Building on Foundations: Venetoclax-Based Combinations in the Treatment of Acute Myeloid Leukemia

Abstract

Frontline acute myeloid leukemia (AML) treatment is determined by a combination of patient and genetic factors. This includes patient fitness (i.e., comorbidities that increase the risk of treatment-related mortality) and genetic characteristics, including cytogenetic events and gene mutations. In older unfit patients, the standard of care treatment is typically venetoclax (VEN) combined with hypomethylating agents (HMA). Recently, several drugs have been developed targeting specific genomic subgroups of AML patients, enabling individualized therapy. This has resulted in investigations of doublet and triplet combinations incorporating VEN aimed at overcoming known resistance mechanisms and improving outcomes in older patients with AML. These combinations include isocitrate dehydrogenase-1/2 (IDH1/2) inhibitors (i.e., ivosidenib and enasidenib), fms-like tyrosine kinase 3 (FLT3) inhibitors (i.e., gilteritinib), anti-CD47 antibodies (i.e., magrolimab), mouse double minute-2 (MDM2) inhibitors, and p53 reactivators (i.e., eprenetapopt). This review summarizes ongoing trials aimed at overcoming known VEN resistance mechanisms and improving outcomes beyond that observed with HMA + VEN combinations in the treatment of AML.

Monocytic Differentiation in Acute Myeloid Leukemia Cells: Diagnostic Criteria, Biological Heterogeneity, Mitochondrial Metabolism, Resistance to and Induction by Targeted Therapies

“…However, it should be emphasized that the differentiation-associated resistance is an important, but not the only, mechanism of venetoclax resistance. The main observations with regards to monocytic differentiation and venetoclax resistance are summarized in Table 4 and are discussed in detail in this main section [ 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 ].…”

“…Third, differentiation-associated decreased reliance on Bcl-2 for metabolic regulation and survival is not a specific mechanism for monocytic differentiation. Finally, these mechanisms should also be considered for venetoclax-based combination therapy (see also Section 7 ) [ 157 ].…”

Editorial: Genetic/epigenetic mechanisms and related clinical strategy in leukemia

“…The exploration of the genetic/epigenetic mechanism of leukemogenesis forms the basis of new treatment development. For example, the discovery of pathogenic gene mutation promoted the progress of targeted therapy such as FLT3 inhibitors and IDH1 inhibitors ( 4 ). An aberrant epigenetic profile was found to contribute to the occurrence of leukemia and hypomethylating agents were subsequently proved useful in the treatment of leukemia ( 5 ).…”