High FLT3-ITD Allelic Ratio Not Tied to Worse OS in AML in BIG-1 Data

In younger adults with acute myeloid leukemia (AML) carrying an FLT3 internal tandem duplication (FLT3-ITD), a high ratio of mutant to wild-type FLT3 alleles was not associated with worse remission or survival outcomes after high-dose anthracycline induction, according to a post hoc analysis of the French BIG-1 study (NCT02416388) published in the American Journal of Hematology.¹

In multivariable models, only midostaurin (Rydapt; Novartis) exposure (lower mortality) and adverse-risk disease under the European LeukemiaNet 2022 (ELN-2022) classification (higher mortality) independently predicted OS. Median overall survival (OS) was 6.9 years among patients with a high allelic ratio (AR) and 7.6 years among those with a low AR, and the AR did not reach significance for any end point.

Allelic Ratio and ELN Risk Classification in FLT3-ITD AML

FLT3-ITD mutations occur in 20% to 30% of AML cases, the authors noted. Under the 2017 ELN guidance, the AR (using a 0.5 cutoff) and NPM1 status sorted these patients into favorable, intermediate, or adverse risk. The 2022 update dropped the AR, citing poor assay standardization, the benefit of FLT3 inhibitors, and the growing role of measurable residual disease, and now places FLT3-ITD AML without favorable- or adverse-risk cytogenetic abnormalities in intermediate risk.

Midostaurin was approved by the FDA in April 2017 for newly diagnosed FLT3 mutation–positive AML based on the phase 3 RATIFY trial (NCT00651261), in which its survival benefit held across FLT3 subtypes, including high- and low-ratio ITD.^2,3 Still, the authors wrote, it was unclear whether patients with a high AR and wild-type NPM1 fare as well as others in the intermediate-risk group with high-dose anthracyclines plus an FLT3 inhibitor.¹

BIG-1, a prospective multicenter trial run by the Acute Leukemia French Intergroup, enrolled a total of 2023 adults aged 18 to 60 years with newly diagnosed AML from January 2015 through July 2021. Induction paired cytarabine with high-dose daunorubicin (90 mg/m² per day for 3 days) or idarubicin (9 mg/m² per day for 5 days). After a June 2018 protocol amendment, patients with FLT3 mutations also received midostaurin 50 mg twice daily on days 8 through 21 of each course, plus up to 1 year of maintenance if they did not undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Of 459 FLT3-ITD–positive patients (median age, 49.9 years), 186 (40.5%) had a high AR, and 153 (33.3%) received midostaurin.

Survival Outcomes by FLT3-ITD Allelic Ratio

Composite complete remission after 1 course was 79.6% with a high AR and 81.7% with a low AR (P = .85). Five-year OS was 51% vs 58% (P = .25), and median relapse-free survival (1.7 vs 2.0 years; P = .50) and event-free survival (1.2 vs 1.4 years; P = .58) did not differ. After adjustment, a high AR was not associated with OS (adjusted HR [aHR], 1.17; 95% CI, 0.86-1.58; P = .31), whereas midostaurin (aHR, 0.69; 95% CI, 0.50-0.95; P = .02) and adverse ELN-2022 risk (aHR, 1.66; 95% CI, 1.18-2.34; P = .004) were. Results were similar with allo-HSCT modeled as a time-varying covariate and with AR analyzed as a continuous measure.

The AR had no prognostic effect whether or not patients received midostaurin.

“This suggests that the benefit of midostaurin is not fully responsible for wiping out the prognostic value of FLT3-ITD AR,” the authors wrote, suggesting that the high-dose anthracycline backbone, a high transplant rate (70.2%), and wider use of gilteritinib (Xospata; Astellas Pharma) at relapse may have contributed.

The study was a post hoc analysis, and midostaurin use was uneven: 40.3% of patients with a high AR received it vs 28.6% with a low AR (P = .009), possibly because clinicians reserved it for more aggressive disease. The findings may also be specific to high-dose anthracyclines; a high AR retained prognostic value in a German-Austrian phase 2 trial that used daunorubicin 60 mg/m² per day,⁴ and the AR’s effect with hypomethylating agents plus venetoclax (Venclexta; Genentech, Abbvie) has not been evaluated.¹

“These results support the removal of FLT3-ITD AR from the most recent ELN-2022 prognostic classification,” the authors concluded, adding that future studies of new drug combinations should still evaluate the AR.

References

1. Leclerc M, Audureau E, Duployez N, et al. Prognostic impact of FLT3-ITD allelic ratio in AML patients treated with high-dose anthracycline and a FLT3 inhibitor. Am J Hematol. Published online October 26, 2026. doi:10.1002/ajh.70540

2. Midostaurin. FDA. Updated 2017. Accessed November 11, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/midostaurin

3. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359

4. Döhner H, Weber D, Krzykalla J, et al. Midostaurin plus intensive chemotherapy for younger and older patients with AML and FLT3 internal tandem duplications. Blood Adv. 2022;6(18):5345-5355. doi:10.1182/bloodadvances.2022007223