Mutation- and MRD-Informed Treatments for Transplant-Ineligible Patients

Authors

Curtis A Lachowiez
Courtney D DiNardo

Publication Date

12-6-2024

Journal

Hematology, ASH Education Program

Abstract

The ongoing development of molecularly targeted therapies in addition to the new standard of care combination of azacitidine and venetoclax (AZA-VEN) has transformed the prognostic outlook for older, transplant-ineligible patients with acute myeloid leukemia (AML). While conventional treatments, such as standard anthracycline and cytarabine- based chemotherapy or hypomethylating agent (HMA) monotherapy, are associated with a generally poor prognosis in this patient population, the use of these novel regimens can result in long-lasting, durable remissions in select patient subgroups. Furthermore, the simultaneous discovery of resistance mechanisms to targeted therapies and AZA-VEN has enabled the identification of patient subgroups with inferior outcomes, leading to the development, of new risk-stratification models and clinical investigations incorporating targeted therapies using an HMA-VEN-based platform. Treatments inclusive of IDH1, IDH2, FLT3, and menin inhibitors combined with HMA-VEN have additionally demonstrated safety and high rates of efficacy in early-phase clinical trials, suggesting these regimens may further improve outcomes within select subgroups of patients with AML in the near future. Additional studies defining the prognostic role of measurable residual disease following VEN-based treatment have further advanced prognostication capabilities and increased the ability for close disease monitoring and early targeted intervention prior to morphologic relapse. This review summarizes these recent developments and their impact on the treatment and survival of transplant-ineligible patients living with AML.

Keywords

Humans, Leukemia, Myeloid, Acute, Mutation, Neoplasm, Residual, Sulfonamides, Bridged Bicyclo Compounds, Heterocyclic, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Molecular Targeted Therapy

DOI

10.1182/hematology.2024000540

PMID

39644009

PMCID

PMC11665587

PubMedCentral® Posted Date

12-6-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes