Low Efficacy and High Mortality Associated with Clofarabine Treatment of Patients with Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes

Background: Clofarabine, a second-generation nucleoside analogue, has been shown in prospective studies to have activity in relapsed or refractory acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndromes (MDS). However, there are few data evaluating performance of the drug in populations of patients not enrolled in clinical trials.

Methods: We reviewed clinical outcomes for 84 patients treated at our center off-study for relapsed or refractory AML (n=81) or MDS (n=3) with clofarabine as monotherapy (n=19) or in combination with cytarabine (n=65). Almost all patients (n=62) receiving combination therapy were administered cytarabine 1 g/m2/day on days 1-5 and clofarabine 40 mg/m2/day on days 2-6 (Faderl et al Blood 2005; 105:940), while monotherapy dosing ranged from 15-30 mg/m2/day x 5 days.

Results: Median age of patients was 51 years; 54% were male. The median prior salvage regimens received was 1 (range, 0-5). Using International Working Group (IWG) response criteria, the overall response rate (ORR) of all treated patients was 21%, with a complete response rate with either complete or incomplete hematopoietic recovery (CRR = CR + CRi) of 14%. For combination therapy, ORR was 22% with CRR of 18%, and monotherapy patients had an ORR of 21% with CRR of 11%. Although limited by small numbers, subgroup analysis did not reveal significant variation in response rates when comparing age, performance status, or prior number of salvage regimens. 30-day mortality or induction death for all patients, combined therapy, and monotherapy was 21%, 23%, and 16% respectively. Overall median survival for all patients was 3 months; a subset of 12 patients who were able to go to allogeneic stem cell transplant had an 18-month median survival.

Conclusion: Clofarabine’s efficacy in a "real-world" setting appears to be less than has been reported in clinical trials, and treatment is associated with a high early mortality rate. Clofarabine's utility in relapsed/refractory AML/MDS may be primarily for cytoreduction in patients who have an allogeneic transplant option.