Targeting BCL-2 in Hematologic Malignancies

Published: Friday, Jan 11, 2019
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


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