Citations

Abstract In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

Purpose Decitabine, a DNA-targeted hypomethylating agent, is approved by the United States Food and Drug Administration for treatment of patients with myelodysplastic syndromes (MDS) on a schedule of 15 mg/m2 administered via intravenous (IV) infusion every 8 hours for 3 days. This study assessed the efficacy and safety of an alternative dosing regimen administered on an outpatient basis in academic and community-based practices. Patients and Methods Patients were treated with decitabine 20 mg/m2 by IV infusion daily for 5 consecutive days every 4 weeks. Eligible patients were ≥ 18 years of age and had MDS (de novo or secondary) of any French-American-British (FAB) subtype and an International Prognostic Scoring System (IPSS) score ≥ 0.5. The primary end point was the overall response rate (ORR) by International Working Group (IWG 2006) criteria; secondary end points included cytogenetic responses, hematologic improvement (HI), response duration, survival, and safety. Results Ninety-nine patients were enrolled; the ORR was 32% (17 complete responses [CR] plus 15 marrow CRs [mCRs]), and the overall improvement rate was 51%, which included 18% HI. Similar response rates were observed in all FAB subtypes and IPSS risk categories. Among patients who improved, 82% demonstrated responses by the end of cycle 2. Among 33 patients assessable for a cytogenetic response, 17 (52%) experienced cytogenetic CR (n = 11) or partial response (n = 6). Conclusion Decitabine given on a 5-day schedule provided meaningful clinical benefit for patients with MDS, with more than half demonstrating improvement. This suggests that decitabine can be administered in an outpatient setting with comparable efficacy and safety to the United States Food and Drug Administration–approved inpatient regimen.