CLL Monthly MinutesLeukemia

Combining Targeted Therapies in CLL

The combination of acalabrutinib, venetoclax, and obinutuzumab has been shown to be an active regimen in previously untreated patients with CLL.
Web Exclusives – November 17, 2021

Treatment for chronic lymphocytic leukemia (CLL) has been revolutionized over the past decade with the development of novel targeted therapies.1 Today, drugs such as the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax are commonly prescribed first-line therapies for many patients with CLL.2 Both of these therapies can be used alone or in combination with immunotherapies such as obinutuzumab.3,4

Because BTK and BCL-2 inhibitors act on different targets within the CLL cell, researchers have predicted that they may work better when used together.5 Previous studies have shown that the first-generation BTK inhibitor ibrutinib plus venetoclax can lead to deep responses in previously untreated patients with CLL.6 However, partly due to the unique safety profile of ibrutinib, certain side effects were seen with the ibrutinib-venetoclax combination, including development of an abnormal heart rhythm (atrial fibrillation), infection, abnormally low numbers of white blood cells called neutrophils (neutropenia), and high blood pressure.6

Acalabrutinib is a next-generation BTK inhibitor that was designed to maximize the efficacy of this class of drugs, while limiting the side effects that were seen with ibrutinib.7 Therefore, researchers have hypothesized that an acalabrutinib-venetoclax combination may also lead to deep remissions with a better safety profile than was seen for ibrutinib-venetoclax.6

In a recent phase 2 study, researchers evaluated the ability of combination therapy with acalabrutinib, venetoclax, and obinutuzumab to achieve remission in previously untreated patients with CLL or small lymphocytic lymphoma.6 Patients received treatment in approximately 1-month cycles, starting acalabrutinib during cycle 1, adding obinutuzumab from cycles 3-7, and receiving venetoclax starting in cycle 4. Remission rates were assessed at the end of cycle 15, although patients could continue therapy until cycle 25.6

Thirty-seven patients were included in this study: half were aged >63 years and 73% were male.6 Most patients in this study had cancers with genetic signatures that put them at high risk for poor outcomes, including immunoglobulin heavy-chain variable region gene-unmutated disease (73%) or TP53 mutations (27%).6

After 15 cycles of treatment, 38% of patients had complete remission with undetectable numbers of CLL cells in their bone marrow.6 Although not everyone achieved complete remission, all patients included in this study showed a response to treatment.6 Notably, the rates of complete remission were similar regardless of whether patients had high-risk genetic signatures, suggesting that this treatment regimen may be beneficial for these patients.6

Looking at safety, all patients had ≥1 side effects, although severe side effects were relatively uncommon.6 Among severe side effects, neutropenia was the most common, although abnormally high levels of blood sugar and phosphate were also observed in a few patients.6 One patient developed atrial fibrillation, causing the patient to stop taking acalabrutinib, 8 patients had upper respiratory tract infections (none were severe), 4 patients developed nonsevere high blood pressure, and 1 patient developed pneumonia.6 Two patients had tumor lysis syndrome—a notably dangerous potential side effect of venetoclax treatment—although these incidents occurred during obinutuzumab initiation and prior to the patients receiving venetoclax.6 Both cases were effectively treated without further issue.6

Overall, this study showed that combination treatment with acalabrutinib, venetoclax, and obinutuzumab is an active regimen that is generally well-tolerated in previously untreated patients with CLL, including those with high-risk disease.6 A phase 3 study (NCT03836261; is currently recruiting a larger population of patients to evaluate this combination further and may provide evidence for its use as standard frontline therapy in patients with CLL.6,8


  1. Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia. J Hematol Oncol. 2021;14:69-89.
  2. Jain N. Evolving treatment paradigm in frontline CLL [published online ahead of print, August 27, 2021]. JCO Oncol Pract. 2021;OP2100486.
  3. CALQUENCE (acalabrutinib). [prescribing information]. Wilmington, DE: AstraZeneca; 2019.
  4. VENCLEXTA (venetoclax). [prescribing information]. South San Francisco, CA: Genentech; 2021.
  5. Deng J, Isik E, Fernandes SM, et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 2017;31:2075-2084.
  6. Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021;22:1391-1402.
  7. Isaac K, Mato AR. Acalabrutinib and its therapeutic potential in the treatment of chronic lymphocytic leukemia: a short review on emerging data. Cancer Manag Res. 2020;12:2079-2085.
  8. Study of acalabrutinib (ACP-196) in combination with venetoclax (ABT-199), with and without obinutuzumab (GA101) versus chemoimmunotherapy for previously untreated CLL. Accessed November 5, 2021.

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Last modified: November 17, 2021

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