Cladribine (2-CDA) Plus Sequential Rituximab in Newly Diagnosed Disseminated Extranodal Marginal Zone B-Cell Lymphomas. A Phase II Study.

Background: Multiple extranodal localizations, nodal spreading and bone marrow (BM) involvement have been associated with shorter overall and event-free survival in Extranodal Marginal Zone Lymphoma (EMZL). No optimal treatment has yet been defined and, in this setting, Rituximab has demonstrated only moderate single agent activity while the role of purine analogs is still controversial, although promising in terms of objective response rate. In order to verify a potential synergy of these agents we conducted a prospective phase II trial evaluating a sequential treatment with 2-CDA, a purine nucleoside analog with proapoptotic and cytotoxic activity on both proliferating and quiescent lymphoid cells, and Rituximab in patients (pts) with untreated disseminated EMZL.

Patients and methods: Pts with histologically confirmed MZL, ECOG < 2 and Stage IV disease were enrolled. 2-CDA was administered at a dose of 0.12 mg/kg on 5 consecutive days as a 2-hour infusion, every 4 weeks for 6 courses on outpatient basis. Thereafter, 4 doses of Rituximab (375 mg/m2, i.v., every 2 weeks) were delivered. Prophylaxis with TMP-SMX was required and filgrastim introduced if grade 3–4 neutropenia had occurred. Responses were evaluated after the 4^th course of 2-CDA and at the end of the entire program.

Results: Twenty-three pts (median age 67 yrs; r 34–81) with advanced [multiple extranodal site (n=16), BM (n=15), distant/diffuse nodal involvement (n=14), orbit (n=8), multicentric skin (n=3), gastric (n=4), leukemic (n=2), lung and pleura (n=3), salivary glands (n=3), Waldeyer’s ring (n= 1), breast (n=1)] EMZL were accrued. B symptoms were present in 4 pts, abnormal LDH in 6. No pts had been irradiated and only 2 had received surgical resection due to emergency (ileum) and diagnostic (lung) procedures. All pts completed treatment program and were evaluable for response. The median number of delivered courses of 2-CDA was 6 (r 3–6). The overall response rate was 91 % [after the 4^th course: CR=4, CRu=11, PR=6; at the end of treatment (i.e. including Rituximab): CR= 18 (78%), PR=3 (13%)]. Interestingly, a histological CR was achieved in 13 out of 15 pts with BM involvement (81%). Only 2 pts, with B symptoms at presentation, had a therapeutical diversion at the 3^rd and 4^th course due to minor response and persisting symptomatic disease. Extrahematological toxicity was negligible. CTCAE Grade 3 and 4 neutropenia occurred in 9 and 5 (22%) pts, respectively and febrile neutropenia occurred in 6 pts (26%). Grade 4 Thrombocytopenia and lymphocytopenia developed in 4 (17%) and 3 (13%) patients, respectively. Delayed grade 3 leuko- and thrombocytopenia occurred two months after 2-CDA withdrawal in three pts and slowly recovered in the following 6–8 weeks. No late opportunistic infection, nor disease recurrence have to date occurred. Failure free survival was 86 % at median follow up of 18 months (range, 4–34).

Conclusions: Our prospective study shows that 2-CDA plus sequential Rituximab represents an effective strategy for the upfront treatment of disseminated EMZL. It is feasible in outpatient setting, and associated with favorable early and late toxicity profiles. While a longer follow-up will assess its impact on disease natural history, our results show for the first time that 2-CDA plus sequential rituximab may achieve very high CR rates even in poor prognosis pts with extragastric and widespread EMZL.