Frontline treatment of MZL

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Frontline therapy for MZL differs greatly based upon the subtype and underlying etiology. For example, a significant proportion of patients with HCV and EMZL will note regression of the lymphomatous process after undergoing antiviral treatment for HCV infection.24,26,54–60 Thus, antiviral therapy for HCV is recommended for all cases of MZL associated with HCV infection.


In patients with gastric EMZL that are positive for H. pylori, antibiotics targeting H. pylori are the initial treatment of choice. With documented H. pylori eradication, the majority of H. pylori-positive patients (up to 75%) will go into remission.61 However, ~50% of patients with gastric H. pylori-positive EMZL will have relapse/progressive disease with antibiotic therapy alone62,63 and require further therapy. A smaller proportion of H. pylori-negative gastric EMZL patients and those with non-gastric EMZL (with or without a known causative microbial agent) will respond to antibiotics alone. Hence, it is reasonable in most patients to attempt antibiotic therapy as a first-line therapy; however, most will require alternative and subsequent therapy.64–70 Though detailed guidelines for response assessment and follow-up have been published,33 there are no consensus guidelines with regard to the optimal second-line treatment after initial therapy failure35,37,38,71 Involved-field radiotherapy (IFRT) (dose of 25–35 Gy) is a reasonable first-line (in H. pylori-negative cases) or second-line option (in H. pylori-positive cases who fail H. pylori eradication therapy) for patients with localized disease, providing excellent local disease control, though distant failures still occur.72–77 Rituximab can be used alternatively if IFRT is not possible. With disseminated gastric or non-gastric disease, observation may be an adequate initial approach.

In patients who require systemic treatment, various combinations have been used and studied. The 2013 StiL trial looked at previously untreated indolent lymphoma and compared the standard of therapy, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), to a combination of bendamustine plus rituximab.78 They found that compared with R-CHOP, the combination of bendamustine and rituximab (BR) had increased progression-free survival (PFS), and there were fewer adverse events (AEs).78 Salar et al subsequently investigated BR specifically in EMZL and had good outcomes.79 Thus, historically for EMZL, bendamustine plus rituximab have been used as an active and well-tolerated first-line treatment.79 More recently, the final results of the randomized multicenter IELSG-19 trial were published.80 This randomized trial focused specifically on frontline therapy for EMZL and included 3 arms: chlorambucil monotherapy, chlorambucil plus rituximab, and rituximab monotherapy.80 What they found was that, between arms, overall survival (OS) was without significant difference.80 However, the chlorambucil plus rituximab arm did provide significantly improved event-free survival (EFS) and PFS,80 and thus, the combination of rituximab with chlorambucil has gained traction as the initial treatment of choice for EMZL.


Asymptomatic patients with SMZL can undergo observation for multiple years with routine clinical examinations and blood counts; observation in these patients does not influence overall outcomes.81,82Based on the consensus guidelines, treatment for SMZL is only indicated for symptomatic splenomegaly, progressive nodal disease, symptomatic cytopenias, and/or autoimmune cytopenias.47,55,59 Initial treatment options include splenectomy, rituximab alone, and chemotherapy combined with rituximab.83–88 Conventionally, initial treatment for patients with symptomatic splenomegaly and/or cytopenias secondary to splenic sequestration was splenectomy, and patients could remain disease-free for many years after the surgery.42,81,82,89,90 More recently, rituximab-based therapy has become a first-line alternative to splenectomy with outcomes comparable with or better than splenectomy.55,59,84,86,91–94 A combination of rituximab and chemotherapy is indicated for those with disseminated disease, constitutional symptoms, and/or having signs of high-grade transformation.55,59


There are no treatment guidelines focusing specifically on NMZL. Treatment and management typically follow that of similarly staged FL.59 In localized disease, targeted radiotherapy is appropriate, while in both limited and advanced-stage diseases with low tumor burden, watchful waiting is employed. No trials to date have looked at NMZL specifically; however, with more advanced-stage disseminated disease requiring treatment, immunochemotherapy regimens comprising rituximab plus chemotherapy with or without an anthracycline are typically used.

Management of relapsed/refractory (R/R) MZL

Treatment for R/R MZL is similar to that of advanced stage or disseminated MZL. It is typically approached in a manner similar to other indolent B-cell lymphomas, such as FL.55 Unfortunately, patients with MZL are often excluded from larger studies of more common indolent B-cell lymphomas, and thus, no disease-specific treatment guidelines have been developed.12 Only smaller disease-specific trials have been performed and must be used in conjunction with extrapolation from larger studies in which MZL was included to assist with optimization of treatment choice.

Across MZL subtypes, if no prior immunochemotherapy has been received, various regimens combining rituximab and chemotherapy-containing regimens have classically been the initial treatment of choice, resulting in overall response rate (ORR) of 85%–93% and complete response rate (CR) of 54%–78%.80,95–98 Grade III–IV myelosuppression is common with these regimens and may exclude some patients from eligibility for these therapies.12

Autologous and allogeneic hematopoietic progenitor cell transplantation (HCT) has been performed in selected patients with R/R MZL, achieving durable remissions and frequently cures, albeit at cost of significant morbidity.99,100 Though standardized guidelines for selecting R/R MZL appropriate for HCT are lacking due to a paucity of data,101–103 HCT can be utilized with excellent outcomes in selected fit patients having aggressively behaving disease.99,100 Autologous transplant is usually indicated in fit patients with transformation to aggressive lymphoma. Chimeric antigen receptor-modified T-cells have consistently demonstrated activity in advanced hematologic malignancies, including different types of lymphomas, and clinical trials are underway in patients with various types of indolent B-cell lymphomas (including MZL).104


The optimal treatment of R/R EMZL remains to be defined. For patients who have progressed after local therapy, single-agent rituximab or multiple rituximab-based chemotherapy combinations are usually employed. In the IELSG19 study, the combination of rituximab with chlorambucil resulted in superior EFS and PFS compared with rituximab and chlorambucil monotherapy. However, this study focused on first-line therapy; only 8% of patients were enrolled after treatment failure, and OS was similar in both groups.80 Thus, though further investigation into the combination of chlorambucil and rituximab, if not previously used, may be warranted, for patients failing locally therapy, single-agent rituximab is still the preferred first option.80 BR regimen has gained popularity in the US for excellent tolerance and superior outcomes in other indolent B-cell lymphomas.105 ORR of 93% has been achieved in patients with R/R EMZL (CR 71%) with the BR regimen with durable remissions at a cost of 29% incidence of Grade III–IV hematological toxicity.106 The proteasome inhibitor bortezomib also has significant single-agent activity in R/R EMZL with an ORR of 48% (CR 31%).107 Similar impressive results were noted when bortezomib was combined with rituximab in R/R MZL.108 ORR of up to 80% (with 54% CRs) were also reported with the combination of rituximab with the immunomodulating agent lenalidomide, with no unexpected toxicities.109