Long-term results of a phase 2 trial of crenolanib combined with 7+3 chemotherapy in adults with newly diagnosed FLT3 mutant AML.
Authors: Wang Eunice S. , Goldberg Aaron David , Walter Roland B. , Collins Robert , Stone Richard M. 
Published: June 2022

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Background: Crenolanib is a potent type I FLT3 inhibitor active against FLT3- ITD, TKD and variant mutations. We report the long-term outcomes of a phase II trial evaluating crenolanib combination therapy in patients (pts) with newly diagnosed FLT3 mutant AML. Methods: Pts (≥ 18 yrs) with newly diagnosed FLT3-AML received 7+3 induction with cytarabine 100 mg/m2/d for 7 days and daunorubicin (DNR) (<60 yrs: 90 mg/m2; ≥60 yrs: 60 mg/m2) or idarubicin (IDA 12 mg/m2) for 3 days. Crenolanib 100 mg TID was administered starting on day 9 until 72 hrs prior to next chemotherapy. Re-induction was allowed. Up to 4 cycles of HiDAC consolidation (<60 yrs: 3 g/m2; ≥60 yrs: 1g/m2) was allowed. Eligible pts could proceed to transplant. Crenolanib maintenance therapy was offered for 1 yr after HiDAC or transplant. Results: 44 pts (22 male) with a median age of 57 yrs (range 19-75) were treated; 15 (34%) pts were >60 yrs. 7 pts had initial WBC >100,000/μL (2 had WBC >200,000). 4 pts had AML following MDS/MPN. 39 (89%) pts had intermediate risk cytogenetics, 3 (7%) had adverse risk, and 2 were unavailable. 33 (75%) pts had FLT3-ITD, 8 (18%) had TKD, and 3 (7%) had ITD and TKD mutations. 11 pts had concomitant NPM1/ DNMT3A mutations, 11 pts had secondary AML-type mutations, and 2 pts had TP53. 28 pts received DNR/crenolanib; 16 pts received IDA/crenolanib. Overall CRc (CR + CRi) was 73% (32/44) after one induction cycle; 86% (38/44) after two cycles. CRc rates > 80% were noted in pts ≤ 60 yo, FLT3-ITD mutations, concomitant FLT3/DMT3A/NPM1 mutations, intermediate risk cytogenetics, and WBC ≥ 100,000/µL. Median time to count recovery was 30 days. MRD-negative CRc was achieved in 94% of evaluable pts (17); 22 pts underwent HSCT. The most common treatment related adverse events (AE) were diarrhea (66%), nausea (57%) and febrile neutropenia (52%). Grade ≥3 AE included febrile neutropenia (50% pts), diarrhea (18%), nausea (6%), and rash (6%). No QTC prolongation was observed. 6 pts required crenolanib dose reduction during induction. High levels of serum crenolanib were achieved and maintained throughout therapy. With a median follow-up of 45 mos (4.4-54.9), the median OS for all pts has not been reached with 57% of pts alive. Median EFS for all pts was 45 mos. In younger pts (≤ 60 yo) OS was 69% and EFS 62%. Cumulative incidence of relapse was 15%. In older pts (61-75), 80% achieved CR/CRi, and median OS was 20 mos. Mutational analysis demonstrated clearance of multiple variant FLT3 mutations and no new FLT3 clones at relapse in pts completing protocol therapy. Conclusions: Long-term outcomes of a phase 2 trial of crenolanib combined with 7+3 induction and consolidation in adults with newly diagnosed FLT3 mutant AML demonstrate high response rates (CRc 86%). With a median follow-up of 45 mos, median OS has not been reached. A phase 3 trial (NCT03258931) randomizing pts with newly diagnosed FLT3 mutant AML to crenolanib vs midostaurin with 7+3 is ongoing. Clinical trial information: NCT02283177.