Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML.

Abstract

Crenolanib is a second-generation tyrosine kinase inhibitor with activity against <i>FLT3-ITD</i>- and <i>TKD</i>-mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed <i>FLT3</i>-mutant AML. Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m²) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m² or idarubicin 12 mg/m², once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m² twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant. Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had <i>FLT3-ITD</i>, and 11 had <i>FLT3-TKD</i> mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new <i>FLT3</i>-mutant clones were detected at relapse in patients completing consolidation. Crenolanib plus intensive chemotherapy in adults with newly diagnosed <i>FLT3</i>-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.