Myelomonocytic and monocytic acute myeloid leukemia demonstrate comparable poor outcomes with venetoclax-based treatment: a monocentric real-world study

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

“…A final question is whether the degree of monocytic AML cell differentiation is decisive for the biological and/clinical impacts of the differentiation. The results from a recent report on responsiveness to venetoclax-based therapy suggest that the prognostic impact of myelomonocytic or monocytic differentiation (i.e., FAB-M4 versus FAB-M5) is similar, at least for this therapeutic strategy [ 164 ]. This observation suggests that these two AML subsets share common mechanisms with regards to the mitochondrial regulation of apoptosis/survival and cell metabolism.…”

“…Monocytic differentiation is associated with venetoclax resistance [7,8,88,151,159]. Patients with newly diagnosed monocytic AML show significantly lower remission rate and overall survival compared to non-monocytic subsets and with no significant differences between the FAB-M4 and FAB-M5 subtypes [164]. Lower remission rate for monocytic variants was also observed for relapse/refractory AML patients, but the overall survival did not differ for these patients [164].…”

“…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 ].…”

“… Genetic clonal heterogeneity seems to be associated with venetoclax resistance [ 138 , 140 ]. Venetoclax resistance is seen both for FAB-M4 and FAB-M5 AML [ 164 ]. …”

“…First, FAB-M4/M5 monocytic AML is associated with venetoclax resistance, but the association seems to be weaker for high-risk/relapsed AML [ 160 , 164 ]. Second, decreased reliance on Bcl-2 for survival and metabolic regulation is one of the mechanisms behind the decreased responsiveness in monocytic AML [ 164 , 165 , 166 , 167 ], but other mechanisms, including more general mechanisms such as mechanisms associated with specific genetic abnormalities, also contribute even in monocytic AML [ 160 ]. Third, differentiation-associated decreased reliance on Bcl-2 for metabolic regulation and survival is not a specific mechanism for monocytic differentiation.…”