Key points: ● It is essential to recognize marginal zone lymphoma (MZL) as a heterogeneous group of diseases (See Figure 1 in original paper: extranodal marginal zone lymphoma [EMZL], nodal marginal zone lymphoma [NMZL] and splenic marginal zone lymphoma [SMZL]) characterized by unique biology, clinical presentation, treatment response, toxicity, and survival. ● A common characteristic across MZL subtypes is their general indolent disease course, emphasizing the need to incorporate patient-centered assessment in clinical trials to better inform the decision-making process. ● Pivotal randomized indolent lymphoma clinical trials analyzed MZL subsets without the appropriate power to capture differences between treatment arms. Furthermore, the current Lugano classification may not fully capture the presentation or treatment responses of some subtypes, preventing access to clinical trials and limiting an efficacy assessment across the disease spectrum. ● Current MZL treatment is thus largely informed by single-arm studies with relatively empiric treatment sequencing among available agents. Although frontline strategies in early and advanced-stage MZL can achieve prolonged disease control, few options exist in the relapsed/refractory setting capable of achieving similar results. See Figure 2 and 3 in original paper. ● Untreated limited-stage EMZL. ○ Gastric: Endoscopy with multiple biopsies 3 months after end of therapy. ■ Helicobacter pylori positive, No t(11;18) or unknown: H. pylori eradication therapy. ■ H. pylori negative, t(11;18) present: Radiotherapy (RT). ○ No-Gastric: RT Single-agent rituximab if RT not feasible ■ Ocular adnexal: Complete excision followed by close observation may be reasonable in selected cases. ■ Pulmonary: Although surgery is generally not recommended, it can be associated with prolonged disease control after complete resection for diagnostic purposes; subsequent active surveillance is usually recommended. In symptomatic patients, those with cavitary large lesions, multifocal parenchymal disease, advanced-stage disease, elevated lactate dehydrogenase, and disease relapse or progression after surgical resection, systemic therapy is commonly warranted. ■ Patients should be evaluated for hepatitis C virus (HCV) infection, because antiviral therapy may be associated with durable responses in those infected (See next abstract study). ● Untreated limited-stage NMZL and SMZL. ○ In patients with NMZL amenable to RT (24 Gy), the authors suggest this approach based on a large retrospective study and data extrapolated from follicular lymphoma (FL) demonstrating long-term responses. ○ Active surveillance is appropriate for asymptomatic patients with NMZL not amenable to RT or SMZL without associated HCV infection. In those with HCV-associated lymphoma, antiviral therapy is warranted in any stage. ● Untreated advanced-stage MZL. ○ The Groupe d’Etude des Lymphomes Folliculaires criteria correlate with symptomatic disease, justifying treatment initiation, and commonly representing eligibility criteria in FL trials. These have been adopted by default in NMZL, although no definitive treatment initiation criteria exist in MZL, and current recommendations are based on expert opinion (See Table 1 in original paper). ○ Bendamustine with rituximab: Bendamustine with rituximab is one of the preferred frontline regimens and typically used in most cases of advanced-stage indolent non-Hodgkin lymphoma, including FL and MZL, when systemic therapy is indicated, associated with better tolerance than R-CHOP (rituximab, cyclophosphamide, doxorubicin [Adriamycin], vincristine, and prednisone). ○ Lenalidomide with rituximab represents a treatment option in frontline and relapsed/refractory disease. ○ The routine use of obinutuzumab-based first-line therapy should be avoided in MZL. ○ Relatively uniquely, based on retrospective data, single-agent rituximab is the preferred agent in patients with symptomatic SMZL requiring therapy. Splenectomy in selected cases. ○ Based on the lack of overall survival benefit and higher infection risks, the authors do not recommend using rituximab maintenance in MZL. ○ In unfit patients chlorambucil with rituximab is another option. ● Relapsed/refractory MZL. ○ Despite no initial survival benefit, lenalidomide with rituximab is a preferred National Comprehensive Cancer Network option in MZL. ○ Zanubrutinib in relapsed/refractory MZL was approved based on the results of a phase 2 clinical trial (MAGNOLIA), but ibrutinib was withdrawn due to a lack of consistent clinical benefit. ○ Based on the need for specialized centers, manufacturing process, toxicity profile, emergence of novel agents, and inclusion of a small number of patients, chimeric antigen receptor T-cells will likely remain an option for a selected group of patients with MZL. ● Progression of disease within 24 months (POD24) after frontline immunochemotherapy is an established prognostic factor in FL associated with shorter survival. In MZL, several studies independently confirmed the shorter survival associated with POD24. A caveat of the POD24 definition in MZL is that most studies included single-agent rituximab in this analysis and did not restrict this definition to previous cytotoxic chemotherapy, unlike FL analyses. No guidelines exist about treatment selection in MZL with POD24. ● Emerging data demonstrate the encouraging efficacy of CD3×CD20 bispecific antibodies and antibody-drug conjugates in achieving deep responses, as well as the potential of circulating tumor DNA in risk stratification and molecular response monitoring. |
