Wealth of BTK Inhibitors Provides Tolerable, Individualized Treatment Options in CLL and MCL


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Prioty Islam, MD, MSc, reviews the benefits of using covalent BTK inhibitors in CLL and MCL; considerations for choosing first-generation vs next-generation covalent BTK inhibitors in patients with these B-cell malignancies; and the potential future role for ibrutinib in the CLL treatment paradigm.

Prioty Islam, MD, MSc

Prioty Islam, MD, MSc

Close attention to adverse effect (AE) profiles, along with shared decision making, can best inform choices regarding optimal BTK inhibitor use in patients with chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL), according to Prioty Islam, MD, MSc, who noted that regimens combining BTK inhibitors and agents such as BCL2 inhibitors may further expand treatment options for these patients in the future.

In 2013, the FDA approved ibrutinib (Imbruvica) for patients with pretreated MCL.1 However, in April 2023, AbbVie announced its voluntary withdrawal of the agent in patients with pretreated MCL and marginal zone lymphoma based on findings from the phase 3 SHINE (NCT01776840) and SELENE (NCT01974440) trials, respectively.2 In February 2014, ibrutinib was approved in patients with pretreated CLL, and in July 2014, the agent received regular approval for patients with CLL, including those with 17p deletions.3 In 2016, the FDA approved the agent as frontline therapy in patients with CLL.4

In 2017, acalabrutinib (Calquence) was approved by the FDA for patients with pretreated MCL,5 and in 2019, the agent received FDA approval for patients with CLL.6

In 2019, the FDA granted accelerated approval to zanubrutinib (Brukinsa)for patients with relapsed/refractory MCL,7 and on January 19, 2023, zanubrutinib received FDA approval for patients with CLL or small lymphocytic lymphoma.8

“We’re in a fortunate position where all the BTK inhibitors have excellent efficacy and reasonable safety,” Islam said in an interview with OncLive®.

In the interview, Islam, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, reviewed the benefits of using covalent BTK inhibitors in CLL and MCL; considerations for choosing first-generation vs next-generation covalent BTK inhibitors in patients with these B-cell malignancies; and the potential future role for ibrutinib in the CLL treatment paradigm.

OncLive: What is the current role of covalent BTK inhibitors in patients with CLL?

Islam: [Covalent] BTK inhibitors are currently approved across all treatment lines in CLL. We can use them interchangeably in the frontline setting for patients who are treatment naïve, or for patients who have progressed on a prior novel agent. If you’re using [covalent BTK inhibitors] in the relapsed setting, it’s usually because those patients have progressed on, say, venetoclax [Venclexta] as a frontline treatment.

We currently have 3 covalent BTK inhibitors available for use in CLL, with our most recent BTK inhibitor, zanubrutinib, just approved [in January 2023], which is exciting. We have many different treatment options to offer patients.

Most key opinion leaders in the CLL space are now using acalabrutinib or zanubrutinib as their first covalent BTK inhibitor of choice because of improved safety and efficacy data. In the relapsed setting, [data with] zanubrutinib showed superior efficacy to ibrutinib. Then, a head-to-head trial showed that acalabrutinib had at least noninferiority with ibrutinib.

Even with patients who have been on, say, ibrutinib, and are responding, I’m starting to have conversations in clinic about switching them over to either acalabrutinib or zanubrutinib because of concerns about long-term safety. [However, these are] 3 effective agents available for patients in all lines. [This is an] excellent time to be using BTK inhibitors in CLL.

Are there still patients with CLL in whom you would consider using ibrutinib instead of acalabrutinib or zanubrutinib?

It rarely comes up that there’s a patient profile where I consider ibrutinib over acalabrutinib or zanubrutinib. The specific scenarios in which that has come up are, for example, in certain patient subsets where only ibrutinib has any kind of safety or efficacy data. Some phase 2 data suggest that ibrutinib in combination with nivolumab [Opdivo] can be effective in [patients with] Richter transformation. In those specific patients, I would not try a next-generation BTK inhibitor because there are no data to support that use. I reach for ibrutinib when there are no other safety or efficacy data, but it’s rare that that comes up in clinic.

In what novel ways are BTK inhibitors being explored in CLL and MCL?

Many clinical trials are investigating combination therapies. We’re evaluating combinations of BTK inhibitors with BCL2 inhibitors. [We are] combining, for example, acalabrutinib and venetoclax in the frontline setting to try to provide patients with an all-oral, time-limited option as an alternative to our current frontline paradigms, which are either continuous BTK inhibitor therapy, or a combination of a BCL2 inhibitor with a monoclonal antibody infusion. There’s much interest in studying novel-novel combinations to create regimens that are more convenient, more tolerable, and hopefully more effective than the regimens we have available. That’s 1 interesting way BTK inhibitors are being explored.

Another interesting way is investigating the use of minimal residual disease to help guide how long patients should truly remain on a BTK inhibitor. Currently, all BTK inhibitors are approved in a continuous treat [to] progression or treat to intolerance strategy. However, the truth is, maybe subsets of patients would do perfectly well with a truncated or attenuated treatment course. We just don’t know who those patients are yet. Several studies are evaluating that as well. If we’re going to [offer] time-limited therapy with a BTK inhibitor, we would probably need to combine it with another novel therapy to try to induce a deeper remission, since complete responses [CRs] with BTK inhibitor monotherapy are rare at this point. We’re usually seeing more partial responses than CRs.

Another emerging area being explored is novel ways to target the BTK protein. We have covalent BTK inhibitors, and we have noncovalent BTK inhibitors, which reversibly bind to the BTK protein. There are other ways we’re targeting that same protein. For example, a wealth of novel agents is being studied that degrade the BTK protein. In that way, [the agents] overcome all the different resistance mechanisms of BTK inhibitors because they essentially eliminate the entire BTK protein, taking it out of that signaling pathway. That’s how you aggregate all the signaling through the B-cell receptor pathway. [Ongoing research is investigating] novel ways of targeting the same protein that build on our experience with covalent and noncovalent BTK inhibitors.

What is your main message for colleagues regarding the evolving role of BTK inhibitors in CLL and MCL?

Within both CLL and MCL, with BTK inhibitors, we have a safe, well-tolerated, non-burdensome treatment option for patients. Even in those with high-risk disease, whether it be CLL with TP53 mutations or 17p deletions, which are traditionally poor-risk markers, or relapsed/refractory MCL, we now have targeted agents that are inducing significant responses, improving quality of life, and producing meaningful clinical outcomes for patients.

BTK inhibitors are approved across all lines of therapy in CLL and are appropriate for use in any line of therapy. For MCL, [BTK inhibitors are approved] in the relapsed/refractory setting.

The most common question I get from practicing oncologists is how to choose [between BTK inhibitors]. [This choice involves] shared decision making with the patients. Each BTK inhibitor has its own toxicity profile. A couple toxicities are seen as class effects, for example, arrhythmias, bleed risk, and hypertension. [We should go] through those AE profiles in detail with patients and talk about the various ways we dose the drugs. Ibrutinib [is given] once daily and acalabrutinib and zanubrutinib [are given] twice daily. Zanubrutinib has the option of being once daily for some patients. Although I don’t necessarily advise that, it is an option if a patient can’t do twice daily. I talk about all those factors with patients. I encourage shared decision making.

Disclosures: Dr Islam reports consulting roles with AbbVie, AstraZeneca, BeiGene, DAVA Oncology, and LOXO Oncology; as well as speaking roles with Targeted Oncology and The Video Journal of Hematologic Oncology (VJHemOnc).


  1. Imbruvica (ibrutinib) capsules now approved in the US for mantle cell lymphoma patients who have received at least one prior therapy. News release. Janssen Biotech, Inc. November 13, 2013. Accessed July 31, 2023. https://www.jnj.com/media-center/press-releases/
  2. Update on Imbruvica (ibrutinib) US accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. News release. AbbVie. April 6, 2023. Accessed July 31, 2023. https://news.abbvie.com/news/press-releases/
  3. Imbruvica (ibrutinib) receives regular approval by U.S. FDA in chronic lymphocytic leukemia (CLL) and CLL patients with del 17p. News Release. Johnson & Johnson. July 28, 2014. Accessed August 1, 2023. https://www.jnj.com/media-center/press-releases/imbruvica-ibrutinib-receives-regular-approval-by-us-fda-in-chronic-lymphocytic-leukemia-cll-and-cll-patients-with-del-17p
  4. US FDA approves Imbruvica (ibrutinib) for first-line treatment of chronic lymphocytic leukemia. News Release. Johnson & Johnson. March 4, 2016. Accessed August 1, 2023. https://johnsonandjohnson.gcs-web.com/news-releases/news-release-details/us-fda-approves-imbruvicar-ibrutinib-first-line-treatment
  5. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. News Release. FDA. October 31, 2017. Accessed August 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-acalabrutinib-mantle-cell-lymphoma
  6. FDA takes second action under international collaboration, approves new treatment option for patients with chronic lymphocytic leukemia. News Release. FDA. November 21, 2019. Accessed July 31, 2023. https://www.fda.gov/news-events/press-announcements/fda-takes-second-action-under-international-collaboration-approves-new-treatment-option-patients
  7. FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage. News Release. FDA. November 14, 2019. Accessed August 1, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-therapy-treat-patients-relapsed-and-refractory-mantle-cell-lymphoma-supported-clinical
  8. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed August 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
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