Cytomolecular mechanisms of relapse after frontline FLT3 inhibitor (FLT3i)-based therapy in FLT3-mutated (mut) acute myeloid leukemia (AML).

6539 Background: Data regarding the mechanisms of relapse and outcomes with salvage therapies in patients (pts) with FLT3 mut AML after frontline FLT3i-based therapy are limited. Methods: This is a retrospective study of pts with FLT3 mut AML who received frontline FLT3i-based therapy at our institution. Molecular and cytogenetic (CG) testing was compared between diagnosis and relapse. Results: 272 pts received frontline treatment with FLT3i from 9/2013-7/2024: 214 FLT3 ITD , 27 FLT3 ITD+TKD and 31 FLT3 TKD . Induction therapy was intensive chemotherapy (IC) in 107 pts and low intensity therapy (LIT) in 165 pts [including HMA+venetoclax(VEN)+FLT3i in 93 pts]. FLT3i's used were gilteritinib (n=105), sorafenib (n=96), quizartinib (n=54), midostaurin (n=16), and crenolanib (n=1). Composite complete remission (CRc = CR + CRi) was attained in 203 pts (75%). 97 pts (36%) underwent allogenic stem cell transplant (ASCT) in 1st remission. After a median (med) follow-up of 46 months (mos), 80 pts (35% of responders) relapsed. Post-ASCT relapses occurred in 22/97 pts (23%). Relapse rates in pts receiving IC+FLT3i, HMA+VEN+FLT3i, and LIT+FLT3i (no VEN) were 23% (p<0.01), 31% (p<0.01), and 65% (ref), respectively. At relapse, loss of a FLT3 mut (ITD and/or TKD) was noted in 34/72 tested pts (47%), with similar rates among transplanted and non-transplanted pts. FLT3 loss at relapse was more common in pts who received IC+FLT3i or HMA+VEN+FLT3i vs LIT+FLT3i (no VEN): 57% vs 32% (p=0.05). Among 55 pts with comprehensive molecular testing at relapse, 24 (44%) had a newly detectable non- FLT3 mut , most commonly RAS pathway (8, 15%), WT1 (7, 13%), TET2 (4, 7%), and IDH1/2 (4, 7%). New mutations at relapse were less common in post-ASCT pts (19% vs 59%; p<0.01). Among FLT3 ITD pts, new FLT3 TKD mut at relapse occurred in 8/58 tested pts (14%): 7 had received frontline type 2 FLT3i. New CG abnormalities at relapse occurred in 27/65 tested pts (42%), most commonly trisomy in 11 pts (17%). No BCR::ABL1 was observed at relapse. 51 pts received 1st salvage therapy after relapse (22 FLT3 wt and 29 FLT3 mut relapses). FLT3 wt relapses had higher CRc rates (41% vs 10%, p=0.02), and a trend to higher med OS (8.6 mos vs 5.7 mos, p=0.13) with salvage therapy compared with FLT3 mut relapses. Conclusions: Loss of FLT3 mut at relapse occurred in almost 50% of pts receiving frontline FLT3i and was more common in pts receiving IC+FLT3i or HMA+VEN+FLT3i. Common mechanisms of clonal evolution included emergent mutations in RAS pathway, WT1 , and DNA methylation genes ( TET2 , IDH1/2 ). Mutational clonal evolution was less frequent in post-ASCT relapses. Persistent FLT3 mut at relapse was associated with a worse prognosis.