Targeting BCL-2 in Hematologic Malignancies

Published: Friday, Jan 11, 2019
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 

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Online CME Activities
TitleExpiration DateCME Credits
Oncology Consultations®: The Advancing Role of CAR T-Cell Therapies in Hematologic MalignanciesApr 30, 20191.5
Advances in™ Diagnostic Guidelines for Effective Clinical Decision - Making in the Management of Hematologic MalignanciesApr 30, 20191.5
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