Relapsed or refractory acute myeloid leukemia (AML) poses significant therapeutic challenges, with limited treatment options and poor survival outcomes.1 Despite advances in frontline therapy, many patients experience disease recurrence or fail to achieve initial remission. Among patients with primary refractory disease, many who receive intensive salvage chemotherapy can achieve remission, though long-term survival remains largely dependent on subsequent allogeneic transplantation.2,3
Traditional salvage regimens have relied on high-dose cytarabine-based combinations.3 While these can achieve remissions, durability is often limited, and treatment-related toxicity presents challenges, particularly in older patients or those with comorbidities.4 Allogeneic hematopoietic stem cell transplantation (HSCT) remains the primary curative strategy for relapsed or refractory disease, though its application in patients without complete remission remains debated.2,3 Outcomes following salvage transplantation show substantial variability based on patient age, disease burden, cytogenetic risk, and donor selection.2 These considerations have driven interest in alternative therapeutic approaches that may improve remission rates or serve as bridges to transplantation.1,5,6
Targeted therapies have introduced new considerations. For patients with FLT3 mutations, inhibitors including gilteritinib, have demonstrated activity as monotherapy.7 Similarly, IDH1 and IDH2 inhibitors provide options for IDH-mutated disease. These agents offer potential for response in heavily pretreated populations, though resistance remains a concern.8
Integrating molecular profiling into salvage therapy requires consideration of several factors. Testing at relapse can identify actionable alterations, including newly acquired mutations emerging under selective pressure.9 FLT3-ITD allelic burden can increase at relapse, potentially influencing expected benefit from inhibition.10
Venetoclax-based combinations have emerged as options for patients unable to tolerate intensive therapy. Combinations with hypomethylating agents or low-dose cytarabine have shown activity, with IDH mutations predicting better response. Prior hypomethylating agent exposure may reduce subsequent response to venetoclax-based combinations.11
Clinical trial participation represents an important consideration, with investigational approaches including bispecific antibodies, cellular therapies, novel targeted agents, and immune-based therapies under evaluation. Community oncologists can facilitate trial access through collaboration with academic centers. Decision-making extends beyond therapeutic options to encompass treatment goals, quality of life considerations, and supportive care needs. For patients with short initial remission, poor performance status, or adverse molecular features, the likelihood of achieving meaningful disease control may be limited, requiring thoughtful discussion regarding benefit and treatment burden.
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