Abstract / Summary
Older or medically unfit patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) have poor outcomes with hypomethylating agent (HMA) monotherapy. Venetoclax plus HMA is a modern lower-intensity standard, but FLT3-mutated AML remains biologically heterogeneous, and triplet regimens combining HMA, venetoclax, and a FLT3 inhibitor are increasingly used despite limited randomized comparative evidence. PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science, Scopus, and major hematology/oncology conference proceedings were searched from inception to 12 June 2026 in accordance with PRISMA 2020 and MOOSE guidance. Eligible studies reported primary clinical outcomes for newly diagnosed FLT3-ITD and/or FLT3-TKD AML treated with frontline lower-intensity HMA alone, VEN-HMA doublet, HMA/LIC plus FLT3 inhibitor, or HMA/LIC plus VEN plus FLT3 inhibitor therapy. Comparative effect estimates and single-arm proportions were synthesized only when clinical and statistical assumptions were defensible. Thirteen eligible records were retained. Direct VEN + AZA versus AZA evidence came from one FLT3-mutated pooled subgroup comparison (42 vs. 22 patients), showing CRc 67% versus 36%, RR 1.83 (95% CI 1.01-3.32), and median OS 12.5 versus 8.6 months. The randomized non-venetoclax LACEWING trial showed higher CRc with gilteritinib + AZA than AZA (58.1% vs. 26.5%; HR for OS 0.916; p = 0.753), illustrating that improved remission does not guarantee survival benefit. The principal comparative triplet evidence was one retrospective study: CR/CRi 93% versus 70%, RR 1.32 (95% CI 1.09-1.61), with median OS not reached versus 9.5 months. Prospective and long-term triplet reports described CR/CRi rates of 93%-96%, deep FLT3-ITD MRD negativity, and median OS up to 38.5 months; several reports derive from overlapping institutional series and non-randomized designs, limiting independent corroboration and causal inference. VEN + AZA improves remission compared with AZA in the FLT3-mutated subgroup, but the evidence base is underpowered for FLT3-specific survival conclusions. Triplet therapy produces the strongest remission-depth and MRD signals but has not shown superiority over VEN-HMA in a randomized frontline comparison. On current evidence, triplets are a promising biologically rational strategy requiring direct randomized validation against the contemporary VEN-HMA standard.