https://www.onclive.com/publications/special-issues/2019/inhibition-of-the-bcl-2-pathway-in-hematologic-malignancies/targeting-bcl2-in-hematologic-malignancies
Targeting BCL-2 in Hematologic Malignancies


The BCL-2 family of proteins are central regulators of apoptosis, programmed cell death, which can occur in response to intrinsic stress signals or environmental cues. During the life span of any organism, proliferation must be balanced with apoptosis, to ensure both appropriate development and proper, mature physiologic cell and organ function. This balance between proliferation and apoptosis is particularly important in such highly proliferative tissues as the bone marrow.1 Deregulation of apoptotic pathways can lead to cancer, with resistance to apoptosis having been identified as a hallmark of human cancer nearly 20 years ago.2 Over the past 2 decades, considerable efforts have focused on the development of therapies that can restore apoptosis in malignant cells.3 

Members of the BCL-2 family of proteins can either inhibit or activate apoptosis. Antiapoptotic family members include BCL-2, BCL-XL, BCL-W, BCL-B, BFL1, and myeloid cell leukemia 1. Proapoptotic family members can be subdivided into 2 subfamilies: (1) the multidomain effector proteins BAX and BAK and (2) the BH3-only proteins BID, BIK, NOXA, PUMA, BAD, and BIM.1 Under normal circumstances, the antiapoptotic and proapoptotic family members bind to each other in various combinations to mutually inhibit their individual functions.1 The antiapoptotic proteins BCL-2 and BCL-XL inhibit the proapoptotic effector proteins BAX and BAK. BH3-only proteins sequester and inhibit BCL-2 and BCL-XL, however, freeing BAX and BAK to initiate the cascade of events that leads to cell death.1 Therefore, strategies to develop inhibitors of antiapoptotic BCL-2 family proteins have focused on agents that can interfere with these interactions and promote the activity of the proapoptotic proteins. Recent advances in agents that can inhibit the antiapoptotic BCL-2 proteins have begun to validate the potential of this approach and provide new treatment options for patients with aggressive disease.

BCL-2 Deregulation in Hematologic Malignancies
In normal, healthy lymphoid cells, prosurvival members of the BCL2 family restrain BAX and BAK in order to maintain cell viability.3 BCL-2 overexpression is one of the most common alterations in lymphoid malignancies, however, which disrupts the balance between the proapoptotic and antiapoptotic proteins.3 Cells that overexpress BCL-2 survive despite exposure to cell death stimuli, and the inappropriate survival of BCL-2–overexpressing cells contributes to the pathogenesis of a variety of malignancies.

Although BCL-2 overexpression is characteristic of multiple hematologic malignancies, the mechanisms leading to overexpression differ among tumor types.3 BCL-2 was first identified as a result of cloning of the t(14;18)(q32;q21) chromosomal translocation in patients with follicular lymphoma (FL).4 This translocation places the immunoglobulin heavy chain gene enhancer in 14q32 in the region of the BCL-2 promoter, leading to upregulation of BCL-2 expression.Elevated BCL-2 expression contributes to survival in multiple hematologic malignancies. Approximately 70% to 90% of cases of FL, 20% to 30% of cases of diffuse large B-cell lymphoma (DLBCL), and 5% to 10% of cases of other less common subtypes of non-Hodgkin lymphoma (NHL) harbor this translocation.

BCL-2 overexpression and impaired apoptosis are also hallmarks of chronic lymphocytic leukemia (CLL).1 Unlike FL and other NHL malignancies, deletion of 13q14 is the most frequently reported genetic lesion in patients with CLL, occurring in 50% to 60% of cases.1,5 The minimal deleted region in this lesion contains the micro-RNAs (miRNAs) miR-15a and miR-16, which normally inhibit BCL-2 transcription.6 Deletion of these miRNAs, which have also been observed in up to 70% of cases of mantle cell lymphoma (MCL), leads to elevated BCL2 expression and constitutive survival of tumor B cells.1,7 

Epigenetic silencing due to high histone deacetylase activity in patients with CLL can also cause decreased expression of miR-15a/16.1 In addition to chromosomal deletion and epigenetic silencing, these miRNAs can be regulated by TP53. Under normal circumstances, TP53 can enhance miR-15a/16 transcription.1 TP53 is often altered in hematologic malignancies, however, including CLL.Loss of TP53 function in CLL and other hematologic cancers impairs miR-15a/16 transcription and promotes elevated BCL-2 expression. In addition, TP53 normally upregulates expression of the proapoptotic BH3-only proteins NOXA and PUMA.9 Therefore, loss of TP53 can also decrease the levels of the proapoptotic proteins, thus shifting the balance between the apoptotic regulators and resulting in aberrant cell survival.

Additional prosurvival mechanisms observed in CLL include hypomethylation of the BCL2 gene promoter, as well as downregulated expression of BAX and BAK, which leads to an increase in the BCL-2/BAX ratio.1,9 BCL-2 overexpression has also been observed in patients with multiple myeloma (MM), acute lymphoblastic leukemia, and some T-cell lymphomas.3 Because of the numerous mechanisms leading to BCL-2 overexpression, targeting antiapoptotic BCL-2 family proteins is an attractive therapeutic strategy for individuals with CLL and other hematologic malignancies.

Benefits of Targeting BCL-2
Inhibiting antiapoptotic BCL-2 functions may have enhanced benefits compared with the use of other targets in hematologic malignancies. Numerous studies have demonstrated that BCL-2 overexpression plays a functional role in driving malignant transformation and therapeutic resistance in patients with CLL, FL, DLBCL, and MM.10,11 In addition, BCL2 mutations in patients with FL have been associated with progression to more aggressive DLBCL.12 Therefore, targeting a driver of tumor progression and resistance may represent an effective approach for treating these diseases.

In addition to the elevated BCL-2 expression observed among those with hematologic malignancies, recurrent alterations in other pathways may provide further rationale for targeting BCL-2. DNA repair pathway defects are common in CLL and contribute to reduced sensitivity or resistance to chemotherapeutic agents.13 For example, TP53 disruption is a strong predictor of resistance to chemotherapy or immunotherapy. The apoptosis pathway is downstream of the DNA repair pathway, however, and human B-lymphoblast cell lines or primary CLL cells with TP53 defects maintain sensitivity to BCL2 inhibitors in culture.1 Because TP53 activates apoptosis by inducing BH3-only proteins, agents that antagonize BCL-2 act downstream of TP53 and may be able to overcome the block to apoptosis that is associated with TP53 disruption.1,3 In addition, because BCL-2 overexpression can block the cell death initiated by cytotoxic therapies, targeting BCL-2 may represent a novel strategy in synergistic combination approaches designed to overcome resistance to other therapies.3

BCL-2–Targeted Therapies
Although more than 20 agents have been developed to target BCL-2 family proteins, only a small number of them have been investigated in clinical trials.14 Early agents failed to demonstrate sufficient efficacy and/or safety, but recent efforts have led to the development of more effective inhibitors with promising clinical outcomes in a variety of hematologic cancers.

Initial efforts to develop anti–BCL-2 therapies focused on strategies to block BCL-2 synthesis. The first agent developed to block BCL-2 synthesis was the antisense oligonucleotide oblimersen.9 Antisense oligonucleotides can prevent the translation of specific proteins by causing enzymatic cleavage of the targeted messenger RNA message. Oblimersen selectively hybridizes to the first 6 codons of the open reading frame for the BCL-2 protein. Binding of the antisense oligonucleotide ultimately prevents BCL-2 protein translation.15 Oblimersen was evaluated in phase III clinical trials but was denied FDA approval because of insufficient clinical efficacy.9

More recent approaches to targeting BCL-2 have focused on BH3 mimetics. The development of advanced technologies, including nuclear magnetic resonance–based approaches combined with structure-activity relationships, has enabled structural understanding of the binding between BH3-only proteins and the prosurvival BCL-2 family proteins.1,16 This understanding has subsequently led to the design of small molecules that activate apoptosis by inhibiting BCL-2 and BCL-XL.1 BH3 mimetics function by competing with the proapoptotic proteins, BAK or BAX, for binding to BCL-2. By sequestering BCL-2, the BH3 mimetics enable BAX or BAK activation, leading to downstream caspase activation and cell death.9

An effective BCL-2 inhibitor must meet the following 4 criteria: (1) The biological activity of the agent must be dependent on BAK and/or BAX, (2) the binding affinity of the compound to ≥1 of the antiapoptotic BCL-2 family proteins must be in the low nanomolar range, (3) the cytotoxic effects of the agent should correlate with proapoptotic BCL-2 protein levels in the cell and with the binding profile of the agent to BCL-2 family members, and (4) in vivo treatment with the agent should result in modulation of relevant biomarkers, such as decreased platelet levels for BCL-XL antagonists or reduced lymphocyte numbers for BCL-2 antagonists.

BCL2 Inhibitor Development History
Numerous BH3 mimetics have been developed and tested, each with its own specificity for various antiapoptotic proteins; however, only venetoclax has gained FDA approval.9 The history of BCL-2 inhibitor development provides necessary context and insight into the approval of venetoclax (ABT-199).

Obatoclax (GX-15-070), which inhibits all BCL-2 family antiapoptotic proteins, including BCL-2, BCL-XL, BCL-W, and MCL-1,17 was investigated in a phase I clinical trial in patients with advanced CLL. Although BAX upregulation correlated with drug exposure, only 1 of the 26 patients treated with obatoclax achieved a partial response.18 In addition, treatment with the drug was associated with unexplained neurologic adverse events (AEs), including somnolence, euphoria, ataxia, and confusion.18 Obatoclax was also evaluated in a separate phase I prospective trial of 13 patients with relapsed CLL, which was designed to assess the combination of obatoclax with fludarabine and rituximab. The overall response rate (ORR) was 85%, with 15% of patients attaining a complete response (CR).17 Neurologic toxicities, including euphoria, ataxia, and dizziness, were also reported in this study.17 The development of obatoclax was discontinued in 2013.11  

Navitoclax (ABT-263), another potent, orally bioavailable BAD-like BH3 mimetic, entered clinical trials in 2006.1,3 Navitoclax inhibits BCL-2, BCL-XL, and BCL-W and has been shown to be much more effective than obatoclax.3 In a phase I trial of navitoclax in patients with relapsed or refractory lymphoid malignancies, clinical activity was observed across all tumor types.19 The best clinical activity was observed in CLL, with a response rate of 50%; all the 7 navitoclax-treated patients with CLL achieved a ≥50% reduction in leukemia cells.19 

Importantly, responses to navitoclax have included patients with poor prognostic features, including deletion of chromosome 17p (del[17p]), which causes loss of TP53, and bulky disease.3 Navitoclax has also been evaluated in combination with rituximab in patients with relapsed/refractory CLL and previously untreated CLL. Navitoclax demonstrated improved response rates compared with treatment with rituximab alone.20,21 However, toxicities have been associated with navitoclax treatment. Grade 3 and 4 neutropenias have been observed in up to 29% of patients in clinical trials of navitoclax. Because the treatment of neutrophils with navitoclax in vitro does not cause apoptosis, the mechanism for this toxicity remains unknown.3 In addition, significant thrombocytopenia that correlates with drug concentrations in the blood has been observed in patients treated with navitoclax. Because BCL-XL is highly expressed in platelets, this AE on platelets is thought to be the result of “on-target” BCL-XL inhibition.1 Although the thrombocytopenia associated with navitoclax treatment limits the clinical use of this agent, the efficacy observed in early trials provided proof-of-concept for the therapeutic potential of targeting BCL-2 family inhibitors.16

Venetoclax
Venetoclax was developed by re engineering navitoclax to generate a molecule that has high binding affinity for BCL-2 and low or no binding affinity for BCL-XL and BCL-W.22 The affinity of venetoclax for BCL-XL or BCL-W is 100-fold less than that for BCL-2, and venetoclax binds to BCL-2 with greater affinity than BIM.1,16 Venetoclax binding to BCL-2 disrupts the ability of BCL-2 to inhibit BAK and BAX, thus allowing these proapoptotic mediators to initiate the cell death cascade.1 

Impressive results were observed in the first clinical trial of venetoclax, which was a phase I dose-escalation study in patients with relapsed/refractory CLL or small lymphocytic lymphoma. The aim of this study was to evaluate the safety, pharmacokinetics, and efficacy of venetoclax. Among all patients with CLL, including those with del(17p) and bulky or fludarabine-refractory disease, the overall survival rate at 2 years was 84%.23 Among the patients with del(17p), the response rate was 71%, including 16% who experienced a CR. This outcome was promising because TP53 loss of function is generally considered a major obstacle to successful therapy in patients with CLL.23 In addition, 5% of venetoclax-treated patients achieved minimal residual disease (MRD) negativity, which is infrequently observed among those with relapsed/refractory disease.9,23 

The most significant safety finding in this trial was tumor lysis syndrome (TLS), which was reported in 18% of patients, particularly those with high tumor burden.23 Based on this early safety concern, an amendment was added to the study protocol to include such TLS prophylaxis measures as intravenous hydration, allopurinol with or without rasburicase, and strict biochemical monitoring.1 In addition, the venetoclax dose was increased for each patient through a stepwise ramp-up phase over several weeks, beginning with 20 mg/day and increasing to a target dose of 400 mg/day. The combination of this ramp-up phase with strict adherence to prophylaxis eliminated additional cases of clinical TLS.23 Neutropenia and gastrointestinal AEs were also observed in patients treated with venetoclax.23 

A separate phase II study evaluated venetoclax in more than 100 patients with relapsed/refractory CLL with del(17p). In this trial, nearly 80% of patients experienced an overall response, 40% achieved MRD negativity, and no cases of clinical TLS were reported.24 Together, these trial results demonstrated that venetoclax monotherapy for the treatment of relapsed/refractory CLL is associated with higher CR rates compared with the use of other agents or combinations of agents and is effective in patients with del(17p) CLL, a population with a very poor prognosis.24,25 These data provided the basis for the initial FDA approval of venetoclax in 2016 as second-line therapy for CLL associated with del(17p).25

Venetoclax has also been evaluated in clinical trials of CLL in combination with other agents. In a phase Ib study of venetoclax plus the anti-CD20 antibody rituximab in patients with relapsed/refractory CLL, the ORR was 86%, with a CR observed in 51% of patients. In addition, 67% of patients were MRD negative after a median follow-up of almost 10 months. After 2 years, 82% of patients were progression-free, and all MRD-negative patients remained in remission at 9.7 months after interruption of venetoclax. This result provided proof that patients in remission do not necessarily need to receive continuous venetoclax therapy. This outcome suggests that eradication of disease may be a realistic outcome for patients with CLL, establishing a new paradigm for CLL treatment.1,26 

Results from the phase III MURANO trial comparing venetoclax plus rituximab versus bendamustine plus rituximab also demonstrated venetoclax benefit across all subgroups analyzed, with 2-year progression-free survival (PFS) rates of 84.9% for venetoclax plus rituximab compared with 36.3% for bendamustine plus rituximab.27 The rates of PFS at 2 years were similar between patients with and without del(17p).27 Grade 3 or 4 TLS occurred in 3.1% of patients in the venetoclax-plus-rituximab group.27 Higher rates of grade 3 or 4 neutropenia were observed in the venetoclax-plus-rituximab group than in the bendamustine-plus-rituximab group.27 The data from this trial led to the expanded FDA approval of venetoclax in June 2018 as a second-line therapy for any patient with CLL. 

Ongoing Trials in CLL
Studies evaluating the combination of venetoclax plus obinutuzumab, another anti-CD20 monoclonal antibody, have also produced encouraging results. In a phase Ib study in patients with relapsed/refractory or previously untreated CLL, all 32 previously untreated patients responded to venetoclax plus obinutuzumab therapy, with a CR observed in 56.3% of patients. MRD negativity was observed in 100% of patients, including those with 17p deletion, and the 1-year PFS rate was 100%.28 
In addition to combinations with anti-CD20 antibodies, venetoclax has been evaluated with the BTK inhibitor ibrutinib. In a phase II trial of venetoclax plus ibrutinib in patients with relapsed/refractory CLL or untreated patients with high-risk features (ie, 17p and 11q deletions, TP53 mutations, unmutated immunoglobulin heavy-chain variable region gene, or ≥65 years), CRs were observed in more than half of all patients. Among the 14 patients with relapsed/refractory CLL, a CR rate of 64% was observed compared with 56% among the 16 high-risk, treatment-naïve patients.29 

In a separate trial of venetoclax plus ibrutinib in 25 patients with relapsed/refractory CLL, early results have reported an ORR of 100% and a CR rate of 60%, with 28% of patients achieving MRD negativity.30 Venetoclax and ibrutinib were also combined with obinutuzumab in a phase Ib study in patients with relapsed/refractory CLL. Among the 12 patients assessed, 92% experienced an overall response, including a CR in 42% of cases and MRD negativity in 50% of cases. A phase II study with this combination of agents is ongoing in patients with relapsed/refractory or treatment-naïve CLL, and a phase III study is planned.31 Together, these findings have provided support for the continued evaluation of venetoclax plus ibrutinib therapies, as well as additional combinations of venetoclax with other agents in patients with CLL.

Use of Venetoclax in Other Hematologic Malignancies
Acute Myelogenous Leukemia
Venetoclax has shown promising signs of efficacy in additional hematologic malignancies. In patients with acute myelogenous leukemia (AML), venetoclax has been evaluated as monotherapy and in combination with other agents. A phase II study of 32 patients with relapsed/refractory AML or with AML unfit for intensive chemotherapy reported ORRs of 19%, with a 33% CR rate in patients with isocitrate dehydrogenase 1/2 (IDH1/2) mutations.32 The results from this study provided the rationale for combining venetoclax with other agents in patients with AML. Multiple studies are evaluating a variety of combination therapies in patients with AML.32 

Preclinical studies have suggested that hypomethylating agents, such as the DNA methyltransferase inhibitor 5-azacytidine, can decrease MCL-1 expression in AML cells.33 A phase Ib study has evaluated venetoclax plus azacytidine or venetoclax plus decitabine in patients ≥65 years with treatment-naïve AML who are ineligible for intensive chemotherapy. Although the historical CR rates for the single hypomethylating agents decitabine and azacytidine are 25.6% and 27.8%, respectively, the combination of venetoclax plus the hypomethylating agents resulted in a CR rate of 67%.33,34 In addition, for patients who are ineligible for induction chemotherapy, this combination represented a bridging strategy to allogenic stem cell transplantation. In November 2018, venetoclax was approved for the treatment of newly diagnosed AML in patients 75 years and older or for those ineligible for intensive induction chemotherapy due to comorbidities. 

An ongoing phase I study is evaluating venetoclax in combination with the MEK inhibitor cobimetinib or the MDM2 inhibitor idasanutlin in relapsed/refractory AML. Upregulation of MCL-1 is thought to be a potential mechanism of resistance to BCL-2 pathway inhibition. Because inhibition of MEK and MDM2 has been shown to downregulate MCL-1, treatment with these inhibitors may improve the efficacy of venetoclax in patients with AML.35 The preliminary analysis of this study demonstrated an ORR of 18% in the venetoclax-plus-cobimetinib arm and 38% in the highest-dose venetoclax-plus-idasanutlin arm.35 Moreover, among the 9 patients with IDH1/2 mutations, a response was observed in 44% of the patients. No responses were observed among the 3 patients with known TP53 mutations.35

Multiple Myeloma
The t(11;14)(q13;q32) translocation is present in approximately 15% to 20% of all patients with MM, and cells with this genetic lesion are highly sensitive to venetoclax in vitro.33 Venetoclax monotherapy has been evaluated in a phase I study in heavily pretreated patients with relapsed/refractory MM. An ORR of 40% was observed in the subgroup of patients harboring the t(11;14) translocation.36 
Combination studies in MM have included a phase I study of venetoclax plus dexamethasone in patients with t(11;14) relapsed/refractory MM. Dexamethasone plus venetoclax has been shown to induce greater release of BIM from BCL-2 than venetoclax alone, resulting in greater activation of BAX/BAK.33 Early results have demonstrated an ORR of 65%, with higher ORRs in patients refractory to bortezomib (82%) and lenalidomide (71%).37 
In addition, proteasome inhibitors, such as bortezomib, have been shown to induce apoptosis through upregulation of NOXA and MCL-1, providing a rationale for combining venetoclax with these agents.33 A phase Ib study of venetoclax plus bortezomib and dexamethasone in patients with relapsed/refractory MM demonstrated an ORR of 67% among the 66 patients enrolled, with an ORR of 97% in patients who were not refractory and had received 1 to 3 prior therapies. In addition, patients whose tumor cells expressed high levels of BCL-2 exhibited higher ORRs compared with those with low BCL-2 expression (94% vs 59%, respectively).38 The observed AEs were mild gastrointestinal toxicities and grade 3 or 4 cytopenias, which was considered an acceptable safety profile.38 Additional trials of venetoclax combinations in patients with MM are ongoing, including combinations with MEK inhibitors (cobimetinib), immune checkpoint inhibitors (atezolizumab), monoclonal antibodies targeting other proteins (daratumumab, an anti-CD38 antibody), and proteasome inhibitors (bortezomib and carfilzomib).33

Non-Hodgkin Lymphoma
Venetoclax has also been assessed in patients with NHL. In a phase I study of 106 patients with relapsed/refractory NHL, 44% achieved an overall response across all NHL tumor subtypes. Patients with MCL experienced the highest ORR of 75%; this rate is similar to the rates of response to venetoclax observed in patients with CLL.39 However, lower response rates were observed in other NHL subtypes. 

The modest activity of venetoclax as a single agent across the NHL subpopulations highlights the importance of considering combination approaches. In a phase I trial, venetoclax was combined with bendamustine and rituximab in patients with relapsed/refractory NHL. Among the 60 patients enrolled, the ORR was 65%, with higher responses observed in patients with FL and marginal zone lymphoma (75% and 100%, respectively).40 

In addition, a phase II study evaluated venetoclax plus ibrutinib in patients with relapsed/refractory and previously untreated MCL. Among the 24 patients enrolled, half harbored TP53 aberrations and 75% had a high-risk prognostic score.41 At week 16, the CR rate was 42%, which is higher than the historical CR rate of 9% observed with ibrutinib alone. MRD negativity was observed in 67% of patients.41 

Several studies are also assessing the use of venetoclax in combination with established chemotherapy regimens for NHL, including rituximab, cyclophosphamide, doxorubicin, vincristine [Oncovin]; and prednisone, and obinutuzumab [GA101], cyclophosphamide, doxorubicin, vincristine, and prednisone.33

Practical and Therapeutic Implications
Safety Considerations
Although promising efficacy has been observed in many trials of venetoclax, associated AEs must be considered when incorporating venetoclax into therapy decisions. TLS is the most serious AE observed in clinical trials of venetoclax. This AE, which is caused by the potency of venetoclax in activating apoptosis, has been largely mitigated by strategies that incorporate ramp-up dose escalation and TLS prophylaxis.1 Beyond TLS, the most common AEs observed across the various venetoclax trials are gastrointestinal AEs and neutropenia. Although approximately 50% of all patients treated with venetoclax have experienced mild nausea or vomiting, discontinuation due to these AEs was rare across the phase I and phase II trials. The mechanisms responsible for the gastrointestinal toxicity are currently unknown, although possibilities include an on-target effect of BCL-2 inhibition or response to the chemical properties or formulation of the molecule.16 

The other common AE associated with venetoclax treatment is neutropenia. Grade 4 neutropenia was observed in 23% to 28% of patients across phase I and phase II trials, and febrile neutropenia was reported in 5% to 6% of patients in phase I and phase II trials in CLL.16 Neutropenia can be easily managed through treatment with growth factors or a short-term pause in venetoclax administration.1 

Infrequent serious infections have also been observed in 17% to 20% of patients in phase I and II trials, with <1% of the cases being fatal.16 Importantly, venetoclax has also been shown to be safe in combination with other agents. Because the AE profiles in combination studies have been similar to venetoclax monotherapy, venetoclax can be used at its maximum dose in combination therapy approaches. The ability to use the maximum venetoclax dose enhances the potential efficacy of this agent in combination studies.1

Resistance
In several hematologic malignancies, resistance to venetoclax can be mediated by upregulation of other antiapoptotic BCL-2 family proteins, including BCL-XL, BFL-1, and MCL-1, which bind to and sequester the proapoptotic BH3 proteins.16 In addition, BCL-2 phosphorylation can prevent venetoclax from displacing BAX and BIM, thereby reducing the efficacy of the agent. In patient-derived CLL cells, the ratio of MCL-1 to BCL-2 protein levels plus the level of phosphorylated BCL-2 can predict the cytotoxic activity of venetoclax in culture. BCL-2 phosphorylation has therefore also been associated with venetoclax resistance in CLL cells.16 

The upregulation of BCL-2 family members leading to venetoclax resistance can be mediated by numerous mechanisms, many of which form the basis for the combination therapy approaches described above. For example, sustained B-cell receptor stimulation in primary CLL cells can cause upregulation of MCL-1, leading to venetoclax resistance. Inhibitors of spleen tyrosine kinase, BTK, PI3K-Δ, MEK, and CDKs can downregulate MCL-1 and overcome this resistance.16 As described above, numerous clinical trials across a variety of hematologic malignancies are ongoing, in order to evaluate these agents in combination with venetoclax. 

Future Directions
The FDA approvals of venetoclax since 2016 have added an important option for the treatment of patients with CLL and AML. With promising results emerging from trials across additional tumor types, venetoclax approval may expand to other hematologic malignancies in the coming years. As development of this agent continues, further exploration of the mechanisms of resistance to venetoclax and continued evaluation of combination therapies will become increasingly important.16 Because high levels of BCL-XL and MCL-1 have been suggested to mediate resistance to venetoclax, selective inhibitors of these proteins are now in clinical development. In addition, the variety of approaches using combination therapies to downregulate the expression of antiapoptotic family members and promote expression of proapoptotic family members continues to expand. As other BCL-2 family inhibitors and effective combination approaches are validated, the identification of appropriate diagnostic and biomarker strategies for risk stratification will become critical. Although evaluation of BCL-2 expression levels represents 1 approach for identifying those patients most likely to benefit from BCL-2 inhibitors, the development of additional approaches based on the expression profiles of additional genes may provide further predictive power. Given the promising results with the early trials of venetoclax, efforts to maximize the therapeutic potential of BCL-2 inhibitors hold the potential to substantially improve outcomes among patients with hematologic malignancies.
 

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