FLT3 Inhibitor Strategies Continue to Improve Survival Across AML Settings

At the 2026 Society of Hematologic Oncology (SOHO) Annual Meeting, a session titled "Choosing the Right Induction Therapy: FLT3 and Mutation Agnostic Strategies" reviewed how FLT3 inhibitors and venetoclax (Venclexta)-based combinations have progressively improved outcomes across the induction, consolidation, and maintenance phases of treatment for FLT3-mutated acute myeloid leukemia (AML).¹

The session opened with the mechanistic rationale for FLT3 inhibition, distinguishing type II inhibitors—sorafenib (Nexavar) and quizartinib (Vanflyta)—that bind the inactive receptor conformation from type I inhibitors—sunitinib (Sutent), midostaurin (Rydapt), lestaurtinib, ponatinib (Iclusig), crenolanib, and gilteritinib (Xospata)—that bind the active, ligand-bound conformation regardless of internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutation status.

Data across every phase of AML treatment demonstrated that FLT3 inhibitors improved overall survival (OS). In newly diagnosed disease, quizartinib added to intensive chemotherapy produced a hazard ratio (HR) of 0.776 (95% CI, 0.615-0.979; P = .0324) vs placebo, and midostaurin extended the median OS to 74.7 months (95% CI, 31.5-not reached [NR]) vs 25.6 months (95% CI, 18.6-42.9) with placebo (P = .009). Following allogeneic stem cell transplant (SCT), 2 studies of sorafenib maintenance each showed improved OS, including a 24-month OS rate of 90.5% (95% CI, 77%-96%) with sorafenib vs 66.2% (95% CI, 49%-79%) with placebo in one population (HR, 0.241; 95% CI, 0.08-0.74; P = .007). In the relapsed/refractory setting, gilteritinib produced a median OS of 9.3 months vs 5.6 months with salvage chemotherapy (HR, 0.665; 95% CI, 0.518-0.853; P = .0013), and quizartinib improved the median OS to 6.2 months (95% CI, 5.3-7.2) vs 4.7 months (95% CI, 4.0-5.5) with salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; P = .0177).

Results from the phase 3 QuANTUM-First trial (NCT02668653), which enrolled patients 18 to 75 years of age with FLT3-ITD-positive AML, supported the FDA approval of quizartinib alongside standard chemotherapy induction and consolidation in July 2023.^2,3 Quizartinib improved the median OS to 31.9 months vs 15.1 months with placebo, representing a 16.8-month absolute improvement corresponding with a 22.4% reduction in the risk of death (HR, 0.776; 95% CI, 0.615-0.979; P = .0324). A subsequent analysis by hematopoietic cell transplantation (HCT) status showed that patients receiving quizartinib had longer OS regardless of whether they underwent allogenic HCT in first complete remission (CR1); among those who did not receive allogenic HCT in CR1, the median OS was not reached (NR) with quizartinib vs 14.2 months (95% CI, 11.2-35.4) with placebo (HR, 0.579; 95% CI, 0.353-0.949).

Additional data indicated that in patients with co-occurring NPM1 and FLT3-ITD mutations, postinduction measurable residual disease (MRD) status can help guide the decision to proceed to HCT: MRD-positive status after induction favored a survival benefit from CR1 allogenic SCT (HR, 0.52; 95% CI, 0.29-0.93), while MRD-negative status suggested HCT could be safely deferred (HR, 0.80; 95% CI, 0.37-1.72).

Ongoing efforts to refine induction therapy selection include the phase 3 HOVON156/AMLSG28-18/PASHA (NCT04027309) trial, a multicenter, open-label study being conducted at 193 sites across 12 countries in Europe plus Australia that is randomly assigning adults with FLT3-mutated newly diagnosed AML or higher-risk myelodysplastic syndrome 1:1 to induction and consolidation with either gilteritinib or midostaurin, followed by up to 1 year of maintenance with the same agent.⁴ OS is the primary end point, and event-free survival, CR rate after induction, and modified event-free survival are key secondary end points.

FLT3 inhibitors are now considered a standard component of maintenance therapy with or without HCT per NCCN guidelines, with gilteritinib preferred following allogenic HCT for FLT3-ITD disease in CR1 without MRD negativity by ultrasensitive assay pretransplant, and quizartinib preferred for patients with a history of FLT3-ITD who previously received a FLT3 inhibitor but are not planned for allogenic HCT. The latter recommendation is supported by data showing that quizartinib continuation therapy in patients who did not undergo allogenic SCT improved median OS (NR) vs 42.5 months with placebo, reflecting a roughly 60% reduction in the risk of death (HR, 0.401; 95% CI, 0.192-0.838). Taken together, these advances, alongside improvements in remission-induction chemotherapy backbones and access to allogenic HCT, have raised 3- to 5-year OS rates in frontline young/fit FLT3-ITD-positive AML to 65% to 75%, compared with 20% to 25% approximately 15 years ago.

“In the last 15 years, there’s been a dramatic amount of progress in the treatment of young [patients with] FLT3-mutations ,” presenting investigator Naval Daver, MD, professor and director of the Leukemia Research Alliance Program in the Department of Leukemia at MD Anderson Cancer Center, stated in the presentation. “[This] is one of the reasons the FDA did not want to move quickly with [approval for a hypomethylating agent (HMA), venetoclax, and gilteritinib]; with all the changes we have done with [alternatives], we are close to a 65% to 75% [3-year OS rate]…We have to be cautious as we introduce new treatments.”

For older or unfit patients with AML, the session also focused on ongoing research at MD Anderson Cancer Center from 2020 to 2025. Outcomes with azacitidine (Vidaza) plus gilteritinib in the phase 3 LACEWING trial (NCT02752035) were compared against azacitidine plus venetoclax in the FLT3-mutated subgroup of VIALE-A (NCT02993523).⁵ In LACEWING, the composite complete remission (CRc) rate was 58.1% with gilteritinib plus azacitidine vs 26.5% with azacitidine alone, though the median OS did not differ significantly (9.82 vs 8.87 months; HR, 0.916; 95% CI, 0.529-1.585; P = .753). In the VIALE-A FLT3-ITD subgroup, CR plus CR with incomplete count recovery (CRi) rates were 63.3% with venetoclax plus azacitidine vs 46.2% with azacitidine alone. Venetoclax plus gilteritinib was positioned as a backbone for a frontline triplet, with salvage data showing that the combination produced a modified CRc (mCRc) rate of 75% among all patients with FLT3-mutated disease (80% among those with prior FLT3 inhibitor exposure), compared with a 54.3% CRc rate reported for single-agent gilteritinib in the phase 3 ADMIRAL trial (NCT02421939) using the same response parameters.

Building on this backbone, data from an MD Anderson study of azacitidine plus venetoclax plus gilteritinib as frontline triplet therapy in FLT3-mutated AML (n = 30), designed to preserve healthier marrow reserve, showed a CR rate of 92% and a CR plus CRi rate of 96%, with 65% of patients achieving FLT3 MRD negativity at a sensitivity of 10^–5. The median OS was NR, with 6-month and 1-year OS rates of 96% and 85%, respectively, comparing favorably with a historical azacitidine/venetoclax cohort showing a median OS of 13.3 months (95% CI 8.4-23.5) with the combination vs 8.6 months (95% CI, 5.9-14.7) with placebo/azacitidine.

The ongoing phase 1/2 VICEROY trial (NCT05520567), a multicenter frontline optimization study of azacitidine, venetoclax, and gilteritinib in adults with newly diagnosed FLT3-mutated (ITD or TKD) AML, is further testing this triplet approach. Interim efficacy data comparing 2 venetoclax dose levels (200 mg vs 400 mg) showed similar CRc rates (90% vs 91%) and median OS (23 vs 22 months), suggesting the lower venetoclax dose may achieve comparable efficacy within the triplet regimen.

References

1. Daver N. Choosing the right induction therapy: FLT3 and mutation agnostic strategies. Presented at: 2026 Society of Hematologic Oncology (SOHO) Annual Meeting; September 9-12, 2026; Houston, TX.
2. Erba HP, Montesinos P, Kim H-J, et al. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10388):1571-1583. doi:10.1016/S0140-6736(23)00464-6
3. FDA approves quizartinib for newly diagnosed acute myeloid leukemia. News release. FDA. July 20, 2023. Accessed September 9, 2026. https://tinyurl.com/4nr4sjbw
4. A study of gilteritinib versus midostaurin in combination with induction and consolidation therapy followed by one-year maintenance in patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndromes with excess blasts-2 with FLT3 mutations eligible for intensive chemotherapy (HOVON 156 AML). ClinicalTrials.gov. Updated December 17, 2026. Accessed September 9, 2026. https://tinyurl.com/bdd4x7z5
5. Wang ES, Montesinos P, Minden MD, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood. 2022;140(17):1845-1857. doi:10.1182/blood.2021014586