The withdrawn approvals of ibrutinib for relapsed/refractory mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) are likely to have a limited impact on patients, according to lymphoma experts.

Hematologists and oncologists say that, for most patients, switching to a different Bruton tyrosine kinase (BTK) inhibitor should not pose any risks.

The only patients for whom the withdrawn approvals could become an issue are those with central nervous system (CNS) involvement, as ibrutinib is the only BTK inhibitor proven to cross the blood-brain barrier, said Brad Kahl, MD, professor of medicine and director of the lymphoma program at Washington University in St. Louis, Missouri.

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Patients with CNS involvement might be able to continue receiving ibrutinib off label, though it may not be covered by insurance.

Ibrutinib was originally approved via the accelerated approval pathway for relapsed/refractory MCL in 2013 and for relapsed/refractory MZL in 2017.1,2

Earlier this month, Janssen Biotech and Pharmacyclics, an AbbVie company, announced the voluntary withdrawal of ibrutinib in the United States for the treatment of patients with MCL who had received at least 1 prior therapy and for patients with MZL who require systemic therapy and had received at least 1 prior anti-CD20-based therapy.3

The decision to withdraw the BTK inhibitor was made in consultation with the US Food and Drug Administration (FDA) based on results from confirmatory phase 3 trials. The decision does not affect any other approved indications of ibrutinib in the US.

Alternative BTK Inhibitors Available  

The news of the ibrutinib withdrawals should not be cause for alarm, said Eduardo Sotomayor, MD, chair of the MCL Consortium for the Lymphoma Research Foundation and director of the Cancer Institute at Tampa General Hospital in Florida.

“It would be a different scenario if this were the only drug available,” Dr Sotomayor said. “Fortunately, we have alternatives at this point for patients who are taking ibrutinib.”

Physicians and patients should discuss whether it would be appropriate to switch to another BTK inhibitor or continue ibrutinib off label, Dr Sotomayor said. He advised hematologists and oncologists to consult with pharmacists and insurers about whether ibrutinib will continue to be available at the dose needed and if it will be covered off label.  

For patients needing alternative BTK inhibitors, acalabrutinib and zanubrutinib are FDA-approved to treat patients with MCL who have received at least 1 prior therapy.4,5 Pirtobrutinib is approved to treat MCL patients who have received at least 2 lines of systemic therapy, including a BTK inhibitor.6 Zanubrutinib is also approved to treat patients with MZL who have received at least 1 anti-CD20-based regimen.7 

Many patients with MCL or MZL have started on, or already switched over to, these newer BTK inhibitors because of the more favorable side effect profiles, compared with ibrutinib, said Julie Vose, MD, chief of the division of oncology and hematology at the University of Nebraska Medical Center in Omaha. Patients who are still taking ibrutinib are likely to have been on the drug for years without significant toxicity.

For patients with MCL or MZL who are currently having success on ibrutinib, Dr Vose said she would probably continue treatment off label if it is accessible. If the drug is unavailable or not covered by insurance, she said making the switch to another BTK inhibitor is safe.

“Ibrutinib has been used less and less in the last few years,” Dr Kahl noted. “It’s a great drug, and, when we first got it, it was the best thing we had. But as often happens, better versions of it came along.”  

Dr Kahl said that, for most of his patients currently taking ibrutinib, he will likely try to switch them to another BTK inhibitor rather than trying to obtain ibrutinib off label. The exceptions are the MCL or MZL patients with CNS involvement who have had success with ibrutinib because it crosses the blood-brain barrier. While other BTK inhibitors may cross the blood-brain barrier, it has not been conclusively established, he said.

For patients making the switch to another BTK inhibitor, Dr Kahl said it is important to think about whether to transition the patient immediately or give them a “treatment holiday,” based on how long they have been on ibrutinib and the quality of their current remission. “That decision will have to be handled on a case-by-case basis,” he said.

Data Supporting Withdrawal

The decision to withdraw ibrutinib for the MCL and MZL indications was based on data from a pair of phase 3 trials designed to confirm the clinical benefit of ibrutinib.3

In the SELENE trial ( Identifier: NCT01974440), researchers evaluated the use of either bendamustine and rituximab (BR) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), with or without ibrutinib, in patients with relapsed/refractory follicular lymphoma or MZL. Though the results have not been published or presented, Janssen and AbbVie reported that the study did not meet its primary endpoint of progression-free survival (PFS).

In the SHINE trial ( Identifier: NCT01776840), researchers evaluated the use of ibrutinib or placebo, each in combination with 6 cycles of BR, followed by rituximab maintenance in patients aged 65 years and older with untreated MCL.

The findings, which were published in The New England Journal of Medicine in 2022, showed that ibrutinib significantly improved PFS, compared with placebo.8 However, overall survival was similar between the groups, and the incidence of grade 3-4 adverse events was higher in the ibrutinib group.

While the SELENE data are straightforward because ibrutinib missed the primary endpoint, the SHINE data are more complicated since the PFS endpoint was achieved, but ibrutinib failed to improve overall survival, Dr Kahl said.

“There’s no question that adding ibrutinib into the mix improved the control of the mantle cell lymphoma, but it came at a cost,” Dr Kahl said. “There were more toxicities and deaths, not from the lymphoma, but due to infections, for example. The study met its primary endpoint, but it didn’t really move the needle in terms of improving patient outcomes in the kind of meaningful way one would want.”

Disclosures: Dr Kahl reported consulting for Janssen, Pharmacyclics/AbbVie, AstraZeneca, BeiGene, and Eli Lily. Dr Sotomayor reported being on the advisory board and serving as a speaker for Janssen, Pharmacyclics, and Eli Lilly. Dr Vose reported consulting for AbbVie and clinical trials with Loxo Oncology/Eli Lilly.


1. Imbruvica (ibrutinib) capsules now approved in the U.S. for mantle cell lymphoma patients who have received at least one prior therapy. News Release. Johnson & Johnson. Published November 13, 2013. Accessed April 22, 2023.

2. U.S. FDA approves Imbruvica (ibrutinib) as first treatment specifically indicated for relapsed/refractory marginal zone lymphoma (MZL) – a rare type of non-Hodgkin’s lymphoma. News Release. AbbVie. Published January 19, 2017. Accessed April 22, 2023.

3. Update on Imbruvica (ibrutinib) US accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. News release. AbbVie. Published April 6, 2023. Accessed April 22, 2023.

4. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. News release. US Food and Drug Administration. Published October 31, 2017. Accessed April 22, 2023.

5. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. News release. US Food and Drug Administration. Published November 15, 2019. Accessed April 22, 2023.

6. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. News release. US Food and Drug Administration. Published January 27, 2023. Accessed April 22, 2023.

7. FDA grants accelerated approval to zanubrutinib for marginal zone lymphoma. News release. US Food and Drug Administration. Published September 16, 2021. Accessed April 22, 2023.

8. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphomaN Engl J Med. 2022;386(26):2482-2494. doi:10.1056/NEJMoa2201817