Experts Evaluate Targeted Therapies in Relapsed or Refractory AML
Key Points
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Targeted therapies approved for relapsed or refractory acute myeloid leukemia (AML) include FLT3 inhibitors, IDH inhibitors, and, most recently, menin inhibitors.
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For relapsed AML with KMT2A rearrangement, revumenib is an effective option to bridge patients to another long-term therapeutic option, including second transplant.
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In post-transplant refractory FLT3- and NPM1–mutated AML, the MORPHO trial directly supports maintenance gilteritinib, although ongoing menin inhibitor trials may introduce new combinations.
Treatment Options for Relapsed or Refractory AML
As part of the Challenging Cases series on the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with Joshua Zeidner, MD, of University of North Carolina, to discuss treatment options for relapsed or refractory AML cases. The field of AML has seen significant advancements with the recent development of novel menin inhibitors, which are currently approved for AML with KMT2A rearrangement or NPM1 mutation.
Relapsed AML With KTM2A Rearrangement
The first case described a 43-year-old woman with no significant medical history with easy bruising, fatigue, and arthralgias for the past month. Bone marrow biopsy confirmed a diagnosis of AML with monocytic differentiation, fluorescence in situ hybridization identified a KMT2A rearrangement, and next-generation sequencing (NGS) found no FLT3 or NPM1 mutations. She was treated with 7+3 induction chemotherapy, achieved a morphologic complete remission (CR) and underwent allogeneic hematopoietic cell transplantation. At 7 months post-transplant, she showed worsening pancytopenia, and a repeat biopsy confirmed AML relapse with the same KMT2A rearrangement.
The development of menin inhibitors has dramatically shifted the treatment landscape for several AML alterations, including KMT2A rearrangement, yielding high response rates as single-agent targeted therapy. For this case, Dr. Zeidner would start revumenib ahead of other options like a hypomethylating agent (HMA) plus venetoclax or salvage cytotoxic chemotherapy. He may consider donor lymphocyte infusions, and, if the patient achieved another remission, he may attempt a second transplant. When using any menin inhibitors, regular QT interval monitoring is required.
Refractory AML With FLT3-ITD, NPM1, and DNMT3A Mutation
Next, the doctors discussed a 54-year-old man with a history of type 2 diabetes mellitus and hypertension who presented with ongoing fatigue, fevers, and petechiae. Biopsy and NGS identified AML with myeloblastic differentiation and FLT3 internal tandem duplication (FLT3-ITD), NPM1, and DNMT3A R882H mutations. He received induction with 7+3 chemotherapy plus quizartinib and consolidation with high-dose cytarabine plus quizartinib before proceeding to transplant. Post-transplant, he had positive FLT3-ITD minimal residual disease (MRD) AML on bone marrow biopsy.
In this patient, Dr. Zeidner would start gilteritinib for at least 2-years as a maintenance option, based on the phase 3 MORPHO trial. Notably, the MORPHO trial only supports using gilteritinib in MRD-positive patients. Based on the phase 3 data backing gilteritinib’s efficacy specifically in MRD–positive post-transplant AML with FLT3 mutations, Dr. Zeidner would sequence it before other options, like revumenib or ziftomenib. If patients in this setting progress on gilteritinib or another FLT3 inhibitor, oncologists should check for mutation gain or loss.
Notably, the treatment paradigm for FLT3-ITD and NPM1–mutated AML may evolve as several ongoing studies explore menin inhibitor maintenance and menin inhibitor combinations across treatment settings, said Dr. Zeidner.