Frontline Bendamustine and Rituximab in Extranodal Marginal Zone Lymphoma: An International Analysis
Authors: Alderuccio Juan Pablo , Beaven Anne W. , Shouse Geoffrey , Epperla Narendranath , Stefanovic Alexandra , Torka Pallawi , Castillo Jorge J. , Argnani Lisa , Voorhees Timothy J , Alpert Ash B , Chowdhury Sayan , Reis Isildinha M. , Zhao Wei , Edwards Dali , Martin Peter , Kamdar Manali , Herrera Alex F. , Friedberg Jonathan W. , Zinzani Pier Luigi , Lossos Izidore S. 
Published: November 2020

Introduction: There is no standard induction therapy in extranodal marginal zone lymphoma (EMZL); current guidelines borrow from follicular lymphoma, where bendamustine and rituximab (BR) is an accepted standard. The data on BR in EMZL is limited (Rummel MJ et al. Lancet 2013 & Salar A et al. Blood 2017), so we explored BR activity as part of an international consortium.
Methods: This retrospective analysis involved 11 cancer centers from US and Italy. We included patients with EMZL treated with frontline BR (1/2008 to 12/2019). Expert pathology review was performed by each participating institution following the 2016 WHO classification. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier and associations with prognostic factors were assessed by log-rank test, univariable (UVA) and multivariable (MVA) Cox regression. MVA Cox models were constructed by selecting variables significant univariately.
Results: 136 patients were identified; however, 18 patients with EMZL only located in bone marrow (BM) were excluded from this analysis to prevent possible inclusion of lymphoplasmacytic lymphoma. Thus, 118 patients were included in this study. Patient characteristics comprised median age of 61.5 years (range 21 to 85 years), women: 56.8%, ECOG performance status 0-1: 86%, stage III-IV: 79.7%, no B symptoms: 81.4%, normal LDH: 75.4%, BM involvement: 25.4%, and MALT-IPI score &lt; 2: 63.6%. Most common extranodal (EN) sites were lung (22%), gastric (13.6%), ocular (11%), soft tissue (10.2%), salivary gland (10%), and gastrointestinal non-gastric (7.6%). Most patients presented with 1 or 2 EN sites (48.3% and 30.5%, respectively). Majority of patients (83.9%) had &lt; 4 nodal sites. Paraprotein was positive in 27 of 80 (33.7%) patients with majority harboring IgM. The median number of BR cycles was 6 (range 1 to 6). Consolidation with radiation therapy was performed in 6% of the patients. Treatment response was determined by PET/CT in 70% and CT scans in the rest. The response to treatment was as follows: CR: 96 (81.4%), PR: 13 (11%), SD: 2 (1.7%), PD: 4 (3.4%), and unknown: 3 (2.5%) patients. No differences in response rate were observed by EN location. The incidence of infectious complications was 14% including herpes zoster (25%), pneumonia (18.7%) and influenza (18.7%). No treatment-related mortality was observed. Rituximab maintenance was implemented in 17% (n= 20) of the patients for a median duration of 11 (range 1 to 46) months. Biopsy-proven transformation to diffuse large B cell lymphoma occurred in 5.9% of the patients. Patients with lymphoma transformation had a higher mean SUV on diagnostic PET/CT (13.48 vs 7.77, P= 0.037, respectively). Secondary malignancies were observed in 6% of the patients with 1 case of acute myeloid leukemia.
With a median follow up of 2.85 (range 0.08 to 9.45) years, the estimated 5-years PFS (Figure 1) and OS (Figure 2) were 72.3% (95%CI 59.3-81.8%) and 85.6% (95%CI 75.0-92.0%), respectively. No survival difference was observed between patients achieving CR or PR followed or not by rituximab maintenance, but the number of patients receiving maintenance was small. Similarly, no survival differences were observed in patients with gastric EMZL compared to non-gastric locations or by MALT-IPI score risk category.
In both UVA and MVA analyses, variables associated with shorter survival were ECOG performance status ≥2 and failure to achieve CR (for MVA: ECOG PS ≥ 2 (HR: 6.56, P=0.006) and failure to achieve CR (HR: 5.35 P&lt;0.001)). The implementation of rituximab maintenance was not associated with lower risk for an event in patients achieving CR and PR (MVA HR: 0.29, P=0.146).
Conclusion: This study represents the largest analysis to date evaluating the activity and safety of BR in untreated EMZL. BR is a highly effective platform in upfront treatment of EMZL with majority of the patients achieving complete and durable remissions. ECOG PS ≥ 2 and failure to achieve CR were identified as prognostic factors associated with worse outcome in BR treated patients. High incidence of herpes zoster infection was observed in this study which has not been previously reported. In addition, increased median PFS and lower incidence of infectious complications was observed in this study compared to prior reports.

Disclosures
Alderuccio: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Inovio Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; OncLive: Honoraria; Puma Biotechnology: Other: Family member; Foundation Medicine: Other: Family member. Beaven:Tessa Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; LoxoOncology: Research Funding; MorphoSysAb: Research Funding; Roche: Research Funding. Shouse:Kite Pharma: Honoraria, Speakers Bureau. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Castillo:TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Kymera: Consultancy; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Voorhees:AstraZeneca: Research Funding. Martin:Regeneron: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy. Kamdar:Roche: Research Funding. Herrera:AstraZeneca: Research Funding; Karyopharm: Consultancy; Immune Design: Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding. Friedberg:Roche: Other: Travel expenses; Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Portola Pharmaceuticals: Consultancy; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy; Astellas: Consultancy; Seattle Genetics: Research Funding. Zinzani:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lossos:Seattle Genetics: Consultancy, Other; Stanford University: Patents & Royalties; Janssen Scientific: Consultancy, Other; Verastem: Consultancy, Honoraria; Janssen Biotech: Honoraria; NCI: Research Funding.