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Page 134 Saliba et al. Cancer Drug Resist 2021;4:125-42 I http://dx.doi.org/10.20517/cdr.2020.95

In summary, mechanisms of resistance to venetoclax monotherapy are varied, from mutation of the drug
binding pocket of BCL2 itself, to amplification of parallel anti-apoptotic signaling pathways, changes in
energy metabolism, and epigenetic alterations.

COMBINATION THERAPY WITH HYPOMETHYLATING AGENTS AND VENETOCLAX
Mechanism of action
Combination therapy is employed to increase treatment efficacy beyond the action of a single agent,
avoid dose-dependent adverse events, and evade potential mechanisms of resistance. With these goals
in mind, the combination of venetoclax and HMAs was explored as a potential drug combination in
preclinical studies. Treament of clinical AML samples initially ex vivo revealed synergy, at low nanomolar
concentrations, between azacitidine and venetoclax [161,162] . Azacitidine treatment in AML cell lines was
also shown to cause several pro-apoptotic changes, including a decrease in MCL1 protein levels [163,164] and
an increase in NOXA through activation of the integrated stress response [157] . Combination therapy with
azacitidine and ABT-737, an inhibitor of BCL2, BCLX , and BCLW, not only displayed synergistic killing
L
of AML cells but also decreased tissue invasion of leukemic cells in vivo, thus dampening a potential
niche microenvironment-based evasion mechanism of resistance in AML [164] . Other preclinical studies
have shown that the HMA/BCL2 inhibitor combination decreases oxidative phosphorylation and avoids
genomic amplifications that reduce venetoclax monotherapy-induced energetic stress [165] . The HMA/
venetoclax combination was made even more attractive by the observation that the cytotoxic synergy
occurs preferentially in neoplastic cells while sparing normal hematopoietic cells [166] .

[19]
Based on these preclinical findings, DiNardo et al. evaluated the safety and efficacy of the combination
of azacitidine or decitabine with venetoclax in previously untreated AML patients 65 years of age or older
who were ineligible for conventional induction chemotherapy. The most common grade 3 and 4 adverse
[19]
events included neutropenic fever, pneumonia, leukopenia, neutropenia, anemia, and thrombocytopenia .
With a median time on study of ~9 months and a median duration of follow-up of ~15 months, the CR/
CRi rate was 67% and the overall leukemia response rate, including patients with partial response and
[19]
morphologically leukemia free state, was 83% . Median overall survival was not reached at the time of the
[19]
initial report . Very similar results were observed in the phase III study of azacitidine and venetoclax in
[28]
treatment-naïve AML patients ineligible for standard induction therapy . Based on the phase II and III
HMA/venetoclax results, as well as a phase II study of LDAC that also showed an increased CR/CRi rate
[20]
and relapse-free survival compared to LDAC alone , the combination of venetoclax with HMA or LDAC
was approved by the U.S. FDA for the treatment of elderly or medically unfit patients with AML.
Resistance to combination therapy
[19]
[28]
The phase II HMA/venetoclax trial and the phase III azacitidine/venetoclax trial both indicate that 1/3
of patients with newly diagnosed AML fail to achieve a CR or CRi with this therapy [19,28] This high rate of
treatment failure has prompted investigation into mechanisms of resistance to the combination.

Based on the mechanism of action of HMAs and venetoclax, it is logical that resistance might involve
changes in BCL2 family members. Results of Pei et al. [167] suggest that resistance to the azacitidine/
venetoclax doublet is mediated by the presence of monocytic AML cells, which upregulate MCL1 to evade
BCL2 blockade and relieve mitochondrial energetic stress. These monocytes, which lose BCL2 expression
and preferentially rely on MCL1 for survival, show outgrowth in relapsed/refractory AML and have a
+
+
-
distinct immunopathogenic signature (CD45-bright/SSC /CD117 /CD11b /CD68 ) that might allow
high
early detection and therapeutic decision making [167] . Additional analysis showed that AML with monocytic
differentiation (previously called M5 AML under the French-American-British classification system) had
little or no response to the combination of azacitidine and venetoclax [167] .