How I treat refractory and relapsed acute myeloid leukemia

Most patients with acute myeloid leukemia (AML) develop refractory/relapsed (R/R) disease even in the presence of novel and targeted therapies. Given the biological complexity of the disease and differences in frontline treatments, there are therapies approved for only subgroups of R/R AML, and enrollment in clinical trials should be first priority. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative strategy for most patients. Therapeutic approaches, including allogeneic HCT, triggered by the presence of measurable residual disease (MRD), have recently evolved to prevent overt hematologic relapse. Salvage therapy with chemotherapy or targeted therapy is frequently administered before HCT to reduce the leukemic burden. Gilteritinib is approved by the Food and Drug Administration and European Medicines Agency for patients with relapsed FLT3 mutated AML, whereas targeted therapy for relapsed IDH1/2 mutated AML has only FDA approval. Patients who are R/R after azacitidine and venetoclax (AZA/VEN) have a dismal outcome. In this setting, even available targeted therapies show unsatisfactory results. Examples of ongoing developments include menin inhibitors, a targeted therapy for patients with mutated NPM1 or KMT2A rearrangements, antibodies targeting the macrophage immune checkpoint CD47, and triple combinations involving AZA/VEN. The latter cause significant myelosuppressive effects, which make it challenging to find the right schedule and dose.