ASH Expert Insights | Professor Jun Ma: Transforming FLT3-ITD AML Treatment from Dynamic Management and Optimized Maintenance to Targeted Breakthrough

At this year’s American Society of Hematology (ASH) Annual Meeting, advances in FLT3-ITD acute myeloid leukemia (AML) delivered important clinical insights. From evolving treatment paradigms to optimized maintenance strategies and breakthroughs in targeted therapy, these studies consistently centered on precision medicine, driving care toward greater efficiency and individualization. On site at ASH, Hematology Frontier invited Professor Jun Ma from the Harbin Institute of Hematology and Oncology to interpret key developments in dynamic management, maintenance therapy, and targeted drug application in FLT3-ITD AML, with the aim of informing clinical decision-making.

Focus on Treatment Paradigms: MRD and Clonal Evolution Drive Dynamic Management

Q1 Multiple ASH studies, including those on MRD-guided post-transplant maintenance and clonal dynamics, suggest that FLT3-ITD AML treatment is no longer a simple choice between “chemotherapy plus transplant” or “to treat or not to treat.” Instead, dynamic management based on MRD status and clonal evolution is emerging as a new standard. How do you view this shift, and how should clinicians integrate NGS-MRD, clonal burden, and clinical features to individualize therapy?

Professor Jun Ma: At this ASH meeting, many studies in FLT3-ITD AML highlighted a shift from static treatment decisions to a dynamic management model, enabled by advances in NGS-based MRD assessment and clonal evolution monitoring. MRD status is now widely recognized as a key marker for response evaluation and treatment adjustment. Conversion from MRD negativity to positivity during follow-up signals a very high risk of relapse and inferior survival, as discussed in abstracts such as 170 and 345.

Another important finding is the prognostic impact of subclonal FLT3-ITD. About 10% of AML patients classified as FLT3-ITD negative by conventional methods harbor small FLT3-ITD clones detectable by high-depth NGS. This underscores the need to consider FLT3-ITD clonal burden, co-mutation profiles, and patient characteristics together. For example, persistent FLT3-ITD MRD positivity after induction should prompt treatment intensification. Patients who convert to MRD negativity but retain microclones or have high ligand levels require close surveillance, while those with MRD negativity and low clonal burden may be managed with regular monitoring and dynamic adjustment.

Overall, dynamic management emphasizes real-time assessment and risk re-stratification, aiming to intervene before overt relapse. This approach embodies the core principles of precision medicine, allowing therapy to be tailored using multidimensional evidence to improve efficacy while limiting toxicity.

Focus on Maintenance Therapy: Clear Value of FLT3 Inhibitors with Room for Optimization

Q2 Several studies at ASH explored the role of FLT3 inhibitor maintenance, including post-transplant settings, different MRD states, and special populations such as older adults and children. What should be the primary goals of maintenance therapy in FLT3-ITD AML, and where does current practice still need improvement?

Professor Jun Ma: Abstracts such as 217, 345, and 592 evaluated FLT3 inhibitor maintenance across various settings. Clinically, the core goals of maintenance therapy are to reduce relapse risk, achieve or sustain MRD clearance, prolong relapse-free survival, improve overall survival, and preserve quality of life. In special populations, safety and tolerability are particularly important.

However, gaps remain between ideal and real-world practice. There are no head-to-head comparisons among available FLT3 inhibitors, and no authoritative guidelines defining the optimal choice based on tolerability or comorbidities. The appropriate duration of maintenance therapy is also unclear, and whether treatment should be prolonged or individualized requires further evidence. Moreover, MRD-guided decision-making is not yet universally implemented, limiting accurate identification of patients most likely to benefit.

Future efforts should focus on clinical trials that clarify optimal regimens and durations, while promoting routine MRD testing to refine maintenance strategies.

Focus on Targeted Breakthroughs: Expanding the Role of FLT3 Inhibitors and Combination Strategies

Q3 More than a dozen studies on quizartinib were presented at ASH. Sub-analyses of the QUIWI trials highlighted the prognostic role of FLT3 microclones and ligand levels in FLT3-ITD–negative AML, while QuANTUM-First emphasized resource utilization benefits in FLT3-ITD–positive disease. How do you assess the overall clinical value of quizartinib across different FLT3 mutation states, and which combination strategies appear most promising?

Professor Jun Ma:[Saut de retour à la ligne] The extensive data on the second-generation FLT3 inhibitor quizartinib addressed key unmet needs in FLT3-ITD AML. In FLT3-ITD–positive patients, the phase III QuANTUM-First trial showed that adding quizartinib to standard chemotherapy with continued treatment significantly improved overall survival and duration of response, reducing the relative risk of death by 22%. Continuous quizartinib from induction through consolidation and maintenance increased the likelihood that MRD-positive patients would convert to and sustain MRD negativity, with consistent benefits regardless of MRD status. These findings suggest deeper and more durable remissions.

In FLT3-ITD–negative AML, follow-up analyses from the QUIWI trials demonstrated that quizartinib’s benefits extend to a broader population, including patients with FLT3 microclones. Approximately 18% of conventionally FLT3-ITD–negative patients harbor microclones detectable by sensitive NGS. Importantly, quizartinib improved OS and EFS regardless of microclone status, with numerically better duration of response in microclone-positive patients, warranting further study.

To expand its applicability, several combination strategies are under investigation. Quizartinib combined with the menin-MLL inhibitor ziftomenib offers a potential all-oral targeted regimen. Combinations with BCL-2 inhibitors or hypomethylating agents have also shown feasibility and early activity in relapsed or refractory AML. While these approaches hold translational promise, further trials are needed to confirm safety and efficacy.

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