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by Dr. C.H. Weaver M.D. 5/2022

Brukinsa (zanubrutinib), Gazyva (obinutuzumab), and Venclexta (venetoclax) (BOVen), given on a treatment schedule driven by minimal residual disease assessment is a promising approach to previously untreated chronic lymphocytic leukemia (CLL), according to new findings from a phase II clinical trial published at the 2020 American Society of Clinical Oncology Annual Meeting. (1)

Combination time‐limited therapy with Gazyva, an anti‐CD20 antibody, and Venclexta, a B‐cell lymphoma 2 (BCL2) inhibitor, has emerged as a standard frontline option for previously untreated CLL. In a recent phase III trial, fixed‐duration treatment with Gazyva plus Venclexta induced undetectable minimal residual disease (uMRD) responses in the majority of patients with newly diagnosed CLL, with uMRD rates of 76% and 57% in the peripheral blood (PB) and bone marrow (BM), respectively. (2)

Additional early‐phase data support the combination of Venclexta with a Bruton's tyrosine kinase (BTK) inhibitor as frontline therapy for CLL. In two recent phase II trials, frontline treatment with ibrutinib plus Venclexta induced uMRD responses of 65%–75% in patients with previously untreated CLL. (3,4) Brukinsa is a BTK inhibitor with fewer side effects than first‐generation BTK inhibitiors and is associated with durable responses and a favorable safety profile. (5)

Building on these findings, researchers created a novel three‐drug combination regimen of Brukinsa, Gazyva, and Venclexta (BOVen) which combines a BTK inhibitor, anti‐CD20 antibody, and BCL2 inhibitor and designed a clinical trail to test the hypothesis that MRD‐directed, time‐limited treatment with BOVen will lead to more rapid disease eradication and durable responses in patients with previously untreated CLL.

To date, the trial has enrolled 39 patients with previously untreated CLL or small lymphocytic lymphoma (SLL) with leukemic involvement who require treatment. All patients were treated with BOVen in 28‐day cycles and after patients completed a minimum of 8 cycles a assessment of uMRD determined the remaining duration of treatment. Once uMRD was determined in the PB and confirmed in BM patients, 2 additional treatment cycles were completed for a maximum total of 24 cycles.

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Treatment with BOVen induced rapid uMRD responses in 62% of patients enabling them to stop therapy after an average of 8 months of treatment. In total, 84% of patients achieved uMRD in the blood and 73.0% percent achieved uMRD in the BM. Other novel triplet therapy combinations are being evaluated as well. 

Gazvya, Imbrvica, and Venclexta in High-Risk CLL

In the CLL2-GIVe trial, 41 patients with high-risk disease (del(17p) or TP53 mutations) were treated with induction therapy consisting of Gazvya (obinutuzumab), Imbruvica, (ibrutinib), and Venclexta (venetoclax) for cycles 1 through 6 and consolidation therapy with venetoclax and ibrutinib for cycles 7 through 12. Patients who did not reach a CR with undetectable minimal residual disease (MRD) after consolidation continued to receive ibrutinib as monotherapy for cycles 13 through 36.

The CR rate was 59% and 78% of patients had undetectable MRD in peripheral blood and 66% of patients had undectable MRD in bone marrow. The estimated progression-free and overall survival rates at 24 months were 95%.6


  1. Fischer K, Al‐Sawaf O, Bahlo J et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019; 380: 2225– 2236.
  2. Tam CS, Siddiqi T, Allan JN et al. Ibrutinib plus venetoclax for first‐line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at the 61st American Society of Hematology Annual Meeting and Exposition; December 7‐10, 2019; Orlando, FL. Abstract 35.
  3. Jain N, Keating M, Thompson P et al. Ibrutinib and venetoclax for first‐line treatment of CLL. N Engl J Med 2019; 380: 2095– 2103.
  4. Tam C, Opat S, D'Sa S et al. ASPEN: Results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). Presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. May 29–31, 2020. Abstract 8007. Available at
  5. Soumerai JD, Mato AR, Carter J et al. Initial results of a multicenter, investigator‐initiated study of MRD driven, time‐limited therapy with zanubrutinib, obinutuzumab, and venetoclax in patients with previously untreated CLL. Presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. May 29–31, 2020. Abstract 8006.
  6. Huber H, Edenhofer S, von Tresckow J, et al. Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia. Blood. 2022 Mar 3;139(9):1318-1329. doi:10.1182/blood.2021013208.