Abstract
Background The FMS-like tyrosine kinase 3 (FLT3) mutation affects approximately 30% of patients with acute myeloid leukemia (AML) and is associated with increased relapse and mortality. FLT3 inhibitors are known to improve survival when used in the induction, consolidation and relapsed/refractory phases of AML. However, due to their novelty, little is known about the impact of FLT3 inhibitors on graft-versus-host disease (GVHD), relapse and survival after hematopoietic stem cell transplantation (HSCT).
Methods We retrospectively analyzed adult patients treated at the University of Southern California Norris Comprehensive Cancer Center between May 2017 and July 2022. All patients had an AML diagnosis with either a FLT3-ITD or FLT3-TKD mutation, received a FLT3 inhibitor at one or more time points during their treatment course, and underwent HSCT. Our primary endpoint was graft-versus-host disease-free, relapse-free survival (GRFS). Secondary endpoints included 2-year overall survival (OS), 2-year relapse-free survival (RFS), and FLT3 inhibitor discontinuation due to adverse side effects. Acute GVHD was defined per the 2018 MAGIC criteria and chronic GVHD was defined per the 2014 NIH criteria.
Results Of the 40 patients included in this study, 30 (75%) had the FLT3-ITD mutation, and 10 (25%) had the FLT3-TKD mutation. Age at time of HSCT ranged from 30-69 years old (median= 47). Males and females were evenly represented, and most patients were Hispanic (55%). The majority of patients (67.5%) were in first complete remission (CR1) at the time of HSCT. ELN 2022 genetic risk stratification was mainly intermediate (77.5%) and adverse (15%). All patients received peripheral blood stem cells, and most (70%) underwent myeloablative conditioning regimens. All patients received a FLT3 inhibitor before HSCT, during the induction/consolidation phase or relapsed/refractory phase before achieving CR. Of the 29 patients who used maintenance therapy after HSCT, 18 (62%) received gilteritinib while 11 (38%) received midostaurin.
Using Cox survival analysis, univariate predictors of adverse events in GRFS were matched unrelated donor (MUD) when compared to haploidentical-HSCT (HR = 4.77, p=0.023), pre-transplant ATG (HR =3.99, p=0.049), and lack of maintenance FLT3 inhibitors (HR = 3.03, p = 0.034). On bivariate analysis, MUD HSCT continued to be predictive when controlling for time from induction to HSCT (Table 1, Model 2) and age at HSCT (Table 1, Model 3). Patients who received a FLT3 inhibitor for post-HSCT maintenance therapy had significantly improved OS (p = 0.033) and RFS (p=0.016) on Kaplan-Meier survival analysis, with an OS of 96.2% and RFS of 89.7% at 24 months, and an OS of 90.1% and RFS of 82.8% at 36 months. Eight patients discontinued FLT3 inhibitors at maintenance due to side effects, having a shorter length of FLT3 inhibitor use, 116 days vs. 230 days (p = 0.005).
Discussion Our results found multiple factors were associated with worsened GRFS, including MUD transplant, pre-transplant ATG and lack of maintenance FLT3 inhibitors. Post-HSCT maintenance, primarily with gilteritinib, resulted in improved OS and RFS in our patients, similar to the findings of prior studies with other FLT3 inhibitors. Amongst our patients receiving FLT3 inhibitors for maintenance, OS at 24 months was 96.2% compared to prior reports of 90.5% with sorafenib and 85% with midostaurin. RFS in our FLT3 inhibitor maintenance group was 89.7% at 24 months, compared to prior reports of 85% with sorafenib and midostaurin. OS and RFS for our FLT3 inhibitor maintenance group remained high at 36 months. Additional studies, such as the ongoing phase III clinical trial BMT CTN Protocol 1506, can be used to confirm our findings.
Disclosures
Nazaretyan:Absorption Systems Inc.: Ended employment in the past 24 months; Fate Therapeutics Inc.: Ended employment in the past 24 months; Intellia Therapeutics: Current Employment. Chaudhary:Oncotartis: Consultancy; Pancella: Consultancy; Angeles Therapeutics: Consultancy, Current equity holder in private company; Moderna: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company; Athelas: Consultancy. Yaghmour:USC: Current Employment.
OffLabel Disclosure:
Gilteritinib and midostaurin for post-SCT maintenance therapy
