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Sequencing BTK Inhibitors in Treatment of Marginal Zone Lymphomas

John P. Leonard, MD

Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
Professor of Medicine
Weill Cornell Medicine
New York Presbyterian Hospital
New York, New York


John P. Leonard, MD, has disclosed that he has received consulting fees from AbbVie, AstraZeneca, Bayer, Bristol-Myers Squibb/Celgene, Epizyme, Genentech/Roche, GenMab, Gilead Sciences/Kite, Incyte, Janssen, Karyopharm, MEI Pharma, Miltenyi, Regeneron, and Sutro and funds for research support from Genentech and Janssen.


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Released: November 2, 2021

With the recent FDA approval of zanubrutinib for patients with relapsed/refractory marginal zone lymphoma (MZL), we now have 2 approved BTK inhibitors to offer our patients under this indication. Below, I share my approach to sequencing available therapies and, in the relapsed setting, choosing between these available BTK inhibitors.

First-line Treatment
The optimal approach to first-line treatment of MZL depends on its presentation, which falls into 3 major categories: splenic, extranodal mucosa-associated lymphatic tissue (MALT), and nodal.

Patients with splenic MZL present with an enlarged spleen, bone marrow involvement, and sometimes cytopenias. We historically used splenectomy, but now patients are more often observed or, if splenomegaly and/or cytopenias develop, treated with rituximab‑based therapy (often alone or with chemotherapy), followed by observation and often retreatment.

MALT lymphomas can occur in many extranodal sites, including gastric/GI, lung, ocular, and skin. We may observe the patient depending on the location, or if the patient has a gastric location that is positive for Helicobacter pylori infection, we may treat with H pylori–directed antimicrobials. Radiation may also be considered for some patients with MALT lymphomas, depending on stage and location.

Nodal MZLs are typically treated like other indolent lymphomas, most commonly with chemoimmunotherapy regimens such as bendamustine/rituximab, R‑CVP, or R‑CHOP, and sometimes with single‑agent rituximab.

Treatment of Relapsed Disease
When patients relapse with MZL, our treatment approach can include regimens used for follicular lymphoma, with the addition of BTK inhibitors as an option. Other possibilities include single-agent rituximab, chemoimmunotherapy, and—in the third-line setting—PI3K inhibitors. Lenalidomide/rituximab is also an option for patients with relapsed MZL, depending on the location. Unlike follicular lymphoma, we do not have an FDA approval for CAR T‑cell therapy to treat MZL. However, like follicular lymphoma, we must be aware of the possibility of transformation to DLBCL—although transformation can be harder to detect because MZL can have higher SUV on PET scans, in some cases without aggressive histology.

BTK Inhibitors
BTK inhibitors are an established stand of care in this setting, given their FDA approvals and efficacy in the setting of relapsed/refractory MZL. Ibrutinib is approved for patients with MZL requiring systemic therapy after at least 1 previous anti-CD20–based regimen and zanubrutinib for relapsed/refractory MZL previously treated with at least 1 previous anti-CD20–based regimen. Both agents can be particularly useful in patients who have already received chemoimmunotherapy or who need an alternative to chemoimmunotherapy.

Data suggest comparable efficacy across BTK inhibitors but better tolerability with the newer agents. I most commonly recommend zanubrutinib over ibrutinib because although it is a newer agent with shorter-term experience, comparative trials in other malignancies have demonstrated at least similar efficacy and better tolerability vs ibrutinib, particularly regarding cardiac toxicity (ie, atrial fibrillation). However, either of these agents are reasonable options. 

To get individualized recommendations on how a panel of 5 experts would manage specific toxicities associated with BTK inhibitors, please visit CCO’s Interactive Decision Support Tool on this topic. 

PI3K Inhibitors
The National Comprehensive Cancer Network® (NCCN®) recommends the PI3K inhibitors copanlisib, duvelisib, and idelalisib as a choice after 2 previous therapies in MZL as well as umbralisib in the relapsed/refractory setting after at least 1 previous anti-CD20–based therapy. Because we have the longest-term data with idelalisib, I have generally used idelalisib for my patients with MZL in this setting, although although one must be familiar with its safety profile. The prescribing information for idelalisib includes black box warnings for fatal and/or serious hepatotoxicity, diarrhea/colitis, pneumonitis, infections, and intestinal perforation. 

Sequencing BTK and PI3K Inhibitors
Although we lack robust comparative data on BTK vs PI3K inhibitors for relapsed MZL, I typically sequence a BTK inhibitor before a PI3K inhibitor because the reported response rates are higher and the duration of response seems longer. Furthermore, we have more direct experience with BTK inhibitors in MZL.

Your Thoughts?
How are you using BTK inhibitors, PI3K inhibitors, and chemoimmunotherapy for your patients with MZL? Do you consider lenalidomide/rituximab? Please join the discussion by adding a comment below and answering the poll.

Do you want to learn more about optimizing the care of patients with MZL? Sign up here to attend the live symposium or simulcast webinar “A Class in Session: Understanding Current and Future Therapeutic Advances Across B-Cell Lymphomas” on Friday, December 10, 2021, at 7:00 PM Eastern time with me and my colleagues, Brad S. Kahl, MD, and Julie M. Vose, MD, MBA, when we will discuss the available evidence, key ongoing clinical issues, and new data in various B-cell lymphomas.

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Supported by educational grants from
Atara Biotherapeutics, Inc.
Bayer HealthCare Pharmaceuticals Inc.
BeiGene, Ltd.
Epizyme
Genentech, a member of the Roche Group
Genmab US, Inc.
Incyte Corporation
Karyopharm Therapeutics
Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc.

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