The role of combination strategies in the treatment of FLT3-mutated acute myeloid leukemia

During the latest AML Hub Steering Committee Meeting on August 11, 2026, key opinion leaders met to discuss the role of combination strategies in the treatment of FLT3-mutated (FLT3m) acute myeloid leukemia (AML). The meeting opened with a presentation by Gail J. Roboz, followed by a discussion featuring Agnieszka Wierzbowska, Charles Craddock, Jorge Sierra, Lars Bullinger, and Roland Walter.

Roboz reviews the rationale for combination strategies in FLT3m AML (Figure 1),^1,2 and discusses updates presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, May 29 – June 2, 2026, Chicago, US, and the European Hematology Association (EHA) 2026 Congress, June 11–14, 2026, Stockholm, SE. She considers potential future directions for FLT3 inhibitor-based combination strategies (Figure 2),^1,3–6 followed by a discussion focused on how best to translate high remission rates into durable disease control and long-term outcomes. The steering committee also explores how treatment strategies may need to be individualized according to patient fitness, molecular profile, treatment response, and access to available therapies.

Key points

• FLT3 inhibitors are an integral component of treatment for patients with FLT3m AML, with combination strategies being evaluated across intensive and less-intensive treatment settings and in both newly diagnosed (ND) and relapsed/refractory (R/R) disease.³
• Early-phase studies of FLT3 inhibitor-based combinations have demonstrated clinical activity in patients with FLT3m AML who are unfit for intensive chemotherapy, supporting continued investigation of triplet and other combination approaches in this setting.²
  • In the phase I/II VICEROY trial (NCT05520567) composite complete remission (CRc) rates of up to 91% were achieved with gilteritinib + venetoclax + azacitidine in older/unfit patients with ND FLT3m AML (N = 43).²
• Recent data continue to expand the evidence base for FLT3 inhibitor combinations, with updates across different treatment settings presented at the 2026 ASCO Annual Meeting and EHA2026 Congress; these included combinations with venetoclax-based therapy and intensive chemotherapy in ND and R/R FLT3m AML.
  • Results from a phase I/II trial (NCT03661307) of quizartinib + decitabine + venetoclax demonstrated complete remission (CR) rates of 91% and 61% in patients with ND (n = 42) or R/R (n = 46) FLT3-internal tandem duplication (ITD) AML.^7,8
  • In a retrospective comparison of intensive chemotherapy (IC) in combination with quizartinib (n = 88) vs midostaurin (n = 127) in patients with ND FLT3-ITD AML, improved remission and survival rates were observed with the quizartinib combination strategy vs midostaurin (CRc, 85.2% vs 73.2%; 1-year overall survival [OS], 93% vs 78%; 1-year event-free survival [EFS], 77% vs 56%).⁹
  • In the phase III HOVON 156 trial (NCT04027309), comparable OS rates were demonstrated with gilteritinib + IC (n = 384) vs midostaurin + IC (n = 384) in patients with ND FLT3m AML; median OS was not reached at the 43-month follow-up.¹⁰
  • Preliminary results from a phase I/II trial investigating the combination of gilteritinib + momelotinib in patients with R/R FLT3m AML​ demonstrated encouraging initial clinical activity, with a CRc rate of 23%.¹¹
• Different FLT3 inhibitors and treatment approaches cannot be directly compared based on response or survival outcomes alone, as trial populations, FLT3 mutation subtype, age, treatment backbone, and transplant strategies may differ substantially.
• For fit patients with FLT3m AML, FLT3 inhibitor-based intensive chemotherapy followed by consideration of allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains an important treatment strategy, although approaches vary across countries and individual patients.¹²
• Measurable residual disease (MRD) is increasingly relevant to treatment decisions in FLT3m AML, with the potential to help identify patients at differing risks of relapse and inform decisions around transplantation and subsequent treatment; however, the optimal role and timing of MRD-guided strategies remain areas of investigation.¹³
• The potential role of FLT3 inhibitors as maintenance therapy warrants further evaluation, including following intensive chemotherapy or allo-HSCT, with prospective randomized studies needed to establish their role and identify patients most likely to benefit.¹⁴
• Achieving remission is an important treatment goal, but remission rates alone may not capture the longer-term value of a treatment strategy in AML. Greater emphasis on deeper responses, including MRD-negative CR, together with survival data, may provide a more comprehensive assessment of treatment benefit.^15,16
• Further prospective randomized studies are needed to define the role of FLT3 inhibitor-based combinations, including the most appropriate FLT3 inhibitor and treatment backbone for different patient populations and settings, as well as optimal dosing, scheduling, and treatment duration; improving long-term outcomes while balancing efficacy and tolerability and addressing resistance and relapse remain key objectives.¹⁷
• The choice between treatment pathways extends beyond achieving an initial remission, with transplantation, MRD monitoring, maintenance, and management of relapse all potentially forming part of an individualized long-term treatment strategy; the optimal approach depends on patient characteristics, molecular response, and availability of therapies.^15–17

This educational activity is independently supported by Daiichi Sankyo. All content is developed by SES in collaboration with an expert steering committee. Funders are allowed no influence.