Treatment and Outcomes of Stage I-II Pulmonary MALT Lymphoma: A Multi-Institutional Observational Study in Japan

Background: Pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a rare, indolent lymphoma that accounts for 7% of all MALT lymphomas. In contrast to other MALT lymphomas such as gastric or ocular adnexal, the site-specific etiology of pulmonary MALT lymphoma is largely unknown. There is no standard treatment for stage I-II pulmonary MALT lymphoma because of the lack of clinical trials. To clarify the patient characteristics, treatment, and prognosis of the patient with stage I-II pulmonary MALT lymphoma in the rituximab era, we conducted a multi-institutional observational study.

Methods: We retrospectively analyzed data from patients diagnosed with pulmonary MALT lymphoma at 31 institutes in Japan between 2013 and 2022. Data were collected from patients with MALT lymphoma with pulmonary involvement regardless of biopsy site and stage; subsequently, patients with stage I-II pulmonary MALT lymphoma were included. The staging was performed according to the Ann Arbor system modified by Ferraro et al (Ann Thorac Surg 2000). Patients with insufficient clinical data were excluded. The following data were collected: initial symptoms, comorbidities, smoking status, baseline laboratory data and chest CT findings (including site, number, and size of pulmonary involvement), treatment choice and response, and survival. Watchful waiting (WW) was defined as follow-up for at least three months after diagnosis. The primary endpoint was the overall survival (OS) of patients with stage I-II pulmonary MALT lymphoma. We analyzed risk factors for OS, progression-free survival (PFS), time to next treatment (TTNT), and time to chemotherapy (TTC) using Cox proportional hazards method. TTNT was assessed in patients who received WW or surgery as first-line treatment. TTNT was defined as the time from the initiation of each treatment until the start of the next treatment. If the initial treatment was WW, TTNT was defined as the time from diagnosis to the start of the next treatment. TTC was defined as the time from diagnosis to the time of initial chemotherapy and was assessed for patients who received WW, surgery, or rituximab monotherapy as first-line treatment.

Results: Of the 200 patients with pulmonary MALT lymphoma, 133 (67%) patients had stage I-II disease. The characteristics of the patients with stage I-II disease were as follows: median age, 68 years (range, 25-88); female, 54%; stage I, 84%; Eastern Cooperative Oncology Group performance score 0, 95%; smoking rate, 44%; history of autoimmune disease, 17%; respiratory symptoms, 12%; elevated serum lactate dehydrogenase level, 9%; Intermediate-risk MALT-International Prognostic Index (MALT-IPI) , 41%; and High-risk MALT-IPI, 5%. The radiologic patterns on chest CT were as follows: a nodule or mass, 55%; consolidation, 38%; multiple involvement, 53%; bilateral involvement, 38%; and median tumor size, 2.5 cm (range, 0.5-7.8). Patients received one of the following four first-line treatments: WW in 71 patients (53%), surgery in 45 (34%), rituximab monotherapy in 11 (8%), and chemoimmunotherapy in 6 (5%), including bendamustine and rituximab (n = 5). During the follow-up period, 2 (2%) patients experienced histological transformation. At a median follow-up of 55 months, the 4-year OS, PFS, TTNT, and TTC were 95%, 85%, 83%, and 89%, respectively. There were no significant differences in OS (P = 0.89) or PFS (P = 0.88) among the four treatment groups. The surgery group tended to be superior to the WW group in TTNT (P = 0.053). There were no significant differences in the TTC among the three treatment groups (P = 0.64). Multivariate analysis identified a single lesion (P = 0.04) as an independent risk factor for OS. Notably, a maximum tumor size ≥ 3 cm was identified as the only independent risk factor for PFS (P = 0.046). Involvement in the right middle lobe was identified as an independent risk factor for TTNT (P = 0.016).

Conclusions: There were no significant differences in survival, irrespective of the first-line treatment modality. A maximum tumor size ≥ 3 cm on CT scan at diagnosis was significantly associated with worse PFS, thus suggesting a potential target for treatment development.

Suzuki:Chugai Pharma: Honoraria, Research Funding; Takeda: Research Funding; Otsuka: Research Funding; Asahi Kasei: Research Funding; Eisai: Research Funding; Kyowa Kirin: Research Funding; Sumitomo Pharma: Research Funding. Miyazaki:Takeda: Research Funding; Otsuka: Research Funding; Chugai: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sumitomo Pharma: Research Funding; Zenyaku Kogyo: Research Funding; SymBio Pharmaceuticals: Honoraria; Ono Pharmaceuticals: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria; Meiji Seika: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Asahi Kasei: Honoraria; Genmab: Honoraria. Asano:Takeda Pharmaceutical Company Limited: Honoraria. Takahashi:AstraZeneca: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Chugai pharma: Speakers Bureau; Janssen: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Meiji Seika Pharma: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Mundipharma: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau; SymBio pharmaceuticals: Speakers Bureau; Ono pharmaceutical: Speakers Bureau; Eisai: Speakers Bureau; Sanofi S.A: Speakers Bureau. Tatetsu:AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria; Chugai Pharmaceutical: Honoraria; Eisai: Honoraria; Novartis: Honoraria; SymBio Pharmaceuticals Limited: Honoraria; Takeda Pharmaceutical: Honoraria; Meiji Seika Pharma: Honoraria; Abbvie Inc: Honoraria; Genmab: Honoraria; Gilead Sciences Inc: Honoraria; Janssen: Honoraria; Kyowa Kirin: Honoraria; Mundipharma: Honoraria; Mesoblast: Patents & Royalties. Arima:Verastem, Inc: Other. Uchida:Novartis: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Nippon Shinyaku: Honoraria; Meiji Seika: Honoraria; Eisai: Honoraria; Chugai: Honoraria; Asahi Kasei: Honoraria; Kissei: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Kirin: Honoraria; Nippon Kayaku: Honoraria; Takeda: Honoraria. Maruyama:MSD: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Honoraria, Research Funding; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Zenyaku: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Otsuka: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Research Funding; Astellas: Research Funding; Nippon Shinyaku: Honoraria; Mundipharma: Honoraria. Kanemura:Janssen Pharmaceutical K.K.: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Asahi Kasei Pharma Co., Ltd.: Honoraria; AstraZeneca K.K.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; AbbVie GK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Murayama:Novartis: Honoraria; Otsuka: Honoraria; Janssen: Honoraria; Mundipharma: Honoraria; Astellas: Honoraria; Ono: Honoraria; Nippon Shinyaku: Honoraria; Kyowa Kirin: Honoraria; Janssen: Honoraria; Chugai: Honoraria; SymBio: Honoraria; Meiji Seika: Honoraria; Sanofi: Honoraria; Eisai: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria; AbbVie: Honoraria. Yano:Kyowa KIRIN: Research Funding; Icon Japan: Research Funding; Novartis Japan: Research Funding; TAIHO Phamaceutical Co., Ltd.: Research Funding; Mebix: Research Funding; Sumitomo Pharma: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Daiichisankyo: Research Funding; Kissei: Research Funding; Dainippon Pharmaceutical: Research Funding; MSD: Speakers Bureau; Takeda: Speakers Bureau; Teijin pharma limited: Research Funding; Takeda: Research Funding; Syneos Health: Research Funding; Abbvie: Research Funding; Eli Lilly Japan K.K: Research Funding; Asahikasei Pharma: Research Funding; Chugai Pharmaceutical Co.,Ltd.: Research Funding; MSD: Research Funding; Astellas Japan: Speakers Bureau; SymBio: Speakers Bureau; Daiichisankyo: Speakers Bureau; Abbvie: Speakers Bureau; Kyowa KIRIN: Speakers Bureau; Pfizer Japan: Speakers Bureau; Astrazeneca: Speakers Bureau; Nippon shinyaku: Speakers Bureau; Chugai Pharmaceutical Co.,Ltd.: Speakers Bureau; Eisai: Speakers Bureau; Janssen: Speakers Bureau; Ono Pharma: Speakers Bureau; Novartis Japan: Speakers Bureau; Japan Airlines: Research Funding. Takahashi:Chugai: Honoraria, Research Funding; Astellas Pharma: Research Funding; Dainihon Sumitomo: Research Funding; Eisai: Honoraria, Research Funding; SymBio Pharmaceuticals: Honoraria; Takeda: Honoraria; Mundi Pharma: Honoraria; Meiji Seika Pharma: Honoraria; Bristol Myers: Honoraria. Iida:Shionogi: Research Funding; Daiichi Sankyo: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Research Funding; Otsuka: Consultancy, Research Funding; GlaxoSmithKlein: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Research Funding; Chugai: Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Kobayashi:Kyorin: Honoraria, Research Funding; Chugai: Research Funding; Taiho: Honoraria, Research Funding; Shionogi: Honoraria, Research Funding; Kyowakirin: Research Funding; Mitsubishi Tanabe: Research Funding; Boehringer: Honoraria, Research Funding; Nippon Kayaku: Honoraria, Research Funding; Lilly: Honoraria, Research Funding; Teijin: Honoraria, Research Funding; Daiichisankyo: Honoraria, Research Funding; AstraZeneca: Honoraria; Pfizer: Honoraria; Ono: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Merck: Honoraria; Insmed: Honoraria; Taisho: Honoraria; MSD: Honoraria; Takeda: Honoraria; Asahi KASEI: Honoraria. Takao:Tanabe Mitsubishi: Research Funding; Kyowa Kirin: Research Funding; Astra Zeneca: Honoraria; Senko Medical Instrument Mfg: Research Funding; Chugai: Honoraria; Covidien: Honoraria; Otsuka: Research Funding; Taiho: Research Funding; CSL Behring: Research Funding; Medtronic: Research Funding; Japan Lifeline: Research Funding. Tawara:Sumitomo Pharma: Research Funding; AbbVie: Honoraria; Alexion: Honoraria; Asahi Kasei: Honoraria; Astellas: Honoraria; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Meiji Seika: Honoraria; MSD: Honoraria; Novartis Japan: Honoraria; Novo Nordisk Pharma Ltd.: Honoraria; Ono: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Chugai: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Yamaguchi:Genmab: Consultancy, Research Funding; BeiGene: Consultancy; Nihon Servier: Consultancy; AstraZeneca: Research Funding; Chugai: Honoraria, Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Research Funding; Kyowa Kirin: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: Honoraria; Meiji Seika: Honoraria; MSD: Honoraria; Nippon Shinyaku: Honoraria; SymBio: Honoraria; Takeda: Honoraria; Eisai: Honoraria.