Research review: Treatment options for marginal zone lymphoma

By Courtney Manser, MD, CCFP (PC) | Medically reviewed by Jeffrey A. Bubis, DO, FACOI, FACP
Published December 4, 2023

Key Takeaways

  • Marginal zone lymphoma (MZL) primarily presents as a slow-growing B-cell non-Hodgkin's lymphoma with the following three subtypes: extranodal, splenic, and nodal.

  • First-line treatment often includes pathogen-targeted therapies, localized radiation, and/or splenectomy in the case of splenic MZL.

  • New targeted treatments such as Bruton’s tyrosine kinase inhibitors (BTKis), most notably zanubrutinib (a second-generation BTKi with increased selectivity), offer promise to improve MZL treatment efficacy and tolerability in patients with recurrent/refractory disease.

Marginal zone lymphomas (MZL) are a group of indolent B-cell non-Hodgkin's lymphomas (NHL) which arise from the marginal zone in the lymph tissue.[] Making up about 8% of all NHL cases, MZL is not insignificant. Historically, MZL has often been treated like other B-cell lymphomas, of which there is no standard treatment.[]

New advances in research have begun to further separate MZL, focusing on specialized, targeted treatment.

Diagnosis of MZL

MZL is comprised of three distinct groupings: extranodal MZL (EMZL), which is often called MALT lymphoma; splenic MZL (SMZL), with or without villous lymphocytes; and nodal MZL (NMZL), with or without monocytoid B cells. EMZL is the most common, accounting for two-thirds of MZL cases, and NMZL is the rarest, accounting for less than 10%.[]

Presentation of MZL varies widely depending on the subtype, as well as where the primary tumor is located. Gastric MALT occurs in the stomach and is often associated with chronic infection of H. pylori. Another pathogen linked to EMZL of the eye is C. psittaci, though support for this association varies across geographic regions. MZL has been associated with hepatitis-C infection, but with a similarly ambiguous association. Further, unlike with MALT associated with H. pylori, response to antibiotics is more variable, according to Jeffrey A. Bubis, DO, FACOI, FACP.

Current treatment protocol

MZL is considered incurable, and standard chemo-immunotherapy and toxicity represent barriers for treatment, write authors publishing in Blood Advances.[]

Treatment depends on the disease type, stage, and reason for treatment, according to Dr. Bubis. He provides an example of a patient presenting with MALT with H. pylori, noting that treatment for the H. pylori can be adequate therapy, with some studies suggesting this leading to long-term, disease-free survival.

Overall, the medical community’s understanding of MZL’s pathophysiology is rapidly evolving, making targeted treatment more possible. First-line treatment of localized MZL is often targeted with treatment of the associated pathogen (with H. pylori showing the strongest response, while data for other pathogens is weak), along with targeted radiation and, in the case of SMZL, splenectomy, according to the authors of an article in Current Oncology.[]

Chemo-immunotherapy is considered first-line for treatment for most symptomatic, advanced MZL. Other treatment avenues include single-agent rituximab, which is used alone or in combination with chemotherapy.

In 2019, the FDA approved lenalidomide used in combination with rituximab as a second-line treatment for patients with MZL. Further targeted treatments have also been developed in recent years to be used in relapsed or refractory MZL. It should be noted that toxicity and/or accessibility are concerns for all treatments, according to the Blood Advances authors. 

Use of BTKis

Bruton’s tyrosine kinase inhibitors (BTKis) work by impairing cell proliferation, migration, and activation of NF-κB.[] Ibrutinib was the first BTKi to be approved for treatment, with an overall response rate in relapsed or refractory MZL of 48%, per the Blood Advances study. However, as noted, toxicity is a concern, given risks including atrial fibrillation/flutter and bleeding risk. 

Related: Managing cardiotoxicity of BTKi treatments

Zanubrutinib, a potent and irreversible BTKi created to improve BTK selectivity, has proven to have increased tolerability and diminished cardiac and bleeding side effects when compared with its first-generation counterpart, based on cross-trial comparisons.

Per the Blood Advances study, zanubrutinib was better tolerated with similar efficacy results to previously available treatments in MZL patients, and it is FDA approved for this indication. 

As zanubrutinib is better tolerated, the study authors hope this will lead to less discontinuation of treatment and therefore better long-term effect. It is now being studied as combination therapy with other treatment options.

What this means for you

Recent studies have aimed to better characterize both the effectiveness and tolerability of treatment options specific to MZL. Unfortunately, chemo-immunotherapy, as well as many other new targeted therapies, are associated with high rates of discontinuation due to their side effect profile. Zanubrutinib, a second-generation BTKi, offers promise by demonstrating efficacy and improved tolerability for MZL patients. Further research needs to be done to determine if combination therapy with zanubrutinib is superior to monotherapy. 

Read Next: Looking forward: How far we’ve come with understanding BTKis
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