Eunice S. Wang, MD, on AML: Long-Term Results With Crenolanib Plus Chemotherapy

We designed a phase II clinical trial evaluating crenolanib added to standard 7+3 intensive chemotherapy for adults with newly diagnosed FLT3 AML. The purpose of this study was to examine the efficacy of adding this novel FLT3 tyrosine kinase inhibitor to standard intensive chemotherapy based on prior results of single agent crenolanib activity in heavily pretreated relapse and refractory FLT3 mutant adult patients. Crenolanib is a pan-FLT3 inhibitor with activity against both the active and inactive formations of FLT3 and has activity against both FLT3, ITD, and TKD mutations. We designed this study to combine it with intensive chemotherapy, for which the standard of care is currently midostaurin plus 7+3 chemotherapy. A total of 44 patients were enrolled on this study, 29 younger than equal to 60 years of age, and 15 older than 60 years of age. 91% of patients had de novo disease, 75% with FLT3 ITD mutations and 18% with TKD mutations. Overall, patients were enrolled in standard intensive therapy with physicians choice of anthracycline, daunorubicin, or idarubicin plus infusional cytarabine for 7 days, followed by crenolanib started at 24 to 48 hours after chemotherapy and continued until 72 hours prior to next chemotherapy cycle. Patients were allowed to get consolidation with high-dose cytarabine or go on to transplantation, followed by 12 months of maintenance crenolanib following either chemo or transplant. The overall remission rate in this trial was 86%. Younger patients younger than are equal to 60 years of age had a CR/CRI rate of 90%, and individual's greater than or equal to 60 years of age had an overall response rate of 80%. At 45 months of long-term follow up, the event-free survival for all 44 patients enrolled in this trial was 45 months. The median overall survival was not reached. In younger patients younger than 60 years of age, the median overall survival was not reached, with 71% of patients alive at 3 years after enrollment on this study. The overall cumulative rate of relapse in patients was 33%, and 15% in patients younger than 60. Of note, patients undergoing transplantation in this younger cohort had similar cumulative rate of relapse than patients getting chemotherapy alone. In conclusion, we think that this combination regimen shows high efficacy, safety, and tolerability as compared to standard 7+3 plus midostaurin. A phase III trial of this combination approach is currently accruing using midostaurin 7+3 as its control arm. Results of this trial are eagerly awaited.