Mechanisms of resistance to targeted therapies for relapsed or refractory acute myeloid leukemia

• Published in: Experimental hematology 2022-07, Vol.111, p.13-24
• Main Authors: Kropp, Erin M, Li, Qing
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Recurrence
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2022.04.001

•Despite advances with IDH1/2, FLT3, and BCL-2 directed therapies, treatment resistance and relapse remain frequent•Activating RAS mutations are associated with treatment resistance in targeted therapy for relapsed refractory AML•Significant clonal heterogeneity complicates relapse following targeted therapy•Mutational evolution as well as dysregulation of downstream signaling pathways, metabolism, and apoptosis all represent mechanisms of relapse following targeted therapy Acute myeloid leukemia (AML) is an aggressive disease of clonal hematopoiesis with a high rate of relapse and refractory disease despite intensive therapy. Traditionally, relapsed or refractory AML has increased therapeutic resistance and poor long-term survival. In recent years, advancements in the mechanistic understanding of leukemogenesis have allowed for the development of targeted therapies. These therapies offer novel alternatives to intensive chemotherapy and have prolonged survival in relapsed or refractory AML. Unfortunately, a significant portion of patients do not respond to these therapies and relapse occurs in most patients who initially responded. This review focuses on the mechanisms of resistance to targeted therapies in relapsed or refractory AML. Proposed mechanisms of relapse and resistance following targeted therapies in AML. Figure created with biorender.com [Display omitted] .