Non-Immunotherapy Approaches for Relapsed or Refractory AML: An Update for 2024

Abstract

Background: Relapsed or refractory (R/R) acute myeloid leukemia (AML) is a challenging, high-risk, clinical scenario with a dismal outcome. Recent insights on the genetic, epigenetic, and metabolic events that drive clonal progression and the advent of novel therapies resulted in the incorporation of several new targeted therapies, alone or in combination, in the R/R setting with the aim of improving response rates and survival. Herein we review current challenges and future opportunities with non-immunotherapeutic approaches to treat R/R AML. Summary: Inhibitors of FLT3 and IDH 1/2 are now FDA-approved for patients with R/R disease and corresponding mutations. These agents are also used in combination with intensive and low-intensity platforms in an attempt to improve response and survival. Several targeted agents are currently being tested alone or in combination in early-phase trials. These include drugs that target apoptotic pathways, drugs that interfere with key survival pathways of the R/R leukemic cell as well as therapies aimed towards the leukemia marrow microenvironment. Menin inhibitors are a promising class of active drugs in NPM1 and KMT2A-rearranged AML. Key-messages: Several new targeted therapies, immunologic and non-immunologic are being studied and are moving through pre-clinical and clinical pipelines. Significant remaining challenges include the development of synergistic combination therapies tailored to the specific biology and clinical context of the patient, and re-defining the role and timing of allogeneic transplantation in patients with R/R disease.

A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia

“…Several early-phase clinical trials are investigating the safety and efficacy of menin inhibitors in AML with KMT2Ar or NPM1mut AML. Very encouraging safety and efficacy data are currently available from studies of two menin inhibitors: SNDX-5613 (revumenib) and KO-539 (ziftomenib) [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Ongoing phase I/II clinical trials evaluating menin inhibitor therapy are listed in Table 1 .…”

“…Grade 3 or higher TRAEs included grade 3 tumor lysis syndrome (TLS) at 50 mg and a grade 3 embolic event at 100 mg. Ziftomenib was well tolerated with no dose interruptions or discontinuations due to TRAEs. There were no treatment-related deaths [ 26 , 29 ].…”

“…The phase 1 KOMET-001 trial showed a manageable safety profile for ziftomenib. Therefore, the 600 mg dose demonstrates meaningful efficacy in heavily pretreated R/R AML [ 27 , 28 , 29 ].…”