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C.Y. Cheah et al.
that regulate the NFkB pathway including t(1;14), t(11;18), A20 inactivation and MYD88 mutations.12
Diagnosis and staging
MALT lymphomas characteristically remain localized for prolonged periods although multi-focal single organ involvement and systemic dissemination can occur in up to 25% of cases (more likely with non-gastric sites).5,13 Patients with advanced stage disease have an inferior prognosis and require different therapeutic strategies from patients with localized disease.8 Thus, careful stag- ing is required and the diagnostic work-up should be tai- lored according to the site involved and any possible underlying infectious or autoimmune causes.5 Bone mar- row involvement is present in fewer than 10% of patients with initially localized MALT lymphoma and patients without cytopenias can possibly be spared this procedure as those with radiologically defined stage IE disease have excellent lymphoma-specific outcomes irrespective of whether bone marrow biopsy is performed or not.14.15 The MALT International Prognostic Index (MALT-IPI) identi- fied three factors (advanced stage disease, age ≥70 years, and elevated lactate dehydrogenase) that may be useful for prognostication.16
Current treatment approaches
Localized disease
Gastric MALT lymphoma
In patients positive for H. pylori infection, standard eradication therapy with a proton pump inhibitor plus dual or triple antibiotics should be instituted. H. pylori eradication alone causes regression of gastric MALT lym- phoma in 75% of cases.5 Re-testing at 2 months with a breath test can be considered - following cessation of pro- ton pump inhibitors for at least 1 month - to ensure erad- ication before re-assessing the lymphoma status endo- scopically 3 months after eradication.17,18 Waiting for 3 months for repeat endoscopy is important, as earlier eval- uation may not reflect the eventual disease response. Patients with tumors carrying the t(11;18) translocation have a lower response rate to H. pylori eradication and alternative approaches (see below) should be considered for these patients.19
For patients with localized disease who are H. pylori- negative, empiric eradication therapy may still be benefi- cial in a significant proportion of patients.20 Similarly, clar- ithromycin therapy has resulted in meaningful response rates in some patients with gastric MALT lymphoma.21
In cases in which eradication therapy has failed, involved site radiotherapy is a reasonable approach with favorable outcomes using moderate doses (24-30 Gy over 3-4 weeks).17,22 One study which included patients with localized gastric or non-gastric MALT lymphoma report- ed 10-year overall and recurrence-free survival rates of 87% and 76%, respectively, with cause-specific survival of 98%.23 Other treatment options include rituximab monotherapy,24 and chemo-immunotherapy such as rit- uximab plus chlorambucil25 or rituximab plus cyclophos- phamide, vincristine and prednisolone (R-CVP).18 Gastrectomy results in significant morbidity and is no longer recommended.
Non-gastric MALT lymphoma
Patients with localized disease in other sites associated with a postulated causative pathogen should be consid-
ered for eradication therapy, although the etiological rela- tionship and outcomes following eradication are less well established. Some investigators have found ocular adnex- al MALT to be associated with C. psittaci with consider- able geographic variability.26 Doxycycline or clar- ithromycin has resulted in response rates of 45-65%.27 Furthermore, disease regression using antibiotics has been reported in C. psittaci-negative cases.28 Thus testing and an empiric trial of eradication can be considered. Data regarding response rates to antibiotics in the other subtypes are scant, and no firm conclusions can be drawn. In contrast to other lymphomas, radiation therapy has a significant role in extranodal MZL.29 The phase II Trans-Tasman Radiation Oncology Group/Australasian Leukemia and Lymphoma Group 05.02 trial established that involved field radiotherapy is a reasonable treatment for localized non-gastric MALT lymphoma, resulting in 5- year progression free survival (PFS) and overall survival (OS) of 79% and 95% respectively.30 Outcomes of dural MZL have been reported to be favorable following radia- tion therapy.31,32 Extranodal MALT of the thyroid, small bowel, colon, and rectum have been managed with obser- vation, surgical resection, radiation therapy, and ritux- imab. MALT lymphoma of the salivary glands has an excellent prognosis irrespective of the primary therapy.33 According to National Comprehensive Cancer Network guidelines, surgery may be considered for lymphomas in certain sites and some selected asymptomatic patients can also be observed.34
Advanced stage disease
Advanced stage MZL of MALT type is incurable and the usually indolent biology allows for a ‘watch and wait’ approach in many patients. When treatment is required, systemic chemo-immunotherapy has been used success- fully. The addition of rituximab to chlorambucil improved outcomes compared to either agent alone.25 R- CVP followed by rituximab maintenance has been shown to be well tolerated and effective.35 Bendamustine and rit- uximab was safe and effective in a phase II trial of 60 patients with a median follow-up of 43 months.36 Event- free survival was 88% at 4 years. A USA-Italian observa- tional series (n=136) confirmed these observations, with estimated 5-year PFS and OS of 72.3% and 85.6%, respectively.37 Similar results were evident from German prospective registry data.38
Nodal marginal zone lymphoma
Nodal MZL is the least common of all the subtypes of MZL, accounting for approximately 10% of MZL and <2% of all non-Hodgkin lymphomas.2,39 The median age at presentation is 60 years and both genders are equally affected.40 The understanding of nodal MZL has been hampered by its rarity, with therapeutic strategies largely based on data from follicular or small lymphocytic lym- phoma. In common with these disorders, the disease gen- erally behaves in an indolent fashion and is often dissem- inated at presentation. Histological transformation is reported in 3-15% of patients with nodal MZL and is often associated with a poor outcome.41 While there is an association with hepatitis C infection,42 a history of autoimmunity is less common than with other forms of MZL.43
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haematologica | 2022; 107(1)