| Abstract: |
BACKGROUND Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). CONCLUSIONS Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. Copyright © 2019 Massachusetts Medical Society. |
| Keywords: |
adult; cancer chemotherapy; controlled study; event free survival; treatment response; aged; aged, 80 and over; middle aged; survival analysis; treatment failure; gene mutation; major clinical study; overall survival; genetics; mutation; leukemia, myeloid, acute; fludarabine; clinical trial; constipation; fatigue; mortality; cancer recurrence; salvage therapy; cancer risk; drug efficacy; drug safety; side effect; treatment duration; antineoplastic agents; comparative study; cytarabine; follow up; follow-up studies; antineoplastic agent; low drug dose; multiple cycle treatment; pyrazines; anemia; etoposide; randomized controlled trial; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; genetic association; recurrence; drug effect; drug resistance; drug resistance, neoplasm; alanine aminotransferase blood level; coughing; drug dose escalation; dyspnea; febrile neutropenia; fever; alanine aminotransferase; alkaline phosphatase; cause of death; hypokalemia; cancer regression; liver; multicenter study; mitoxantrone; peripheral edema; remission; remission induction; recurrent disease; alkaline phosphatase blood level; headache; hazard ratio; phase 3 clinical trial; idarubicin; aniline compounds; administration, oral; granulocyte colony stimulating factor; pyrazine derivative; azacitidine; platelet count; oral drug administration; cd135 antigen; midostaurin; acute myeloid leukemia; aniline derivative; fms-like tyrosine kinase 3; flt3 gene; very elderly; humans; human; male; female; priority journal; article; gilteritinib
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