Response Kinetics and Clinical Benefits of Nonintensive AML Therapies in the Absence of Morphologic Response

The ultimate goal of treatment for acute myeloid leukemia (AML) is to improve survival, and the best means of doing so is through the induction of morphologic remission, which is historically most reliably achieved with intensive chemotherapy regimens. Older patients with AML are less likely to be candidates for or to benefit from intensive chemotherapy. Patients deemed ineligible for intensive therapy may nevertheless benefit from lower-intensity therapies and from newly available targeted AML treatments. Recently approved lower-intensity treatments for AML include enasidenib, ivosidenib, glasdegib, venetoclax, midostaurin, and gilteritinib, and additional promising agents are in later stages of clinical development. Noncytotoxic agents may result in slower kinetics of therapeutic activity compared to intensive regimens, and although they are generally better tolerated than intensive chemotherapy, bone marrow responses are less frequent and may take longer to achieve. Notably, newer therapies might have been considered ineffective had they been judged solely by 2003 International Working Group response criteria for AML, which were based on experience with intensive regimens in predominantly younger patients. Lower-intensity therapies may require several treatment cycles to induce responses, and failure to achieve rapid morphologic remission may not signal the need for treatment cessation or transition to alternative therapies. Additionally, even in the absence of a conventional complete remission, lower-intensity therapies may provide meaningful clinical benefit, including improved survival and quality of life, by inducing hematologic improvement and transfusion independence. Reviewed here are the mechanisms of activity and response kinetics of lower-intensity AML therapies, as well as the clinical benefits resulting from nontraditional AML responses.