Venetoclax, Bendamustine, and Rituximab in Patients With Relapsed or Refractory NHL

A Phase Ib Dose-Finding Study

S. de Vos; L. J. Swinnen; D. Wang; E. Reid; N. Fowler; J. Cordero; M. Dunbar; S. H. Enschede; C. Nolan; A. M. Petrich; J. A. Ross; A. H. Salem; M. Verdugo; S. Agarwal; L. Zhou; M. Kozloff; L. J. Nastoupil; C. R. Flowers


Ann Oncol. 2018;29(9):1932-1938. 

In This Article

Abstract and Introduction


Background: Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine–rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL).

Patients and methods: BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50–1200 mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy.

Results: Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3 months [95% confidence interval (CI) 10.4–NR], not yet reached, and 10.7 months (95% CI 4.3–21.0), respectively.

Conclusions: This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL.


The B-cell leukemia/lymphoma-2 (BCL-2) protein family members are key regulators of the apoptotic pathway.[1] The antiapoptotic proteins of the BCL-2 family promote cell survival by preventing activation of the pro-apoptotic proteins BAX/BAK, which are responsible for the initiation of the mitochondrial apoptosis pathway.[2,3] Overexpression of BCL-2 family members commonly occurs in hematologic malignancies, including non-Hodgkin's lymphoma (NHL), and is a hallmark of indolent NHL subtypes,[4,5] as well as being associated with tumor initiation and disease progression.[6–8] BCL-2 overexpression has also been linked to increased incidence of resistance to commonly used chemo-immunotherapies, such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen.[9,10]

Venetoclax is a highly selective, potent, orally bioavailable BCL-2 inhibitor. Preclinical data demonstrated that venetoclax monotherapy has broad cell-killing activity against a panel of NHL cell lines including follicular lymphoma (FL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).[8] In a phase I single-agent study, venetoclax was generally well tolerated and demonstrated promising antitumor activity in patients with relapsed/refractory NHL; overall response rate (ORR) was 44%, 13% of patients experienced complete response (CR).[11] Given the heterogeneity of clinical responses across the different subtypes of NHL, combining venetoclax with other agents was considered, particularly for FL and DLBCL. Furthermore, as venetoclax does not inhibit BCL-XL and MCL-1,[12] 2 major anti-apoptotic BCL-2 proteins that are believed to contribute to drug resistance, a combinatorial approach using agents that eliminate cancer cells through apoptosis, such as rituximab and chemotherapy, may provide further benefit.

A commonly used treatment regimen in patients with relapsed/refractory NHL is combined bendamustine and rituximab (BR). An ORR of up to 90%, CRs of 41%–60%, and median progression-free survival (PFS) of 23–24 months have been observed in the indolent subtypes [MCL, FL, small lymphocytic lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma (MZL)],[13,14] compared with ORRs of 46%–63%, CRs of 15%–37%, and median PFS of 3.6–6.7 months for patients with DLBCL.[15,16] However, many tumors ultimately become resistant to these agents.

In preclinical studies, venetoclax demonstrated synergy when combined with BR; data from NHL xenograft models harboring t(14; 18) translocations demonstrated that the combination resulted in 100% complete tumor regressions.[8] Here, we report the results of a phase Ib trial of a combination of venetoclax with BR in patients with relapsed/refractory NHL.