High dose cytarabine (HiDAC) is the most effective single agent studied to date for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active single agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. Based on the results of a limited phase 1 trial (

), we conducted a phase 2 study of HiDAC (2g/m2 over 3 hours) followed immediately by CLOF (40 mg/m2 infused over 2 hours), given daily for 5 days, in 39 adults with AML in first relapse (n = 27), second relapse (n = 3), or refractory to initial induction chemotherapy (n = 9). Prophylactic intravenous hydrocortisone was incorporated to decrease the occurrence of skin toxicity. Patients with persistent leukemia on day 12–14 (n = 12) received a second course of HiDAC → CLOF for 3 days. The mean age was 53.4 years (range 18.4 – 79.0). Accrual began March 2006 and was completed in July 2008. Thirtyseven of 39 patients are evaluable for response (two patients were treated recently and are not included in this analysis): 14/37 achieved a complete remission (CR), 2/37 a CR with incomplete blood count recovery (CRi) for an overall response (CR or CRi) in 16/37 (43%; 95% CI 27 – 59%). Twelve of 37 (32%) patients had resistant disease, 3/37 (8%) died of complications during marrow aplasia, 5/37 (14%) died of complications of their AML with unknown bone marrow status, and 1/37 (3%) refused further evaluation or treatment. CR or CRi was achieved in 11/25 patients in first relapse, 2/3 in second relapse, and 3/9 with refractory AML. Twelve patients received a second induction – 2/12 (17%) achieved a CR and 1/12 (8%) a CRi. Toxicity data are complete in 36 patients; the most frequent grade 3/4 non-hematologic toxicities were transient elevations of AST/ALT observed in 23/36 (64%) patients, hyperbilirubinemia in 8/36 (22%), infection in 16/36 (44%), and rash in 8/36 (22%). Patients who achieved CR or CRi received up to 3 additional courses of HiDAC → CLOF each daily for 5 days. Twenty-seven of 39 (69%) patients have died with a median survival of 119 days (95% CI 71 – 322 days). In summary, HiDAC → CLOF is a very active combination in adults with relapsed and refractory AML, a group in whom CR/CRi rates of 30–35% are achieved with many salvage regimens. Toxicities are comparable to other salvage regimens with transient elevations in transaminases identified as the most frequent toxicity.

Disclosures: Powell:Genzyme Oncology: Research Funding. Off Label Use: Clofarabine is not approved for treatment of AML.

Author notes

Corresponding author