FLT3-ITD Allelic Ratio and Response to Midostaurin-Based Induction in Newly Diagnosed Acute Myeloid Leukemia

Abstract

The FLT3-ITD allelic ratio was central to risk classification for five years and has now been removed from it. The trial that established midostaurin as standard of care had already shown that benefit did not track the ratio, and the measurement proved too poorly reproducible between laboratories to survive. Objectives: To review the published evidence on the FLT3-ITD allelic ratio in newly diagnosed acute myeloid leukaemia: what it predicted before FLT3 inhibition, how midostaurin benefit distributed across ratio subgroups, why it was withdrawn from risk classification, and what has replaced it. Material and Methods: Narrative review of randomised trials, correlative analyses, consensus classifications and validation studies indexed in PubMed and the
major haematology journals. Studies were eligible if they reported outcomes stratified by FLT3-ITD allelic ratio, the effect of FLT3-directed therapy in defined mutation subgroups, or the performance of risk classifications incorporating the ratio. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators. Results: In the randomised trial of 717 patients that established midostaurin, median overall survival was 74.7 months against 25.6 months with placebo (HR 0.78, 95% CI 0.66-0.93). Benefit was similar across mutation subgroups, with hazard ratios of 0.65 (95% CI 0.39-1.08) for FLT3-TKD, 0.81 (0.60-1.11) for low allelic ratio ITD and 0.80 (0.57-1.12) for high allelic ratio ITD, so the ratio did not identify who benefited. The 2017 classification had defined four NPM1/FLT3-ITD genotypes using a ratio cutoff of 0.5, and retrospective analysis confirmed both that these genotypes separated survival and that midostaurin benefited all three resulting risk groups. Five-year survival on midostaurin was 73, 52 and 43 per cent in favourable, intermediate and adverse groups. The 2022 revision removed the allelic ratio entirely, citing limited reproducibility, and now assigns all FLT3-ITD disease to intermediate risk irrespective of ratio or NPM1 status. Conclusion: The allelic ratio was prognostic in the era before FLT3 inhibition and is no longer used, for two independent reasons: midostaurin benefit does not depend on it, and the measurement itself cannot be reproduced reliably enough between laboratories to bear clinical weight. Abbreviations: AML – Acute Myeloid Leukaemia, FLT3 – FMS-Like Tyrosine Kinase 3, ITD – Internal Tandem Duplication, TKD – Tyrosine Kinase Domain, AR – Allelic Ratio, NPM1 – Nucleophosmin 1, ELN – European LeukemiaNet, MRD – Measurable Residual Disease, alloHCT – Allogeneic Haematopoietic Cell Transplantation, CR1 – First Complete Remission, OS – Overall Survival, EFS – Event-Free Survival, TKI – Tyrosine Kinase Inhibitor.