Acute Myeloid Leukemia in Older Patients: From New Biological Insights to Targeted Therapies

Abstract

Acute myeloid leukemia (AML) is a heterogeneous blood-related neoplasm that predominantly afflicts older adults with a poor prognosis due to their physical condition and the presence of medical accompanying comorbidities, adverse biological disease features, and suitability for induction intensive chemotherapy and allogenic stem cells transplantation. Recent research into the molecular and biological factors contributing to disease development and progression has led to significant advancements in treatment approaches for older patients with AML. This review article discusses the latest biological and therapeutic developments that are transforming the management of AML in older adults.

Keywords: genomic profiling; hypomethylating agents; intensive chemotherapy; quality of life; supportive care; targeted therapies; transplantation clinical trials; venetoclax-based combinations.

Figure 1

Effects of critical mutations on cellular function and pathophysiology of AML. In the cytoplasm, isocitrate is converted to alpha-ketoglutarate (A-KG). However, IDH1 mutations reduce A-KG to D-2-hydroxyglutarate (D-2-HG), an oncometabolite. D-2-HG then travels to the nucleus and inhibits TET2, blocking DNA demethylation. Additionally, D-2-HG is created via reduction in the mitochondria by mutant IDH2 enzymes from Krebs cycle-generated A-KG. IDH1 inhibitors target the cytoplasmic reduction of A-KG to D-2-HG, while IDH2 inhibitors target the same process in the mitochondria. NPM1, which generally resides in the nucleolus and minimally binds XPO1, can travel to the nucleoplasm in stress conditions. In the nucleoplasm, it inhibits HDM2, which is significant because HDM2’s normal function is to inhibit TP53. Thus, by inhibiting HDM2, NPM1 can increase TP53, which has important implications for cell regulation in stressful conditions. Mutant NPM1 (NPM1c) has a higher affinity to XPO1 and is prone to nuclear export, leading to critical protein export from the nucleus. Additionally, the consequent result of mutant NPM1 and XPO1-NPM1c can increase HOX expression. Furthermore, NPM1c and KMT2Ar interact with menin, facilitating leukemogenic cellular changes, which can be targeted via menin inhibition. Reprinted from Figure 1 in Ref. [3].

Figure 2

Suggested treatment algorithm for newly diagnosed AML. HMA: hypomethylating agent. AZA: azacitidine. LDAC: low-dose ara-C. CLAD: cladribine. Ven: venetoclax (adapted from [25]).