Editors Note: With the growing adoption of targeted therapies including FLT3 inhibitors and menin inhibitors in the treatment landscape of acute myeloid leukemia (AML), optimizing therapeutic strategies, overcoming secondary resistance, and delivering precision care have emerged as key clinical priorities. Meanwhile, the value of measurable residual disease (MRD) monitoring is increasingly recognized in treatment response assessment, transplantation decision-making, and maintenance therapy.In an interview with Oncology Frontier-Hematology Frontier, Prof. Harry Paul Erba from Duke University School of Medicine, USA, shared in-depth insights based on the latest research advances and clinical practice. He elaborated on patient selection for FLT3-mutated AML, the combination and sequential application of targeted agents, therapeutic options after resistance onset, and MRD-guided individualized treatment, providing valuable reference for optimizing the holistic full-course management of AML.
Oncology Frontier-Hematology Frontier：Professor Erba, incorporating FLT3 and Menin inhibitors into the standard of care for AML holds great promise. How should clinicians precisely select the patient populations most likely to benefit, and how can the overlapping toxicities of multi-drug combinations be effectively balanced?
Professor Harry Paul Erba：Incorporating FLT3 inhibitors into intensive chemotherapy regimens has significantly improved survival outcomes in patients with FLT3-mutated AML. Clinical data from midostaurin and quizartinib have demonstrated these benefits. Compared with midostaurin, gilteritinib improves relapse-free survival. These findings underscore the clinical importance of identifying patients who are fit enough to tolerate intensive chemotherapy.
However, with the increasing use of lower-intensity regimens, such as hypomethylating agents combined with the BCL-2 inhibitor venetoclax, many clinicians—particularly in the United States—are inclined to administer these regimens locally, even when patients may actually be eligible for intensive chemotherapy. As a result, such patients are no longer referred to academic centers for further evaluation. It is important to recognize that the goal of hypomethylating agent plus venetoclax therapy, with or without quizartinib or gilteritinib, is generally to prolong survival rather than achieve a cure. These regimens typically require ongoing treatment unless patients subsequently proceed to allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Transplantation decisions involve multiple challenges. Some patients who initially appear eligible for transplantation may decline, because of concerns about transplant-related toxicity and complications. Others regard transplantation as a “last resort.” However, clinical experience indicates that transplantation should ideally be performed while the disease is in remission; proceeding to transplantation after relapse is often much less successful. Furthermore, recent single institution studies with small sample sizes have not yet clearly demonstrated a survival benefit for allogeneic stem cell transplantation for less intensive, triple therapy for older FLT3 mutated AML patients.
Therefore, patients being considered for lower-intensity therapy require careful evaluation. For patients who are eligible for intensive chemotherapy but decline transplantation, intensive chemotherapy combined with an FLT3 inhibitor, followed by maintenance therapy, may be a treatment strategy worth considering. The QUANTUM-First study showed that, compared with chemotherapy alone, the addition of quizartinib to intensive chemotherapy, followed by maintenance therapy, significantly reduced the risk of death. Long-term follow-up data further support the survival benefit of this treatment strategy.
One of the key challenges facing hematologists today is accurately identifying patients who are genuinely unfit for intensive chemotherapy. The Ferrara position statement outlines several clinical characteristics associated with ineligibility for intensive chemotherapy, including age ≥75 years, poor baseline performance status, impaired organ function, the presence of another metastatic malignancy, and active infection. For these patients, azacitidine plus venetoclax is generally a preferred option, with the addition of an FLT3 inhibitor considered according to the patient’s molecular profile and clinical circumstances.
In addition, certain molecular subgroups may derive substantial benefit from intensive chemotherapy. For example, patients harboring concurrent NPM1, DNMT3A, and FLT3-ITD mutations, including older patients, may achieve long-term survival with a “7+3” induction followed by high dose cytarabine consolidation combined with quizartinib. This strategy involves a time-limited course of intensive chemotherapy followed by oral maintenance therapy, offering a potentially effective and feasible treatment approach.
In summary, AML treatment decisions should focus on two key questions: Is the patient truly unfit for intensive chemotherapy? And, given the patient’s molecular mutation profile, can intensive chemotherapy offer a realistic opportunity for cure?
Oncology Frontier-Hematology Frontier：Secondary resistance remains a major challenge in targeted therapy. Based on current research, can the combination or sequential use of FLT3 and Menin inhibitors effectively prevent the emergence of resistant clones? What subsequent strategies should be chosen if relapse occurs?
Professor Harry Paul Erba：An established principle in oncology drug development is to combine agents with different mechanisms of action, thereby targeting multiple pathways simultaneously to reduce the emergence of drug resistance. However, this strategy presents unique challenges in AML, where combination therapy often exacerbates myelosuppression and may even lead to early mortality. Therefore, in patients who are unfit for intensive chemotherapy, indiscriminately adding more agents may do more harm than good.
A key question that remains to be answered is whether these targeted agents should be administered in combination or through sequential or alternating regimens. Unfortunately, pharmaceutical companies have limited incentives to conduct such studies. If a drug is used in only one cycle of an alternating regimen, it may be difficult to obtain regulatory approval. Consequently, addressing these critical questions will depend largely on clinical trials designed and led by academic institutions.
Recent studies suggest that resistance in most cases of AML arises from the emergence of new clones that are no longer sensitive to the original targeted inhibitors. We observed this phenomenon in the QUANTUM-First study, although the relevant data have not yet been published. In our own clinical practice, some patients who relapsed after receiving 7+3 chemotherapy combined with quizartinib no longer had detectable FLT3-ITD mutations upon reassessment. This highlights the considerable challenges involved in preventing resistance and relapse through currently available approaches alone.
As our understanding of resistance mechanisms deepens, we hope to develop subsequent therapies that specifically target these mechanisms. For example, relapse following gilteritinib treatment is often associated with mutations in the RAS pathway, whereas azacitidine combined with venetoclax has limited efficacy in RAS-mutated AML. In the future, as RAS inhibitors advance through development, they may offer a treatment option for this patient population. Overall, substantial research and drug development efforts are still needed to target the secondary mutations and pathways that enable AML to escape the effects of targeted inhibitors.
Oncology Frontier-Hematology Frontier：As targeted agents enter first-line and maintenance therapies, MRD monitoring becomes increasingly critical. Do you think MRD negativity can serve as a benchmark for evaluating efficacy and guiding treatment discontinuation? What is the optimal duration of maintenance therapy after achieving a deep remission?
Professor Harry Paul Erba：Two large randomized trials have systematically evaluated next-generation sequencing (NGS)-based, FLT3-ITD-specific measurable residual disease (MRD) assays, with a sensitivity of up to 10⁻⁵. Both the QUANTUM-First and MORPHO trials demonstrated that, regardless of the intervention received, patients who were MRD-positive had worse prognoses and survival outcomes than those who were MRD-negative. Therefore, MRD has the potential to serve as a surrogate endpoint in FLT3-mutated AML, potentially accelerating drug development without the need to wait for long-term survival data.
Survival endpoints themselves have limitations. For example, in a European study comparing gilteritinib with midostaurin, gilteritinib significantly improved relapse-free survival (RFS), but no difference in overall survival (OS) was observed between the two groups. This was likely because patients in the midostaurin arm could receive gilteritinib as salvage therapy following relapse. This highlights the importance of preventing relapse, particularly when two drugs achieve similar remission rates. Once the disease relapses, subsequent treatment must be initiated, and few patients would prefer to receive one first-line regimen only to switch to salvage therapy after relapse, provided the toxicity profile is acceptable. This consideration also applies to the gilteritinib-versus-midostaurin study.
However, establishing MRD as a surrogate endpoint does not mean that it can already directly guide every treatment decision. The key question now is how clinicians should adjust treatment strategies when patients remain persistently MRD-positive or MRD-negative above or below a defined threshold.
– In NPM1-mutated AML: A pooled analysis of the UK AML17 and AML19 trials showed that patients who achieved MRD negativity after two cycles of intensive chemotherapy did not derive an OS benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). Although this conclusion was based on a retrospective analysis and the induction regimens varied, I would be inclined to defer transplantation in patients with NPM1-mutated AML who are MRD-negative, particularly given the expanding range of salvage treatment options for relapsed NPM1-mutated disease. These include the FDA-approved menin inhibitors, venetoclax-based combinations, and gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate (ADC).
– In FLT3-ITD-mutated AML: MRD-guided decision-making is more challenging in patients treated with “7+3” chemotherapy combined with quizartinib. The QUANTUM-First trial demonstrated that quizartinib significantly increased MRD negativity rates and that MRD negativity was associated with better outcomes. However, the study did not establish a specific MRD threshold that could be used as a basis for discontinuing treatment.
The role of MRD in guiding post-transplant maintenance therapy is currently the clearest. The MORPHO trial demonstrated that, among patients who were MRD-positive before transplantation, gilteritinib maintenance was associated with improvements in both RFS and OS compared with placebo. This suggests that if a patient remains MRD-negative for one year while receiving post-transplant FLT3 inhibitor maintenance, treatment discontinuation may be considered, given that the graft-versus-leukemia (GVL) effect is likely to have taken hold and the risk of relapse is very low. Conversely, if MRD remains detectable, treatment should be continued. In the QUANTUM-First trial, maintenance therapy was prescribed for 144 weeks (36 cycles of 28 days each). In clinical practice, however, treatment duration may be individualized based on serial MRD monitoring. The European LeukemiaNet (ELN) is currently developing relevant guidelines and strongly recommends using MRD testing to guide post-transplant FLT3 inhibitor therapy.
