Background:Crenolanib is a potent type 1 FLT3 inhibitor with activity both as a single agent and in combination with chemotherapy in patients (pts) with FLT3 mutant (FLT3m) acute myeloid leukemia (AML). Here we report the results from a placebo-controlled, randomized double-blind trial evaluating the efficacy and safety of crenolanib vs placebo added to salvage chemotherapy in adults with R/R FLT3m AML (NCT03250338, EudraCT no. 2017-001600-29).Materials and Methods:Fit adults with R/R FLT3m AML were randomized 1:1 to salvage induction chemo (FLAG-IDA/HAM) + crenolanib (100 mg TID) or placebo, followed by intermediate-dose cytarabine consolidation + crenolanib or placebo, and (if eligible, hematopoietic stem cell transplantation (HSCT)) followed by crenolanib or placebo monotherapy for up to 1 year. Pts were stratified by age, duration of last remission, FLT3 mutation type, prior therapies, salvage regimen and site. The primary endpoint was event-free survival (EFS), defined as the time from randomization to failure to achieve remission, relapse or death. Secondary endpoints included overall survival (OS), CR/CRi rate and safety.Patient Demographics:One hundred and six pts were enrolled across 43 sites in the US and Europe between August 2018 and March 2024. Seventy-two pts received backbone FLAG-IDA and 34 received HAM. Consolidation IDAC was administered to 29 pts, and 32 were bridged to HSCT. Fifty-two pts received crenolanib + salvage chemo and 54 received salvage chemo alone. Both arms were well balanced. The median age was 55 years (range 19–75), with 25% ≥ 65 years. Ninety-four pts had FLT3-ITD, 7 had FLT3-TKD and 5 had both ITD + TKD mutations. Out of 95 pts with known NPM1 status, 59 (62%) had co-occurring NPM1 mutations. Almost half (47%, n=50) had refractory or relapsed disease within 6 months (mos) of their last treatment. Pts were heavily pretreated: 69% (n=73) received at least one previous FLT3 TKI, 27% (n=29) received ≥2 prior therapies and 25% (n=26) received prior allogeneic HSCTs.Results:Safety:Among the 52 pts who received chemo + crenolanib, grade 3/4 adverse events of interest during induction included GI bleeding in 8 pts (15%) and LFT elevations in 8 pts (15%). There were 12 treatment-related deaths (7 on the chemo + crenolanib arm and 5 on the chemo alone arm). The causes of death were 3 sepsis, 4 pneumonia and 5 post-HSCT complications. Only 8/52 pts required crenolanib dose reductions.Efficacy:Among all 106 pts, crenolanib vs placebo added to salvage chemotherapy resulted in a higher overall response rate (CR/CRi) of 60% (31/52) vs 39% (21/54) and lower rate of refractory disease [placebo 59% (32/54) vs crenolanib 34% (18/52)]. At a median follow-up of 37.3 mos, the addition of crenolanib significantly improved the median EFS (3.4 vs 0.0 mos; HR=0.64; p-value=0.0145). There was also a numerical improvement in OS in the chemo + crenolanib arm vs chemo alone (10.4 vs 8.7 mos; HR=0.83; p-value=0.3958).Previous studies have demonstrated improved outcomes in NPM1 and FLT3 co-mutated AML pts receiving FLT3 inhibitors. Analysis of 59 NPM1/FLT3 co-mutated AML pts demonstrated an improved CR/CRi rate of 70% (23/33) with chemo + crenolanib vs 46% (12/26) with salvage chemo alone. The addition of crenolanib to chemotherapy lowered the rate of refractory disease from 54% (14/26) with chemotherapy alone to 27% (9/33) with chemo + crenolanib. Median EFS significantly improved from 0.0 mos in the chemo alone arm to 6.1 mos in the chemo + crenolanib arm (HR=0.53; p-value=0.0162). More importantly, there was a statistically significant improvement in median OS from 6.3 mos with chemo alone to 12.4 mos with chemo + crenolanib (HR=0.53; p-value=0.0314) in this subset.Conclusion:In this randomized, placebo-controlled, double-blind study, the addition of crenolanib to salvage chemotherapy met its primary endpoint, demonstrating a statistically significant improvement in EFS as well as an improved CR/CRi rate and a trend toward improved OS over chemotherapy alone in 106 fit adult pts with heavily pre-treated R/R FLT3m AML. The benefit was more pronounced in pts with NPM1/FLT3 co-mutated disease (n=59), with statistically significant improvement seen in not only remission rate and EFS but in overall survival as well. This data supports the further development of crenolanib in adults with R/R FLT3m AML, particularly those with NPM1/FLT3 co-mutated disease.

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2025
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