Targeting Menin and CD47 to Address Unmet Needs in Acute Myeloid Leukemia

SIMPLE SUMMARY: Despite recent, rapid drug development success for patients with acute myeloid leukemia, distinct molecular and genetic aberrations still confer a poor prognosis. In this review, we explore the preclinical and early clinical development of two promising approaches: disrupting menin signaling leading to cell differentiation or blocking CD47 to unlock the innate immune system. These two approaches may improve treatment for patients with high unmet needs today. ABSTRACT: After forty years of essentially unchanged treatment in acute myeloid leukemia (AML), innovation over the past five years has been rapid, with nine drug approvals from 2016 to 2021. Increased understanding of the molecular changes and genetic ontology of disease have led to targeting mutations in isocitrate dehydrogenase, FMS-like tyrosine kinase 3 (FLT3), B-cell lymphoma 2 and hedgehog pathways. Yet outcomes remain variable; especially in defined molecular and genetic subgroups such as NPM1 (Nucleophosmin 1) mutations, 11q23/KMT2A rearranged and TP53 mutations. Emerging therapies seek to address these unmet needs, and all three of these subgroups have promising new therapeutic approaches. Here, we will discuss the normal biological roles of menin in acute leukemia, notably in KMT2A translocations and NPM1 mutation, as well as current drug development. We will also explore how CD47 inhibition may move immunotherapy into front-line settings and unlock new treatment strategies in TP53 mutated disease. We will then consider how these new therapeutic advances may change the management of AML overall.