An emerging triplet option for newly diagnosed FLT3-mutated acute myeloid leukemia

FLT3 inhibitors represent a critical component of intensive induction chemotherapy regimens for newly diagnosed FLT3-mutated acute myeloid leukemia (AML).^1,2 However, there is currently no clear standard of care for older and unfit patients with FLT3-mutated AML. The phase III RATIFY trial, which established midostaurin plus standard chemotherapy as first-line treatment for AML with FLT3 mutations, did not include patients 60 years or older.² In the phase III QuANTUM-First trial, which evaluated quizartinib plus standard chemotherapy in patients up to the age of 75 years with FLT3-internal tandem duplication (ITD)-mutated AML, the survival benefit conferred by addition of quizartinib was not observed in those aged 60-75 years in subgroup analysis.¹ In light of this, the optimal therapeutic approach in older and unfit patients with FLT3-mutated AML warrants further investigation.

The hypomethylating agent (HMA) azacitidine plus venetoclax confers high initial rates of remission in older and unfit patients with newly diagnosed FLT3-mutated AML.³ However, FLT3-ITD mutations represent a major mechanism of adaptive resistance, with FLT3-ITD clonal expansion leading to shorter response duration and inferior overall survival (OS).⁴ The median OS of AML patients with FLT3-ITD mutations treated with a HMA and venetoclax is 9.9 months compared with 14.7 months among FLT3 wild-type patients.⁵ Due to this decreased durability of remission, the European LeukemiaNet (ELN) 2024 genetic risk classification for AML patients treated with non-intensive therapy categorizes FLT3-ITD mutations as intermediate risk.⁶ FLT3 mutations lead to MCL-1 and BCL-xL overexpression, decreasing the efficacy of venetoclax-mediated BCL-2 inhibition. Preclinical data suggest that this adverse impact of FLT3 mutations may be overcome by the combination of FLT3 inhibitors and BCL-2 inhibitors.⁷, ⁸ Recent phase I/II clinical studies have shown remarkably high (>90%) rates of remission in FLT3-mutated AML treated with frontline HMA, venetoclax, and FLT3 inhibitors, but interpretation of these studies has been limited by relatively short follow-up.^9,10

In this issue of Haematologica, Short et al. provide a retrospective analysis of long-term outcomes of AML patients with FLT3 mutations treated with frontline HMA, venetoclax, and FLT3 inhibitor triplets.¹¹ Given the very high initial remission rates seen with these combinations, long-term outcome data have been urgently awaited to assess the response durability (Table 1). The median age of the patient population studied is 70 years, with 36% of patients ≥75 years old, making the work highly relevant for patients with AML in whom the median age at diagnosis is 68 years. Here, Short et al. demonstrate encouraging 3-year relapse-free survival (RFS) and OS outcomes with HMA, venetoclax, and FLT3 inhibitors, particularly in patients with FLT3-tyrosine kinase domain (TKD) mutations in whom 3-year RFS and OS rates were high at 76%. FLT3-ITD-mutated patients had less durable responses with 3-year RFS and OS rates of 38% and 45%, respectively, as well as shorter median OS compared to FLT3-TKD-mutated AML (28.1 vs. 39.3 months). While allogeneic stem cell transplant (SCT) in first remission improves survival in FLT3-mutated AML and is recommended for fit patients, allogeneic SCT in first remission did not significantly affect OS in this study population.⁶ Despite patients undergoing allogeneic SCT in first remission being significantly younger than those who did not undergo transplantation (median age: 67 years vs. 72 years; P=0.001), 3-year OS was comparable (55% vs. 61%; P=0.49), as was relapse rate (20% vs. 28%; P=0.45). Allogeneic SCT similarly did not improve survival in patients <75 years old, FLT3-ITD-mutated AML, or ELN 2022 adverse-risk disease. While these findings may reflect higher rates of transplant-related mortality in this older population, allogeneic SCT can still be considered for select patients, potentially informed by measurable residual disease (MRD) evaluation and future randomized studies.

Table 1.Summary of clinical outcomes with hypomethylating agent, venetoclax, and FLT3-inhibitor triplet regimens in the overall, FLT3-ITD, and FLT3-TKD mutated cohorts.

Figure 1.Mechanisms of resistance to FLT3-inhibitor regimens. Clonal evolution and progression with FLT3 wild-type disease is an important mechanism of resistance to therapy. Further, development of RAS pathway mutations mediates resistance to FLT3-inhibitor monotherapy as well as venetoclax-based regimens.

Short et al. demonstrate that FLT3-ITD MRD retains its prognostic importance in triplet-treated patients. Patients with FLT3-ITD MRD positivity (MRD⁺) by next-generation sequencing by cycle 4 had significantly poorer 2-year RFS and OS compared to those who were MRD-negative (MRD^–) (RFS 62% vs. 20%; OS 73% vs. 40%). This is similar in concept to work done characterizing the prognostic significance of NPM1 molecular MRD for patients treated with HMA plus venetoclax or low-dose cytarabine plus venetoclax, among whom patients with bone marrow MRD^– for NPM1 by reverse transcription quantitative polymerase chain testing by the end of cycle 4 had a 2-year OS of 84% compared with 46% if MRD⁺.¹²

Notably, the work by Short et al. also highlights mechanisms of resistance to HMA, venetoclax, and FLT3 inhibitor triplets (Figure 1). Specifically, RAS pathway mutations were associated with decreased duration of response, just as they serve as a mechanism of resistance when FLT3 inhibitors are given as monotherapy and in venetoclax-based regimens.^13,14 Indeed, 3-year OS among those with baseline RAS pathway mutations was 22% compared to 63% among those without RAS pathway mutations. Furthermore, clonal evolution and progression with FLT3 wild-type disease serves as another mechanism of therapeutic resistance, with 65% of relapses in this study driven by outgrowth of FLT3 wild-type clones.

Although the long-term data presented by Short et al. are encouraging, the true impact of adding a FLT3 inhibitor to HMA and venetoclax will only be shown in randomized studies. Notably, the phase III LACEWING trial of gilteritinib plus azacitidine versus azacitidine for patients with newly diagnosed FLT3-mutant AML ineligible for intensive chemotherapy failed to show an OS benefit.¹⁵ Randomized data are needed to prospectively compare outcomes for FLT3-mutated AML treated with HMA, venetoclax, and FLT3 inhibitor triplet therapy versus HMA and venetoclax doublet therapy to further characterize responses, survival, and the impact of MRD and allogeneic SCT. Triplet regimens are notably myelosuppressive, and future studies will also need to optimize dosing schedules including the duration of venetoclax and FLT3 inhibitors with each cycle, and the use of growth factors. In the study by Short et al., granulocyte colony-stimulating factor was given to 58% of responders (42/72) in cycle 1. Ongoing randomized trials include a phase II NCI-sponsored MyeloMATCH study of azacitidine and venetoclax versus azacitidine, venetoclax and gilteritinib in older and unfit patients with newly diagnosed FLT3-mutated AML (NCT06317649), as well as a phase I/II randomized dose-ranging and expansion study of azacitidine, venetoclax and gilteritinib in patients with newly diagnosed FLT3-mutated AML ineligible for intensive chemotherapy (NCT05520567).

Footnotes

• Received October 24, 2025
• Accepted November 3, 2025

Correspondence

A.D. Goldberg goldbera@mskcc.org

Disclosures

ADG has participated in advisory boards and/or provided consultancy services for AbbVie, Astellas Pharma, Bristol-Myers Squibb, Cardinal Health, Ikena Oncology, IntrinsiQ, Molecular Partners, Remedy Plan Therapeutics and Syndax; has received honoraria from DAVA Oncology, OncLive and Plexus Communications; has received research funding from AbbVie, Aprea, Aptose, AROG, Celularity, Kura, Pfizer and Prelude and has served on data safety monitoring committees for AbbVie and Kura. LB has no conflicts of interest to disclose.

Contributions

LB and ADG co-wrote the editorial.