SAN DIEGO, CA—Pre-transplant chemotherapy regimens that included the purine nucleoside analog clofarabine did not negatively affect outcomes in younger patients with acute myeloid leukemia (AML) who were undergoing allogenic stem cell transplant (allo-SCT) compared with those pretreated with non-clofarabine containing regimens, according to results of a study reported during the 53rd American Society of Hematology Annual Meeting and Exposition. The University of Texas M.D. Anderson Cancer Center, Houston, is actively investigating the use of clofarabine in combination with idarubicin and cytarabine as frontline therapy for younger patients with newly diagnosed AML.

One of the primary adverse events associated with clofarabine is hepatotoxicity (i.e., elevated alanine transaminase [ALT] and/or bilirubin levels); rarely, severe hepatotoxicity and veno-occlusive disease have been reported. In addition, allo-SCT, indicated for those in first remission with poor risk features (such as adverse cytogenetics and diploid karyotype with FLT3 mutations), can increase risk of liver toxicity and veno-occlusive disease. For these reasons, Michael S. Mathisen, PharmD, and colleagues conducted a retrospective review to determine the effect of a clofarabine-containing regimen on outcomes in this patient population.

A total of 42 patients with AML who had undergone allo-SCT after receiving pre-transplant chemotherapy with one of the following two frontline regimens was identified: CIA: clofarabine 20mg/m2/day IV for 5 days + idarubicin 10mg/m2/day IV for 3 days + cytarabine 1,000mg/m2/day IV for 5 days (n=20) or a non-clofarabine containing regimen: IA: idarubicin 12mg/m2/day IV for 3 days and cytarabine 1,500mg/m2/day via IV continuous infusion over 24 hours for 4 days (n=22). Consolidation cycles contained the same agents given according to an attenuated schedule.

Patients were all receiving CIA or IA as their frontline regimen for AML. Variables extracted from each patient’s medical record included age, number of cycles of chemotherapy, complete remission (CR) rate, allo-SCT in CR, stem cell source, conditioning regimen, engraftment day, incidence of veno-occlusive disease, incidence of acute hepatotoxicity post-transplant, incidence of graft versus host disease (GVHD), early death, and early relapse. Patient and transplant characteristics were comparable between cohorts. Patient age was similar between groups (mean age was 43 years in the CIA arm and 45 years in the IA arm); 25% were male in the CIA group vs 64% in the IA group (P=0.0001). Most had undergone a matched related donor or matched unrelated donor allo-SCT (clofarabine regimen, 80%, vs non-clofarabine regimen, 82%). The majority received busulfan-fludarabine based conditioning (clofarabine regimen, 70%, vs non-clofarabine regimen, 82%); two patients in each group received clofarabine as part of their conditioning program. Mean engraftment was 13.9 days in the clofarabine group and 14.5 days in the non-clofarabine group (P=0.70). Generally, no appreciable difference was observed in acute post-transplant hepatotoxicity. Median peak 30-day ALT was 81U/L (range 30–830) in the clofarabine group and 72U/L (range 16–332) in the non-clofarabine group (P=0.76); median peak 30-day bilirubin level was 0.9mg/dL (range 0.5–2.8) and 0.8mg/dL (range 0.4–3.7), respectively (P=0.86). No cases of veno-occlusive disease occurred in the clofarabine group vs one case in the non-clofarabine group (P=1.0). Incidence of acute GVHD was four cases in the clofarabine group vs nine in the non-clofarabine group (P=0.19); for liver GVHD, the total number of cases was one in each group (P=1.0). Relapse rates at 30 and 100 days did not differ between groups. At 30 days, none of the patients had died. At 100 days, 15% of patents in the clofarabine group had relapsed, compared with 18% in the non-clofarabine group (P=1.0).

Kaplan-Meier analysis of survival failed to show a deleterious effect of prior clofarabine-containing therapy in overall survival after allo-SCT. Median survival for patients exposed to prior clofarabine-containing regimens is not reached, compared with 15.8 months for those not exposed to clofarabine (P=0.07 by log-rank test and P=0.03 by Gehan-Breslow-Wilcoxon test). There were no significant differences in early death rates, defined as those being within the first 8 weeks of therapy. Study investigators concluded that use of clofarabine does not negatively impact the outcomes for younger AML patients undergoing allo-SCT.