Final Results of a Multicenter Phase II Trial with Bendamustine and Rituximab As First Line Treatment for Patients with MALT Lymphoma (MALT-2008–01)

There is currently no established treatment for the management of MALT lymphoma requiring systemic treatment. For patients failing to antibiotics or those with local advanced, refractory or disseminated disease several chemotherapy treatments have been studied. Considering the activity of Bendamustine in relapsed/refractory indolent lymphomas, with or without anti-CD20 antibodies, immunochemotherapy with Bendamustine plus Rituximab (BR) seems very attractive as first-line treatment for MALT lymphoma.

A nation-wide prospective phase II trial (EUDRACT 2008–007725–39) has been carried out in Spain by the GELTAMO group in untreated patients with CD20-positive MALT lymphoma. Patients with lymphoma arisen at any extranodal site and of any stage (Ann Arbor I-IV) could be enrolled. In addition, localized gastric MALT lymphoma previously refractory to H. pylori eradication or those with skin lymphoma not suitable for local therapy or previously treated with selective radiotherapy/surgery were also eligible. Treatment consisted of Bendamustine (90 mg/m² d1–2) and Rituximab (375 mg/m² d1), every 28 d. Pts were evaluated after completing 3 cycles: if complete remission (CR), pts received a further cycle (total of 4) and if partial response (PR), pts received 3 more cycles (total of 6). The aims were: feasibility and security of the combination and rate and quality of the responses, and event free survival. From May 2009 to May 2010, 60 patients were enrolled. Clinical characteristics: median age 62 years (range, 26–84); 34 (57%) female; Ann Arbor stage: I in 49%, II in 17% and III-IV in 34%; B-symptoms 5%. 20 patients (33%) had the lymphoma in the stomach, 35 (58%) in extra-gastric sites and the remaining 5 cases (8%) lymphoma was multifocal. The most common extra-gastric sites were lung and ocular adnexa in 11 and 7 patients, respectively.

A total of 264 cycles of BR were delivered in the whole population. Only 2 patients received less than 4 cycles. Rituximab dose was no modified at any cycle and only 5 patients required dose reduction of Bendamustine (median dose intensity: 0.98). Only 2 patients have not completed treatment due to toxicity: 1 case after 2 cycles due to severe rituximab-associated toxicity and another one after grade 4 febrile neutropenia in the 5^th cycle. Grade 3–4 neutropenia was seen in 18% of patients. A total of 25 grade 3–4 non-haematologic toxicities were documented in 12 patients. Of note, 11 of these episodes were infectious (2 febrile neutropenia, 2 cytomegalovirus enteritis and 7 other).Response after 3 cycles of R was evaluable in 58 patients: 44 achieved CR or uCR and 14 patients PR, for an overall response rate (ORR) of 100% with a CR rate of 76%. CR rate after 3 cycles was higher in patients with gastric origin in comparison with non-gastric (90% vs 64%) (multifocal cases 100%). At the end of treatment, ORR was 100% with CR/uCR of 98%. A remarkable finding was that only 14 pts (23%) required more than 4 cycles of BR. With a median follow-up of 16 months (range, 3–40), one death has been recorded due to a neurologic syndrome and none patient has relapsed.

The combination of Bendamustine and Rituximab in first line treatment of MALT lymphoma achieved an ORR of 100% after only 3 cycles. CR rate after completing treatment plan was 98%. Interestingly, a large majority of patients (85%) required only 4 cycles of treatment. This regimen was safe and well accepted by patients, making this response-adapted schedule a foremost therapeutic strategy for this type of lymphoma.

Off Label Use: Bendamustine and rituximab are not currently approved for MALT lymphoma in first line, although both are commonly used in the relapse setting.