proceeded with consolidation therapy with clofarabine 15 mg/m²IV daily X 3 days (days 1-3) and cytarabine 20 mg SC twice daily X 5 days (days 1-5) for a maximum of 12 cycles. Cycles were repeated every 4 to 8 weeks depending on hematopoietic recovery and resolution of toxicities.

Between January 2012 and March 2013, 29 patients were enrolled. The clinical characteristics are summarized in Table 1. Twenty four patients were evaluable for response (5 patients were too early for response). The overall response rate (ORR) was 50% (8 [33%] achieved complete remission (CR)/ complete remission with incomplete platelets recovery (CRp)/marrow CR, and 4 [17%] had stable disease with hematological improvement). With a median follow up of 4.9 months (range, 1.9-16.7), the median overall survival (OS) was 4.8 months (range, 0.5-13.5). Most toxicities were grade </= 2 and included: elevated liver enzymes in 41% of the patients, elevated bilirubin (38%), rash (28%), nausea (31%), headache (24%), and febrile neutropenia (28%). Grade >/= 3 toxicities included: elevated liver enzymes (3%) and elevated bilirubin (3%). Four-week mortality was 12%.

The combination of clofarabine and low-dose cytarabine has an ORR of 50% in patients with MDS who failed prior therapy with HMA. The study continues to accrue and updated results with longer follow up will be presented at the meeting.

Off Label Use: Clofarabine use in MDS. Faderl:Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.