Venetoclax in Acute Myeloid Leukemia: Evolving Landscape, Resistance Mechanisms, and Future Directions

Abstract

Venetoclax, a potent and selective BCL-2 inhibitor, has revolutionized the treatment paradigm for acute myeloid leukemia (AML), particularly in older or unfit patients ineligible for intensive chemotherapy. Its combination with hypomethylating agents (HMAs) such as azacitidine or low-dose cytarabine (LDAC) has demonstrated significant improvements in overall survival (OS) and remission rates compared to historical controls. However, despite these advances, resistance to venetoclax-based therapies remains a significant challenge. This review provides a comprehensive overview of venetoclax in AML, delving into its mechanism of action, clinical efficacy, emerging resistance mechanisms, and strategies to overcome these challenges. We further explore the evolving landscape of venetoclax-based combinations, including novel therapeutic strategies aimed at improving long-term outcomes and expanding its applicability across diverse AML subtypes. This review concludes by discussing future directions for venetoclax research, including the development of more effective combination regimens and personalized approaches based on genomic and proteomic profiling.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by the uncontrolled proliferation of myeloid blasts in the bone marrow and peripheral blood. The incidence of AML increases with age, and the majority of patients are diagnosed in their seventh decade of life or later. Traditionally, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been the standard of care for younger, fit patients. However, older patients or those with significant comorbidities are often ineligible for intensive chemotherapy due to its associated toxicities and mortality. Consequently, the prognosis for this patient population has historically been poor, with limited therapeutic options available.

The discovery and development of venetoclax (ABT-199), a selective inhibitor of the B-cell lymphoma-2 (BCL-2) protein, has significantly impacted the treatment landscape of AML. BCL-2 is an anti-apoptotic protein that is frequently overexpressed in AML cells, promoting their survival and contributing to chemotherapy resistance. Venetoclax binds to BCL-2 with high affinity, displacing pro-apoptotic proteins and triggering programmed cell death. The synergistic activity of venetoclax with HMAs or LDAC has been demonstrated in preclinical and clinical studies, leading to the approval of venetoclax in combination with these agents for the treatment of newly diagnosed AML in adults who are ineligible for intensive chemotherapy. While venetoclax-based therapies have shown remarkable efficacy in inducing remission and improving survival, the emergence of resistance remains a critical barrier to long-term disease control. Therefore, understanding the mechanisms of venetoclax resistance and developing strategies to overcome them are essential for further improving outcomes in AML.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Mechanism of Action: Targeting BCL-2 and Restoring Apoptosis

The BCL-2 family of proteins plays a critical role in regulating apoptosis, a process of programmed cell death that is essential for maintaining cellular homeostasis. This family comprises both pro-apoptotic (e.g., BAX, BAK, BIM, PUMA) and anti-apoptotic (e.g., BCL-2, BCL-xL, MCL-1) members. The balance between these opposing forces determines the fate of a cell, with a predominance of pro-apoptotic signals leading to cell death and a predominance of anti-apoptotic signals promoting cell survival. In AML, the overexpression of anti-apoptotic proteins, particularly BCL-2, is a frequent occurrence. BCL-2 sequesters pro-apoptotic proteins like BIM, preventing them from activating BAX and BAK, which are essential for permeabilizing the mitochondrial outer membrane and initiating the apoptotic cascade. This dysregulation of apoptosis contributes to the survival and proliferation of leukemic cells, making them resistant to chemotherapy and other forms of treatment.

Venetoclax is a highly selective and potent inhibitor of BCL-2. It binds to BCL-2 with high affinity, displacing pro-apoptotic proteins like BIM and restoring the apoptotic pathway. By liberating BIM, venetoclax allows it to bind to and activate BAX and BAK, leading to mitochondrial outer membrane permeabilization, cytochrome c release, and activation of caspases, ultimately resulting in cell death. The selectivity of venetoclax for BCL-2 is crucial, as it minimizes off-target effects on other BCL-2 family members like BCL-xL and MCL-1. While BCL-2 is often the primary target in AML, resistance can occur through upregulation or increased dependence on these other anti-apoptotic proteins. This will be further discussed in the section on resistance mechanisms.

The efficacy of venetoclax is dependent on the level of BCL-2 expression in AML cells. Studies have shown that patients with higher BCL-2 expression levels are more likely to respond to venetoclax-based therapies. However, BCL-2 expression alone is not a perfect predictor of response, and other factors, such as the levels of pro-apoptotic proteins and the presence of co-occurring mutations, also contribute to treatment outcomes. Furthermore, the bone marrow microenvironment can influence the sensitivity of AML cells to venetoclax, with interactions between leukemic cells and stromal cells potentially providing a protective effect.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Clinical Efficacy: Venetoclax in Combination with HMAs and LDAC

The approval of venetoclax in combination with azacitidine or decitabine (HMAs) and LDAC has transformed the treatment landscape for older or unfit patients with newly diagnosed AML. The pivotal clinical trials demonstrating the efficacy of these combinations have led to their widespread adoption as standard-of-care therapies.

The VIALE-A trial, a phase 3 randomized controlled trial, evaluated the efficacy of venetoclax plus azacitidine versus azacitidine alone in patients with newly diagnosed AML who were ineligible for intensive chemotherapy. The results of this trial showed a significant improvement in overall survival (OS) for patients treated with venetoclax plus azacitidine compared to azacitidine alone (median OS of 14.7 months vs. 9.6 months, respectively; hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.52-0.85; p < 0.001). The combination also resulted in a higher complete remission (CR) rate (36.7% vs. 17.9%) and a higher rate of composite complete remission (CRc) (66.4% vs 28.3%). The most common adverse events associated with the combination were cytopenias, including thrombocytopenia, neutropenia, and anemia. These toxicities require careful monitoring and management, often involving dose modifications and supportive care.

Similarly, studies evaluating the combination of venetoclax with LDAC have shown promising results, particularly in patients who are not candidates for intensive chemotherapy or HMAs. While direct comparisons between venetoclax/HMA and venetoclax/LDAC are lacking, both regimens offer valuable treatment options with distinct toxicity profiles. Venetoclax/LDAC is generally associated with less severe myelosuppression than venetoclax/HMA, potentially making it a more suitable option for patients with pre-existing cytopenias or those who are at higher risk of infections.

Beyond the initial phase 3 trials, real-world data have further confirmed the efficacy of venetoclax-based combinations in a broader population of patients with AML. These studies have shown that venetoclax-based therapies can induce durable remissions and improve survival in patients with various risk factors, including advanced age, comorbidities, and adverse cytogenetic abnormalities. However, real-world studies also highlight the importance of optimizing dosing strategies and managing toxicities to maximize treatment benefit.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Resistance Mechanisms: Overcoming Challenges to Long-Term Efficacy

Despite the significant advances in AML treatment brought about by venetoclax, resistance to venetoclax-based therapies remains a major clinical challenge. Resistance can be either de novo (present at the initiation of treatment) or acquired (developing during treatment). Understanding the mechanisms underlying venetoclax resistance is crucial for developing strategies to overcome this obstacle and improve long-term outcomes. Several mechanisms of resistance have been identified, including:

• Upregulation of other anti-apoptotic proteins: One of the most common mechanisms of venetoclax resistance is the upregulation of other anti-apoptotic proteins, such as MCL-1 and BCL-xL. By increasing the expression of these proteins, AML cells can bypass the inhibition of BCL-2 by venetoclax and maintain their survival. This mechanism highlights the importance of developing strategies to target multiple anti-apoptotic proteins simultaneously. For example, dual BCL-2/MCL-1 inhibitors are currently being investigated in preclinical and clinical studies.
• Mutations in BCL-2: Mutations in BCL-2 itself can also lead to venetoclax resistance. These mutations can alter the structure of BCL-2, preventing venetoclax from binding effectively. Specific mutations, such as the G101V mutation, have been shown to confer resistance to venetoclax in vitro and in vivo. The identification of these mutations through genomic sequencing can help to predict which patients are unlikely to respond to venetoclax and guide treatment decisions.
• Mutations in other genes involved in apoptosis: Mutations in genes involved in the apoptotic pathway, such as TP53, can also contribute to venetoclax resistance. TP53 is a tumor suppressor gene that plays a critical role in regulating apoptosis in response to DNA damage. Mutations in TP53 can impair the apoptotic response and render AML cells resistant to venetoclax and other therapies.
• Alterations in the bone marrow microenvironment: The bone marrow microenvironment can also play a role in venetoclax resistance. Stromal cells in the bone marrow can secrete factors that protect AML cells from venetoclax-induced apoptosis. For example, cytokines such as IL-6 and TNF-α can activate signaling pathways that promote cell survival and inhibit apoptosis. Targeting the bone marrow microenvironment with therapies that disrupt these interactions may enhance the efficacy of venetoclax.
• Efflux pumps: Increased expression of drug efflux pumps, such as P-glycoprotein (P-gp), can also contribute to venetoclax resistance. These pumps actively transport venetoclax out of AML cells, reducing its intracellular concentration and limiting its efficacy. Inhibitors of P-gp and other efflux pumps are being investigated as potential strategies to overcome this mechanism of resistance.
• Metabolic adaptation: Recent studies have highlighted the role of metabolic adaptation in venetoclax resistance. AML cells can alter their metabolic pathways to become less dependent on BCL-2 inhibition. For example, some AML cells can increase their reliance on oxidative phosphorylation or glycolysis to generate energy. Targeting these metabolic pathways with specific inhibitors may enhance the efficacy of venetoclax.

Overcoming venetoclax resistance requires a multifaceted approach, including the development of novel therapeutic strategies that target alternative survival pathways, personalized treatment approaches based on genomic and proteomic profiling, and strategies to modulate the bone marrow microenvironment.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Combination Strategies: Enhancing Efficacy and Overcoming Resistance

Given the challenges posed by venetoclax resistance, significant efforts are underway to develop novel combination strategies that can enhance efficacy and overcome resistance. These strategies can be broadly categorized into the following:

• Combinations with other targeted therapies: Combining venetoclax with other targeted therapies that target different survival pathways in AML cells is a promising approach. For example, venetoclax is being investigated in combination with FLT3 inhibitors, IDH inhibitors, and other targeted agents. These combinations have the potential to synergistically kill AML cells and overcome resistance to individual agents. Notably, the combination of venetoclax and FLT3 inhibitors has shown particular promise in FLT3-mutated AML. Clinical trials are evaluating the efficacy and safety of these combinations in various AML subtypes.
• Combinations with chemotherapy: While venetoclax is primarily used in combination with HMAs or LDAC in older or unfit patients, there is increasing interest in exploring its use in combination with intensive chemotherapy in younger, fit patients. Several clinical trials are evaluating the feasibility and efficacy of adding venetoclax to standard chemotherapy regimens. Early results suggest that this approach may improve remission rates and survival in some patients. However, the addition of venetoclax to chemotherapy can also increase the risk of myelosuppression, requiring careful monitoring and management.
• Combinations with immunotherapies: Immunotherapies, such as immune checkpoint inhibitors and CAR-T cell therapy, are emerging as promising treatment options for AML. Combining venetoclax with immunotherapies may enhance the anti-leukemic immune response and improve outcomes. For example, venetoclax has been shown to increase the expression of PD-L1 on AML cells, making them more susceptible to immune checkpoint inhibitors. Clinical trials are evaluating the efficacy of combining venetoclax with immune checkpoint inhibitors in AML.
• Novel agents targeting resistance mechanisms: As discussed earlier, several mechanisms contribute to venetoclax resistance, including upregulation of MCL-1, mutations in BCL-2, and alterations in the bone marrow microenvironment. Novel agents are being developed to target these resistance mechanisms. For example, dual BCL-2/MCL-1 inhibitors are designed to simultaneously inhibit both proteins, overcoming resistance caused by MCL-1 upregulation. Similarly, agents that disrupt the interactions between AML cells and stromal cells in the bone marrow are being investigated as potential strategies to enhance the efficacy of venetoclax. These novel agents hold promise for improving outcomes in patients with venetoclax-resistant AML.

The selection of the optimal combination strategy should be guided by the individual characteristics of the patient and their leukemia, including their age, comorbidities, cytogenetic abnormalities, and molecular mutations. Personalized treatment approaches based on comprehensive genomic and proteomic profiling are essential for maximizing the benefits of venetoclax-based therapies.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Patient Selection and Monitoring Strategies

Optimal patient selection is crucial for maximizing the benefits of venetoclax-based therapies. While venetoclax is approved for use in older or unfit patients with newly diagnosed AML, its use can be considered in other patient populations as well. Factors to consider when selecting patients for venetoclax-based therapies include:

• Age and comorbidities: Venetoclax is particularly well-suited for older patients or those with significant comorbidities who are ineligible for intensive chemotherapy. However, it can also be considered in younger patients with relapsed or refractory AML.
• Cytogenetic abnormalities: Certain cytogenetic abnormalities, such as TP53 mutations, are associated with a lower response rate to venetoclax-based therapies. Patients with these abnormalities may benefit from alternative treatment strategies or enrollment in clinical trials.
• Molecular mutations: Molecular mutations, such as FLT3 mutations, can influence the response to venetoclax-based therapies. Patients with FLT3-mutated AML may benefit from the addition of a FLT3 inhibitor to venetoclax-based therapy.
• Performance status: Patients with a poor performance status may be less tolerant of the toxicities associated with venetoclax-based therapies. Careful consideration should be given to the risks and benefits of treatment in these patients.
• Prior treatment history: Patients who have received prior chemotherapy may be more likely to develop myelosuppression with venetoclax-based therapies. Dose modifications may be necessary in these patients.

Regular monitoring is essential for managing the toxicities associated with venetoclax-based therapies. Key monitoring strategies include:

• Complete blood counts (CBCs): CBCs should be monitored frequently, particularly during the first few weeks of treatment, to detect and manage cytopenias. Dose modifications may be necessary to manage thrombocytopenia, neutropenia, and anemia.
• Electrolytes: Venetoclax can cause tumor lysis syndrome (TLS), a potentially life-threatening complication characterized by the rapid release of intracellular contents into the bloodstream. Electrolytes, such as potassium, phosphate, and uric acid, should be monitored closely to detect and manage TLS. Prophylactic measures, such as hydration and allopurinol, should be implemented to prevent TLS.
• Renal function: Venetoclax can cause renal impairment, particularly in patients with pre-existing renal disease. Renal function should be monitored regularly.
• Infections: Patients receiving venetoclax-based therapies are at increased risk of infections, particularly bacterial and fungal infections. Prophylactic antibiotics and antifungals may be necessary in some patients. Patients should be monitored closely for signs and symptoms of infection, and prompt treatment should be initiated if infection occurs.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Future Directions

The future of venetoclax in AML is bright, with ongoing research aimed at optimizing its use and expanding its applicability across diverse patient populations. Key areas of focus include:

• Development of more effective combination regimens: Clinical trials are underway to evaluate the efficacy and safety of venetoclax in combination with novel targeted therapies, immunotherapies, and chemotherapy regimens. These combinations hold promise for improving outcomes and overcoming resistance.
• Personalized treatment approaches based on genomic and proteomic profiling: Comprehensive genomic and proteomic profiling is essential for identifying patients who are most likely to respond to venetoclax-based therapies and for tailoring treatment strategies to overcome resistance mechanisms. Future research should focus on developing predictive biomarkers that can guide treatment decisions.
• Strategies to modulate the bone marrow microenvironment: The bone marrow microenvironment plays a critical role in venetoclax resistance. Research is needed to develop strategies that can disrupt the interactions between AML cells and stromal cells in the bone marrow, thereby enhancing the efficacy of venetoclax.
• Development of novel BCL-2 inhibitors: While venetoclax is a highly effective BCL-2 inhibitor, resistance can still occur. The development of novel BCL-2 inhibitors with improved binding affinity or different mechanisms of action may overcome resistance to venetoclax.
• Exploration of venetoclax in other hematological malignancies: Venetoclax is currently approved for use in chronic lymphocytic leukemia (CLL) and AML. However, it may also be effective in other hematological malignancies, such as multiple myeloma and lymphoma. Clinical trials are underway to evaluate the efficacy of venetoclax in these diseases.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Conclusion

Venetoclax has revolutionized the treatment of AML, particularly in older or unfit patients ineligible for intensive chemotherapy. Its combination with HMAs or LDAC has demonstrated significant improvements in overall survival and remission rates. However, resistance to venetoclax-based therapies remains a significant challenge. Understanding the mechanisms of venetoclax resistance and developing strategies to overcome them are essential for further improving outcomes in AML. Ongoing research efforts are focused on developing more effective combination regimens, personalized treatment approaches, and novel agents that target resistance mechanisms. With continued advancements in our understanding of AML biology and the development of innovative therapies, the future looks promising for patients with this challenging disease.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

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