Marginal Zone Lymphoma: Subtypes, Treatments, the Role of the Pharmacist

Marginal zone lymphoma (MZL)—a low-grade, B-cell, non-Hodgkin lymphoma—is relatively rare, explained a panel of experts during an Insights series video discussion for Pharmacy Times.® The disease arises from a marginal zone of the lymph nodes, spleen, or mucosa-associated lymphoid tissue (MALT), and accounts for around 10% of non-Hodgkin lymphoma cases.

“Nodal MZL is even rarer,” said Amitkumar Mehta, MD, during the Insights discussion. “About 4000 cases of nodal MZL happen every year. The main pathophysiology of MZL is chronic antigen stimulation and that can happen for a variety of reasons.”

When describing the pathophysiology of MZL, Mehta noted the role of chronic antigen stimulation; in external MZL, Helicobacter pylori can cause chronic antigen stimulation in a condition known as H pylori gastritis.

“The other important part that I want to emphasize is hepatitis C,” Mehta said. “It is seen in about one-quarter to one-third of patients with MZL associated with hepatitis C infection. So that is one of the tests that we would definitely conduct in all the patients apart from other regular tests for lymphomas.”

When asked to review the differences between MZL and other B-cell disorders, Javier Munoz, MD, MS, FACP, highlighted the broad spectrum of conditions under the MZL umbrella.

“It is not 1 disease but many. MZL represents a group of lymphomas that have historically been classified together, but truly are different,” Munoz said. “Some of these external lymphomas grow from epithelial cells in the stomach or in the periocular area; hence, they can remain localized in that area for a long time.”

Additionally, Munoz noted that since the clinical manifestations of MZL can be powerful, it is important to remain cautious and not give a blank check for treatment recommendations.

“Treatment needs to be individualized so that patients with localized disease could potentially receive localized treatments like radiation,” Munoz said.

The panel also reviewed patient management and explained that frequently, active surveillance is required. Patients are monitored for symptoms and treatment criteria before therapy is selected in order to avoid accidental diagnosis and mistreatment. According to Mehta, only around 15% to 20% of MZL patients have symptoms, so it is critical to make sure patients have not been misdiagnosed.

“For early stage, there is a potential for cure,” Mehta said. “You could achieve that by giving radiation. You’re to always have a risk-benefit in that situation, but it depends on the site where you’re going to radiate. If it is auxiliary lymph node, definitely you can radiate and you can have patients cured with low-grade lymphoma. For advanced stage, again, following the same guidelines, if they meet the indications for treatment, that’s when you jump in and do systemic therapy.”

The panelists also highlighted the potential for B-cell depletion therapies, which are frequently powerful treatments for the disease. According to Bhavesh Shah, RPh, BCOP, following 4 doses of rituximab, patients can still be in remission from MZL 7 years after treatment. In terms of maintenance therapy, Mehta also highlighted the importance of considering the subtype of MZL when selecting a therapy.

“Whether this is nodal vs mucosa-associated MZL or splenic MZL, all would have a different goal of therapy. Amongst this, I feel that advanced stage nodal marginal lymphomas are the ones that are going to give you trouble. The others, they have relatively better outcomes.” Mehta said. “For low-grade lymphomas, maintenance therapy definitely improves progression-free survival, but the impact on overall survival we have not seen yet. I think that applies to MZL also.”

Mehta also commented on the impact of the COVID-19 pandemic on treatment options for these patients, explaining that when putting patients on maintenance therapy, there are 2 specific disadvantages to consider during the pandemic.

“One, they have to come more frequently to the clinic to get the infusion. That’s why they’re at relatively high risk of catching COVID-19; hospitals are the main source,” Mehta said. “The second, which is important, is chronic B-cell depletion. That leads to hypogammaglobulinemia, which puts them at a high risk of infections in general. Pneumonia and sinus infections are most common, and they also have a high risk of catching COVID-19 in this situation.”

Mehta explained further that several small, short-term studies were recently conducted that showed patients with lymphoma on maintenance therapy have been shown to not have as strong an immune response to vaccination against COVID-19 compared to other patients. These study results highlight the need to proceed with caution when approaching therapy selection, as requiring patients to return to the hospital for treatment during the pandemic, even for patients on maintenance therapy, continues to put patients at an increased risk for COVID-19 exposure.

MZL Treatment Selection Guidelines

Reviewing the National Comprehensive Cancer Network (NCCN) treatment guidelines for MZL, Shah commented on the impact these guidelines can have on current practice, stating that certain institutions directly place NCCN guidelines into their electronic medical record.

The panelists agreed that while these guidelines have considerable impact on treatment selection and payer coverage, it’s important to treat them first and foremost as recommendations.

“NCCN guidelines are not gospel, but it’s extremely helpful for us to validate some of these therapies. To recommend the second-line therapy, first, we need to know which was the first-line therapy,” Munoz said. “This is important as we tend to lump together multiple indolent lymphomas in the same bucket. The BRIGHT study included follicular lymphoma, MZL, even mantle cell lymphoma, which most of us consider an aggressive lymphoma, not an indolent one.”

As a result, there are a number of NCCN-recommended treatments for MZL, including bendamustine plus rituximab, bendamustine plus obinutuzumab, R-CVP, R-CHOP, R-squared (lenalidomide plus rituximab), BTK inhibitors, and PI3 kinase inhibitors.

“So we have a plethora of options, which is a good problem to have,” Munoz said. “Now, how do we choose? Again, it depends on the first-line therapy, the duration of response to that first-line therapy, performance status comorbidities, patient preference, age. I personally look for excuses not to prescribe chemotherapy, so I’m grateful to have nonchemotherapy options in second-line therapy.”

The panel also emphasized the important role pharmacists play in managing toxicities and drug interactions for patients with MZL. As patients with this disease are expected to undertake long-term therapies with increased risks of toxicity, having the direct involvement of a pharmacist is crucial to ensure patients receive the appropriate treatment.

“My nurse and our pharmacist are critical team members. They are my right hand; they help me to review concomitant medications, make sure I’m not missing any possible interactions, particularly proton pump inhibitors,” Munoz said. “As you know, that is important when it comes to acalabrutinib. And I always follow the algorithms, or the recommendations regarding dose reductions or dose interruptions, and we make these decisions as a team including the patient, keeping the patient front and center when it comes to his or her symptoms.”