Rituximab‐Bendamustine (R‐Benda) in MALT lymphoma complicating primary Sjögren syndrome (pSS)

Several autoimmune diseases are associated with an increased risk of lymphoma and primary Sjögren syndrome (pSS) is the one with the highest risk. The most frequent histological type is marginal zone lymphoma (MZL), especially lymphoma of the mucosa associated lymphoid tissue (MALT) (Nocturne & Mariette, 2015). The management of MALT lymphomas is not homogeneous. Several studies have demonstrated the efficacy and safety of the combination of rituximab with Bendamustine (R-Benda) in low grade B cell lymphomas including mantle cell lymphomas (MCLs) and extra-gastric MALT lymphomas (Salar et al, 2014). However, R-Benda has not been assessed in MALT lymphomas complicating pSS. This retrospective study is the first to assess the safety profile and efficacy of R-Benda in MALT lymphoma complicating pSS. R-Benda was administrated every 4 weeks with rituximab 375 mg/m2 day 1 and Bendamustine 90 mg/m2 day 1 and 2. Maintenance treatment with rituximab was proposed for 1–2 years (one injection of rituximab 375 mg/m2 day 1, every 3 months). The characteristics and study details of the 13 patients included in the study are summarized in Table 1 and Figure S1. Lymphomas were exclusively extra-nodal MALT lymphomas mainly affecting the salivary glands, particularly the parotids. The first point to discuss regarding our series is the necessity of treatment in MALT lymphomas complicating pSS. As noted above, therapeutic strategy is not homogeneous and a “wait and see” policy may be proposed. Treatment decisions may depend on the stage of the disease. Treatment of stage IV (or diffuse disease) is homogeneous, but the Ann Harbor stage IV definition remains ambiguous in MALT lymphoma. We considered that the majority of our patients (10/13) were Ann Arbor stage IV because they had multiple extra-nodal sites, most frequently the involvement of multiple salivary glands. Most of the patients did not present any systemic signs that could be considered as indication for treatment in MZL: only 5/13 (38%) of our patients had some. The most important argument for treating pSS-associated lymphomas is that chronic antigenic stimulation plays a key role in MALT lymphoma. Eradication of the infectious agent that drives this stimulation represents the cornerstone of the aetiological treatment in lymphomas complicating infection by hepatitis C virus or Helicobacter pylori (Ohkubo et al, 2017). In contrast to these 2 situations, the nature of the antigen is still unknown in pSS and currently cannot be eradicated. MALT lymphomas represent the top of the iceberg of chronic B cell stimulation in pSS, as assessed by a high EULAR (European League Against Rheumatism) Sjögren syndrome Disease Activity Index (ESSDAI) in our 13 patients, which assesses systemic activity. Thus, systemic treatment that includes B-cell targeted therapy is the only approach for stopping this chronic B-cell stimulation, which can be responsible for other systemic complications and may promote the transformation into high grade lymphoma. Rituximab as the sole therapy appears insufficient to obtain complete remission in MALT lymphoma (Lévy et al, 2013). The gold standard strategy is a combination of rituximab with an alkylating agent and/or fludarabine (RFC) (Salar et al, 2009; Zucca et al, 2013). It was recently shown that, in patients with previously untreated indolent lymphoma, R-Benda can be considered as a preferred first-line treatment approach in comparison to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) because of increased progression-free survival and fewer toxic effects (Rummel et al, 2013). R-Benda has been assessed more recently in the treatment of MALT lymphoma with promising results (Kiesewetter et al, 2014). The question of safety is crucial. Infections were the most frequent (69·3%) adverse event in our series (Table 2); these were mostly grade 2 infections that resolved with a short course of oral antibiotics. The most frequent biological adverse effects were lymphopenia (n = 11; 85%), although 3 patients already had a low lymphocyte count before treatment, which is a sign of disease activity in pSS. Neutropenia, which may also be partly linked to the underlying autoimmune disease, occurred in 6 (46%) patients. These patients benefited from granulocyte colony-stimulating factor as secondary prophylaxis. Hypogammaglobinemia was noted in 6 (46%) patients (Figure S2). Other adverse events were mainly non-severe, including anaemia (8/13), thrombocytopenia (5/13) and cytolysis (6/13). Thus, these results confirmed that safety profile of R-Benda is acceptable, but it is absolutely mandatory to vigilantly monitor cytopenias, which are manageable by reducing the dosage of bendamustine (from 90 to 60 mg/m2). Moreover, the combination of rituximab with bendamustine might worsen the risk of hypogammaglobinemia with a cumulative effect. After 6 cycles, all the patients were no longer symptomatic. A positron emission tomography scan was performed in 9 patients, all of whom showed complete regression of lymphomatous lesions. Concerning the systemic activity of pSS, the mean ESSDAI before treatment was 28·15, 16·15 without lymphoma and decreased to 2·7 after chemotherapy, not only linked to control of lymphoma. To our knowledge, this study is the first to assess the impact of chemotherapy on the activity of pSS. This might suggest that treating lymphoma may help to control disease activity in those patients with the most severe forms of the disease and may limit the risk of occurrence of other systemic complications. It may represent a key argument in favour of treating low grade lymphomas in this context. Finally, maintenance therapy, validated in follicular lymphoma and MCLs, is questionable in MALT lymphoma complicating pSS considering the excellent efficacy achieved in these cases after 6 cycles of induction therapy with R-Benda. In conclusion, R-Benda appears to be an interesting option in the treatment of MALT lymphoma complicating pSS, both in terms of tolerance and efficacy and is associated with the control of auto-immune disease activity. It would be relevant to carry out a prospective trial comparing this therapeutic to the rituximab-chlorambucil reference treatment (Zucca et al, 2013). LD, JH, RS, LF, OH, XM and GN wrote the paper. LD, RS, XW, GN analyzed the data. LD, JH, RS, XM, GN performed research. XM, GN designed research. The authors have no conflict of interest to report. Fig S1. Flow chart. Fig S2. Evolution of gammaglobulinemia during R-Benda treatment (A) and maintenance therapy (B). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.