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Marginal zone lymphomas are usually managed with either radiation therapy or watch and wait except forHelicobacter pyloripositive gastric MALT lymphomas. We hereby describe the successful application of systemic upfront therapy for patients with advanced as as well as recurrent disease.Marginal zone lymphomas (MZLs) are indolent disorders composed of 3 subtypes: extranodal marginal zone lymphoma (MALT), splenic marginal zone lymphoma (SMZL), and nodal marginal zone lymphoma (NMZL). Early-stage MALT is treated with radiotherapy or antibiotics, and advanced MALT and NMZL are managed with either watch and wait or chemotherapy. SMZLs are treated with splenectomy or rituximab. However, because these approaches have failed to cure patients with SMZL and NMZL, we have systematically used upfront chemotherapy for them, as well as for advanced MALT. We report the outcomes of this approach.A total of 44 patients with MZL were identified from our database and divided into 2 groups. Group 1 (22 with early-stage MALT) patients received either radiotherapy (n = 17) or antibiotics with or without surgery (n = 5). Group 2 included 9 patients with advanced MALT, 9 with SMZL, and 4 with NMZL. Group 2 was treated with FND-R (fludarabine 25 mg/m2 on days 1 to 3, mitoxantrone 10 mg/m2 on day 1, dexamethasone 20 mg on days 1 to 5, and rituximab 375 mg/m2 on day 1; n = 14) or CHOP-R (cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 2 mg intravenous push on day 1, prednisone 100 mg/m2 orally on days 1 to 5, rituximab 375 mg/m2 on day 1; n = 8), followed by maintenance rituximab for 70%.All patients achieved complete remission, and only 2 patients in group 1 had developed a relapse at 70 and 75 months. Both relapses were stage I MALT that had initially been treated with radiotherapy. Both were salvaged with FND-R and remained free of disease at 27 and 39 months after the relapse. At 10 years, the failure-free survival for the 44 patients was 80% and the overall survival was 100%. None of the patients in group 2 developed a relapse. The long-term toxicities have been acceptable.The excellent responses using upfront chemotherapy for MZL suggests that this disorder is curable. Our results should be confirmed in a prospective trial.