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. Author manuscript; available in PMC: 2025 Jun 9.
Published in final edited form as: Clin Lymphoma Myeloma Leuk. 2021 Jul 18;21(12):805–811. doi: 10.1016/j.clml.2021.07.012

SOHO State of the Art Updates and Next Questions: The Past, Present and Future of Venetoclax-Based Therapies in AML

Anagha Inguva 1, Daniel A Pollyea 1
PMCID: PMC12148621  NIHMSID: NIHMS2082030  PMID: 34389272

Abstract

The use of venetoclax in combination with hypomethylating agents (HMA) has changed the paradigm for the treatment of acute myeloid leukemia (AML) in elderly patients and those unfit for intensive chemotherapy. A phase 3 study has shown superior response rates and improved overall survival for patients treated with venetoclax + azacitidine compared with the previous standard of care, azacitidine alone. This success has led to multiple exciting follow-up studies, including investigations related to the discovery of predictors of response, relapse, and the mechanism of action of this therapy. While venetoclax + HMA has shown significant benefit in elderly patients unfit for chemotherapy, further questions remain as to how this therapy can be expanded into other populations including relapsed or refractory patients and younger newly diagnosed patients with adverse risk features. In this article, we discuss the clinical outcomes of AML with venetoclax + HMA, established and potential predictors of response to this regimen, its mechanisms of action, and speculate on the future of venetoclax + HMA therapy in AML.

Keywords: Azacitidine, BCL2 and relapsed/refractory, Leukemia stem cells, Targeted therapies

Introduction

Before the approval of venetoclax + hypomethylating agents (HMA) for acute myeloid leukemia (AML) in elderly patients and those unfit for intensive chemotherapy, this population had extremely limited therapeutic options.1 These mainly included HMAs (azacitidine or decitabine), low dose cytarabine or supportive care.2,3 Patients treated with HMAs had complete remission (CR) and CR with incomplete count recovery (CRi) rates of less than 30%, and long-term survival rates for patients over the age of 60 who did not undergo allogeneic stem cell transplantation were less than 3%.4

Venetoclax was first explored in AML as a monotherapy in relapsed or refractory patients, showing an overall response rate of 19%.5 To improve efficacy, clinical trials combining venetoclax with standard of care HMAs were conducted in newly diagnosed elderly patients unfit for chemotherapy. These studies showed a significantly higher response rate with venetoclax + HMA (78%) compared with venetoclax monotherapy in the relapsed or refractory setting.6,7 Based on these data, venetoclax + HMA was approved by the United States Food and Drug Administration (FDA) for the treatment of AML in patients older than 75 or with comorbidities precluding intensive chemotherapy.8 The confirmatory phase 3 trial showed a median overall survival (OS) of 14.7 months for patients treated with venetoclax + azacitidine versus 9.6 months for patients treated with azacitidine alone.9 Additionally, rates of composite complete remission were significantly higher in patients treated with venetoclax + azacitidine (66.4% vs 28.3%; P <.001).9 Analysis of long-term follow-up from Phase 1b studies revealed a median remission duration of 18 months and a median OS of 16 months.10

While venetoclax-based therapies in AML have been successful, many questions remain. In the following sections, we discuss proposed mechanisms of action of venetoclax in AML, predictors of response to venetoclax-based therapies, disease features in patients who relapse after venetoclax + HMA therapy, and the potential future role of venetoclax in AML.

Mechanisms of Action of Venetoclax Plus Hypomethylating Agents in AML

Venetoclax inhibits BCL2 activity by displacing protein interactions at the BH3 domain of BCL2, leading to increased apoptosis.11 This activity has been leveraged in other non-myeloid malignancies, including multiple myeloma, acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL),12–14 and initial studies have suggested that targeting of the canonical antiapoptotic function of BCL2 contributes to the mechanism of venetoclax in AML.15 The BCL2 family of proteins are classified into 4 main groups: suppressors, activators, effectors and sensitizers.16,17 By disrupting the BH3 domain, venetoclax releases the activator and effector proteins BIM, BAX, and BAK to execute their proapoptotic function.16,17 These proteins oligomerize and cause mitochondrial outer membrane permeabilization (MOMP) leading to cytochrome C release and apoptosis.16,17 To measure the dependence of a cell on BCL2 proteins and the threshold of a cell to MOMP, BH3 profiling was developed.18,19 This technique involves treating cells with either BAD or MS-1 peptides and measuring MOMP as an indicator of apoptosis, with increased MOMP upon BAD treatment associated with BCL2 reliance and increased MOMP upon MS-1 treatment associated with MCL1 reliance.18 In some contexts, venetoclax + HMA has been shown to modulate BH3 priming and subsequent apoptosis in AML.15,20 Additionally, pretreatment with azacitidine increased venetoclax-mediated cell death compared to control in AML cell lines.20 Further, treatment with azacitidine increased expression of the pro-apoptotic proteins NOXA and PUMA in AML cell lines and patient specimens,20 resulting in increased binding of NOXA and PUMA to BCL2.

Venetoclax is FDA-approved for CLL, in which the main mechanism of resistance is a mutation in BCL2, Gly101Val, leading to decreased venetoclax binding21 Intriguingly, this mutation has not been found in AML patients treated with venetoclax-based regimens.15,22,23 This observation, as well as the fact that unlike CLL, AML does not have universal over-expression of BCL2,24,25 suggests a different mechanism of action, involving a noncanonical role of BCL2 in AML, may be contributing. In preclinical models, venetoclax killed primary human AML leukemia stem cells (LSC) by inhibiting oxidative phosphorylation (OXPHOS), a unique and specific metabolic vulnerability of this population.26 Mass cytometric analysis of AML samples from patients before and after venetoclax + azacitidine treatment showed a greater than 50% reduction of LSCs.7 Further, metabolic analysis of LSCs isolated from AML patients before and after venetoclax + azacitidine revealed decreased amino acid levels, indicating a role for venetoclax + azacitidine in modulating LSC metabolism.27 Culturing LSCs with supraphysiological levels of amino acids prior to venetoclax + azacitidine treatment rescued them from decreased OXPHOS and eventual cell death.27 Based on these data, a proposed mechanism of venetoclax + azacitidine activity in AML is through decreased amino acid transport to fuel the tricarboxylic acid (TCA) cycle, leading to decreased OXHPOS and eventual LSC death.27 This LSC-directed mechanism may be responsible for the durable responses seen with venetoclax + azacitidine.7,27,28

In addition to modulating mitochondrial metabolism, venetoclax also modulates the mitochondrial structure of human AML cells, leading to mitochondrial stress and cell death.29 A CRISPR/cas9 loss of function screen in AML cell lines revealed negative selection of genes involved in mitochondrial processes such as transport, organization and OXPHOS.29 Human AML cell lines treated with venetoclax showed decreased number of cristae and increased width of cristae lumens, indicating abnormal mitochondrial morphology.29 Another study showed venetoclax can modulate other mitochondrial metabolism pathways, specifically heme biosynthesis.30 A CRISPR loss of function screen conducted in AML cell lines in the presence or absence of venetoclax revealed the heme biosynthesis pathway cooperates with BCL2 to sustain cell survival.30 Further, patient samples treated with both succinylacetone, an inhibitor of the heme biosynthesis pathway, and venetoclax, showed increased cell death compared to monotherapy, suggesting synergy between BCL2 inhibition and heme biosynthesis.30 Importantly, these studies were done in cell lines, which may not reflect the biology and heterogeneity of patient samples.31,32

In both cell lines and primary human AML cells, venetoclax and HMAs have been shown to induce reactive oxygen species (ROS).7,33 In response to increased ROS levels, Nrf2 is activated to upregulate the expression of genes involved in neutralization of ROS as a protective mechanism. In AML cells, HMA activates Nrf2, most likely as a response to increased ROS. However, venetoclax treatment abrogated activation of Nrf2, resulting in cell death in both AML cell lines and primary human samples.33 Venetoclax modulated Nrf2 activity by dissociating BCL2 from Nrf2, therefore allowing ubiquitination/degradation of Nrf2. This study suggests modulation of ROS is another mechanism of venetoclax + HMA-mediated AML cell killing.

Additional studies have suggested venetoclax + HMA therapy has a role in modulating T-cell-mediated killing of AML cells.34 In one study, T-cells were isolated from AML patients before and after venetoclax + azacitidine treatment; compared to pretreatment, post-treatment T-cells had increased expression of the T-cell activation marker CD25 and T-cell activating receptor NKG2D, suggesting increased T-cell activity upon venetoclax + HMA therapy.34 Further, T-cells isolated from AML patients pretreatment and after cycle 1 of venetoclax + azacitidine showed increased levels of ROS and decreased respiratory chain super complex formation.34 Inhibition of ROS using N-acetylcysteine showed decreased T-cell activation, indicating venetoclax induction of ROS in T-cells is a mechanism of venetoclax-mediated T-cell activation in AML patients.34 In the same study, azacitidine was shown to modulate AML cells by sensitizing them to T-cell mediated toxicity.34 Taken together, these studies suggest a unique synergy between venetoclax and HMA that results in superior outcomes for patients compared to monotherapy with either agent (Figure 1).

Figure 1.

Figure 1

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Mechanisms of action of venetoclax + hypomethylating agents in AML. Unique mechanisms of action of venetoclax + hypomethylating agent (HMA) in AML that have been described in the literature are depicted. 1) Venetoclax has been shown to disrupt binding of BCL2 to BIM/BAX, allowing these proapoptotic proteins to carry out their functions. 2) Venetoclax + HMAs have been shown to inhibit uptake of amino acids into leukemia stem cells, resulting in decreased fuel for the TCA cycle and oxidative phosphorylation. 3) Venetoclax has been shown to disrupt mitochondrial structure by disrupting the interactions of CLPB and OPA1 at the mitochondrial matrix and cristae. 4) Venetoclax has been shown to disrupt BCL2-mediated heme biosynthesis activity. 5) Venetoclax has been shown to abrogate Nrf2 cytoprotective mechanisms by disrupting BCL2 and Nrf2 interactions. 6) Patients treated with venetoclax + HMA have been shown to have increased expression of T-cell activity markers NKG2D and CD25. Further, venetoclax + HMAs were shown to increase ROS production in T-cells of patients. Figure created with BioRender.com.

Abrreviations: AML = acute myeloid leukemia; ROS = reactive oxygen species; TCA = tricarboxylic acid.

Predictors of Response to Venetoclax Plus Hypomethylating Agents

Initial response rates to venetoclax + HMA are 60% to 70%; this means that upfront resistance occurs in 30% to 40% of patients.22,35,36 Therefore, it is crucial to determine factors that predict sensitivity to this regimen at baseline, so that future studies can target these deficiencies by adding to venetoclax + HMA backbone therapies, or developing non-venetoclax containing regimens. Response prediction in AML has been largely defined by studies involving predominately younger patients receiving intensive chemotherapy regimens.37 It should therefore not be surprising that those factors are not necessarily predictive in older patients receiving a therapy with a different mechanism of action.9,38 Specifically, Pei et al analyzed outcomes in 100 patients with newly diagnosed, previously untreated AML who received venetoclax + azacitidine. A multivariate analysis revealed the French American British (FAB)39 category M5 (acute monocytic leukemia) was the only predictor of refractory disease in an analysis that included conventional risk factors such as secondary AML, ELN risk group or mutational status.38 This unexpected relationship between AML maturation status and venetoclax response corroborated an ex vivo sensitivity assay in primary human AML patient samples.40

Initial analyses have suggested several gene mutations are associated with higher response rates with venetoclax + HMA, including IDH1, IDH2, NPM1 and splicesome mutations.7,41–44 Specifically, patients with these mutations had CR/CRi rates better than observed with the phase 3 study benchmark of 66.4%.9 Conversely, gene mutations associated with upfront resistance to venetoclax + HMA have been postulated based on mechanisms of action, including TP53 and RAS pathway mutations, but these were either not evaluated (RAS) or not significant predictors of resistance (TP53) in the phase 3 study.9,41, 45–47 Finally, patients with AML from an antecedent myeloproliferative neoplasm have been reported in case series to have suboptimal response rates; such patients were excluded from the phase 3 venetoclax + azacitidine study, and more work is required to understand whether this observation persists with more robust clinical data.48,49

Interestingly, initial studies showed protein expression of BCL2 in primary AML samples did not correlate with venetoclax sensitivity. Rather, dependence on certain apoptotic family members (BCL2 or MCL1) correlated with venetoclax sensitivity.15,50 BH3 profiling of 19 patients treated with venetoclax + HMA therapy showed reliance on MCL1 was inversely related to response to venetoclax + HMA; however, reliance on BCL2 did not correlate with response.15 It is important to note that these studies measured the correlation of BH3 profiling to responses, rather than acquired resistance or relapse. In addition, while BH3 profiling with the BAD peptide has been shown to predict venetoclax sensitivity in models of ALL and CLL, the data are not as clear in AML.51–53 Further, analysis of both the blast and LSC populations from seven AML patients did not show differences in BH3 profiling activity among venetoclax-sensitive versus resistant patients.7

Relapse After Venetoclax Plus Hypomethylating Agent Therapies in AML

While a majority of patients respond to venetoclax + HMA, most responders ultimately progress. Identifying the mechanisms behind relapse are crucial to improving outcomes for these patients.

As previously discussed, one of the strongest predictors of refractory disease was monocytic differentiation.38,54 Intriguingly, monocytic disease features were also enriched in patients who relapsed on therapy,38 suggesting that this factor predicts poor response to and relapse after venetoclax.38 Further analysis of monocytic AML cells derived from primary human patient samples revealed they have decreased expression of BCL2 and increased expression of MCL1.38 Inhibition of MCL1 by siRNA or an MCL1 inhibitor led to decreased OXPHOS activity, viability, colony formation and engraftment in the LSC population.38 Other studies have also supported targeting MCL1 to circumvent venetoclax resistance in AML cell lines and patient samples.15,54–57 In addition to direct targeting of MCL1, multiple studies have shown MCL1 can be targeted by inhibiting upstream pathways including MAPK signaling and XPO1.58,59 Taken together, these data suggest venetoclax resistance can be overcome by MCL1 inhibition.

Another analysis of patients who relapsed on venetoclax-based regimens showed 13.6% of patients gained mutations in the proapoptotic protein BAX with a variant allele frequency of 0.75% to 48%.60 Although this analysis was performed in a small cohort of patients (n = 44), these data suggest BAX mutations as a potential predictor of venetoclax resistance. Other mutations have been shown to confer resistance to venetoclax + HMA in AML. Inactivation of TP53 was shown to decrease venetoclax-mediated apoptosis in AML cell lines.61 Further analysis revealed inactivation of TP53 led to increased OXPHOS activity, presumably protecting cells from venetoclax-mediated changes in mitochondrial metabolism, therefore promoting cell survival.61 TP53 loss impaired BAX/BAK activation in AML cell lines, therefore delaying apoptosis and leading to sublethal responses upon venetoclax treatment.46 Targeting BCL2 and MCL1 was shown to increase early apoptotic activity in TP53 deficient cells, supporting MCL1 targeting as a strategy to combat venetoclax resistance.46 RAS mutations were shown to confer resistance to venetoclax + HMA in AML patient samples by modulating cellular metabolism.9 Specifically, AML patient samples with RAS pathway mutations showed increased fatty acid oxidation (FAO) metabolism, which abrogates the reliance of amino acids to fuel OXPHOS activity, as fatty acids can also be used to fuel the TCA cycle, resulting in resistance to venetoclax + HMA. Inhibiting FAO resensitized RAS-mutant cells to venetoclax + azacitidine.9 RAS mutations were also shown to modulate venetoclax resistance by activating MCL1 via MAPK pathway activation in AML cell lines.58 Finally, in the phase 3 venetoclax + azacitidine study, patients with mutations in FLT3 ITD, TP53,and NPM1 all had hazard ratios that did not significantly favor venetoclax + azacitidine versus azacitidine with respect to OS, suggesting these mutations may be associated with resistance to this regimen.9 Patients with poor risk cytogenetics also crossed this null hypothesis between favoring venetoclax + azacitidine and azacitidine alone, requiring more attention to be paid to this subgroup’s OS outcomes with venetoclax-based regimens as well.

As venetoclax + HMA-mediated changes in mitochondrial biology are crucial to the mechanism of action of this therapy in AML, it is plausible that resistance is mediated by changes in these pathways. Specifically, a CRISPR screen in venetoclax-resistant AML cell lines showed targeting mitochondrial translation was a potential strategy to overcome resistance.62 Treatment of venetoclax-resistant cells with either tedezolid or doxycycline, antibiotics that inhibit mitochondrial protein synthesis, led to resensitization to venetoclax.62 In addition to FAO mediated resistance, nicotinamide metabolism was also shown to modulate venetoclax + HMA resistance in primary AML specimens, and genetic and pharmacologic inhibition of the nicotinamide metabolism pathway led to resensitization to venetoclax + HMA.63 These all represent potential ways to overcome resistance to venetoclax-based regimens and prevent or delay relapsed disease.

The Role of Venetoclax-Based Regimens in the Relapsed or Refractory Setting

Most venetoclax clinical trials have focused on elderly, previously untreated, newly diagnosed patients. However, venetoclax-based regimens have clinical activity in the relapsed or refractory setting as well (Table 1), albeit more modest than what has been observed in treatment-naïve patients. Therefore, understanding how this regimen can be modified to improve outcomes for these patients is crucial. Pharmacodynamic studies have suggested longer exposure to decitabine with venetoclax may lead to superior outcomes in patients with high-risk AML. To test this hypothesis in relapsed or refractory AML, 55 patients were treated with decitabine for 10 days in conjunction with venetoclax. The overall response rate was 62%, the median OS was 7.8 months and median duration of response was 16.8 months. Additionally, patients who responded and were able to undergo successful stem cell transplant had a median OS of 22 months.64

Table 1.

Activity of Venetoclax With Hypomethylating Agents in Relapsed or Refractory AML Patients

Number of Patients in Trial Overall Response Rate Median Overall Survival Reference
43 21% 3 mo 66
33 64% 6.5 mo 67
23 43% 10.8 mo 68
25 52% 5.5 mo 69
14 35.7% 4.7 mo 70
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A retrospective analysis of clinical and molecular characteristics of 86 patients with relapsed or refractory AML revealed certain mutations conferred sensitivity or resistance to venetoclax + HMA.65 Similar to treatment naïve patients, mutations in NPM1 correlated with higher response rates, while mutations in TP53, RAS, and SF3B1 conferred resistance.65 More work is necessary to identify which relapsed or refractory patients may maximally benefit from venetoclax-based therapies.

The Future of Venetoclax-Based Therapies in AML

Currently, there are over 80 clinical trials recruiting AML patients for venetoclax-based therapies. One potential strategy is to add additional targeted therapies to venetoclax-based regimens, including those designed to inhibit IDH, TP53 and FLT3 mutations. Other agents being combined with venetoclax target various pathways involved in proliferation, cell survival, immune regulation and metabolism. A summary of some combination trials currently underway are summarized in Table 2. It is our hope that before the field widely adopts the addition of therapies to the venetoclax + HMA backbone, we improve our ability to predict outcomes with the current regimen and make judicious and conservative changes at the individual patient level. For example, a significant population of patients has very durable responses to venetoclax + HMA alone; these patients should be identified at baseline, as they would minimally benefit from additional up-front therapies, and any additional toxicity contributions would be unnecessary and unfortunate.9,10 Conversely, patients likely to be refractory to venetoclax + HMA should similarly be identified at diagnosis, and these patients should be candidates to receive additional therapies to overcome resistance, or novel non venetoclax-containing regimens. Finally, patients who achieve remission but are at risk of relapse, who can perhaps be identified by a metric such as measurable residual disease at some accepted postremission timepoint, should have additional therapies introduced to prevent disease recurrence.

Table 2.

List of Current Clinical Trials Combining Venetoclax + Hypomethylating Agents With Novel Therapies

Pathway Target Novel Agent-Molecular Target National Clinical Trial Number
Mutations/overexpressed targets in AML Ivosidenib-IDH1 NCT03471260
Enasidenib-IDH2 NCT04092179
Quizartinib-FLT3 NCT03735875
HDM201-TP53 NCT03940352
Gemtuzumab-ozogamicin-CD33 NCT04070768
Lintuzumab-Ac225-CD33 NCT03867682
IMGN632-CD123 NCT04086264
Proliferation OPB-111077-STAT3 NCT03063944
Ruxolitinib-JAK1/2 NCT03874052
BP1001-Grb2 NCT02781883
CYC065-CDK NCT04017546
Cytarabine and Mitoxantrone-DNA NCT04330820
Cell survival Pevonedistat-NEDD8 NCT04172844
Selinexor-XPO1 NCT03955783
AZD5991-MCL1 NCT03218683
S64315-MCL1 NCT03672695
Immune regulation Pembrolizumab-PD-1 NCT04284787
MBG453-CD47 NCT04150029
ALX148-CD47 NCT04755244
Magrolimab-CD47 NCT04435691
CA-4948-IRAK4 NCT04278768
Metabolism Pegcrisantaspase-Asparagine NCT04666649
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Abbreviation: AML = acute myeloid leukemia.

Finally, expanding the use of venetoclax + HMA beyond the current labeled indication for some newly diagnosed patients may also occur in the future. A retrospective analysis of older patients with NPM1 mutations who received induction chemotherapy vs. venetoclax + HMA showed a superior CR rate (88% and 56%) for venetoclax + HMA, as well as improved OS.42 Venetoclax-based therapies might also have a role in younger patients with disease features that predict adverse outcomes with standard chemotherapy. This approach is being explored in clinical trials, both single-arm and randomized designs (NCT03573024, NCT04801797), and are awaited with anticipation.

Conclusion

The development of venetoclax-based therapies has significantly improved outcomes in patients who have historically had poor outcomes. Continuing to understand how venetoclax modulates AML biology will be crucial in developing new therapies and to maximize success for patients.

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