Crenolanib plus salvage chemotherapy improves outcomes in FLT3-mutant and NPM1 co-mutated relapsed/ refractory (R/R) Acute Myeloid Leukemia (AML): Results from a randomized, placebo-controlled, double-blind trial
Year: 2025
Type: conference-abstract
Abstract: 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.
Source: Blood
Authors: Thomas Cluzeau, Pierre Yves Dumas, Pau Montesinos, Gaia Ciolli, Céline Berthon, Felicetto Ferrara, Adriano Venditti, José Antonio Pérez-Simón, Maria Calbacho, Richard Noppeney, Monia Lunghi, Chiara Cattaneo, Fabrizio Pane, Francesco Lanza, Juan Miguel Bergua Burgues, Alessandro Isidori, Yngvar Floisand, Vinay Jain, Eunice Wang
Institutions: Centre Hospitalier Universitaire de Nice, Centre Hospitalier Universitaire de Bordeaux, Hospital Universitari i Politècnic La Fe, Azienda Ospedaliero-Universitaria Careggi, Centre Hospitalier Universitaire de Lille, Ospedale Antonio Cardarelli, University of Rome Tor Vergata, Hospital Universitario Virgen del Rocío, Research Institute Hospital 12 de Octubre, Krankenhaus der Barmherzigen Brüder Trier, Azienda Ospedaliero Universitaria Maggiore della Carita, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, University of Naples Federico II, Ospedale "Santa Maria delle Croci" di Ravenna, Hospital San Pedro de Alcántara, Arog Pharmaceuticals (United States), Roswell Park Comprehensive Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417001909