Rituximab +/- Ibrutinib As First Line Therapy for Marginal Zone Lymphoma

Background: Disseminated marginal zone lymphoma (MZL) is an indolent disease often observable at diagnosis with treatment indications similar to other indolent lymphomas. First-line therapy is typically rituximab alone or in combination with chemotherapy (e.g. bendamustine). Due to the long-life expectancy, avoiding alkylating agents to reduce bone marrow damage could be beneficial. In addition, a “chemotherapy free” option could have fewer and less severe complications. Bruton tyrosine kinase inhibitors (BTKi) are active and approved or NCCN-recommended beyond first line therapy in MZL. Moreover, BTKi are approved for first line therapy in Waldenstrom's Macroglobulinemia, a disease with both diagnostic and pathophysiologic overlap with MZL. We conducted a multicenter randomized trial of rituximab induction plus ibrutinib/placebo (RI vs RP) for patients with MZL in need of first line systemic therapy. Complete response (CR) rate at 30 months was the primary endpoint and progression free survival (PFS) was secondary. The target sample size was 63 in each arm. The study was closed after 22 eligible patients enrolled due to low accrual.

Methods: Patients (pts) with either nodal, splenic or extranodal MZL were eligible. Prior surgery, radiation, antibiotic or antiviral therapy for MZL were allowed if followed by disease progression requiring treatment. Documented evidence of need for treatment included, but was not limited to, threatened end-organ function, bulky disease (>5 cm), symptoms, requirement for transfusion or growth factor support, or significant need for intervention. Transformation to DLBCL was excluded prior to entry including bone marrow assessment. Randomization occurred prior to rituximab weekly x 4 to either daily placebo (RP) or ibrutinib (RI) 560 mg starting on day 1 and continued until disease progression (PD), intolerance or CR at 30 months. Those with partial response (PR) or stable disease (SD) at 30 months could continue placebo or ibrutinib. CR assessment required both a negative FDG-PET and bone marrow biopsy.

RESULTS: 22 pts enrolled (Feb 2020-March 2023) with baseline characteristics including: median age 67 years (35-78) and White race 17. Stage II (3), III/IV (17). Subtype: splenic 16, nodal 4, extranodal 2. Prior therapy: splenectomy 1, radiation 0, other surgery 0, antiviral/antibiotic 0. Median maximal tumor dimension was 3.7 cm (range 1.6-23.6); with >5 cm in 9 pts. Median time from diagnosis to treatment was 32 days (5-4712 with only 3 > 1 year). 11 pts were randomized to each arm. Responses: RP: 3 CR, 4 PR, 3 SD, 1 inevaluable; RI: 7 CR, 4 PR. No patient achieved CR30, but 3 had CR at 29 months: 2 RP, 1 RI. With a median follow up of 35 months (13-50), the median PFS by Log Rank was 14 mo (RP) vs 29 (RI), though this difference was not statistically significant in the setting of small numbers. Treatment was well tolerated. Only 1 pt experienced grade 3 events at least possibly related: hypoxia and dyspnea. This was attributed to COVID-19 and occurred on the RP arm. 1 CR patient with baseline clonal hematopoiesis developed myelodysplasia. Treatment improved baseline activities in 4/5 pts (1 RP, 3 RI). Baseline pain improved in 8 pt: 4 RP, 4 RI. All pts were alive at the data cuff off.

Conclusions: This study is a chemotherapy free frontline trial in MZL and the first to utilize ibrutinib in frontline MZL. All pts received rituximab induction and were randomized at entry to RP vs RI. The COVID-19 pandemic affected site activation and accrual, ultimately contributing to low accrual and early study termination. Nonetheless, the results suggest a marked difference in median PFS favoring the RI arm, although small numbers preclude a statistically significant result. Notably, our results are qualitatively similar to those of Dimopoulos (NEJM, 2018) in Waldenstrom's Macroglobulinemia, a disease with similar characteristics to MZL. In that study, the median PFS by Log Rank was 20 months (RP) vs not reached (RI); and 30-month PFS 28% (RP) vs 82% (RI). (Hazard ratio for progression or death, 0.20; P<0.001). Further, our trial supports pursing a chemotherapy free first line approach in MZL.

Noy:guidepoint global: Consultancy; epizyme: Consultancy; OncLIve: Honoraria; NSCI: Honoraria; health advance: Consultancy; janssen Global: Consultancy, Other: drug provided for research; EUSA: Consultancy; Medallion Healthcare: Honoraria; clearview: Consultancy; Beigene: Consultancy; ADC therapeutics: Consultancy; AstraZeneca: Consultancy; PER: Honoraria; Cornerstone Pharma: Honoraria, Research Funding. Batlevi:F. Hoffmann-La Roche Ltd/Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; Memorial Sloan Kettering Cancer Center: Ended employment in the past 24 months; BMS, Seattle Genetics, Kite, Karyopharm, TG Therapeutics, ADC Therapeutics, AbbVie, Genentech, Inc., Treeline Bioscience: Consultancy; Regeneron, Moderna: Divested equity in a private or publicly-traded company in the past 24 months; Epizyme, Autolus, Roche, Vincerx: Research Funding; Dava Oncology, TouchIME, Medscape: Honoraria. Epstein-Peterson:Kymera: Research Funding; Viracta: Research Funding; Amgen: Research Funding; Genmab: Consultancy; OncLive: Honoraria. Falchi:Genentech, Roche, Genmab, Abbvie, Sanofi, EvolveImmune: Honoraria; AbbVie, Genentech, ADC Therapeutics, Seagen, Ipsen: Membership on an entity's Board of Directors or advisory committees; Genentech, Roche, Genmab, AbbVie, Innate, BeiGene: Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EvolveImmune: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taylor Francis: Other: Journal Editor; Kaplan: Other: CME Presentation: Projects in Knowledge. Habermann:Lilly: Other: Data Monitoring Committee. Lue:Kymera Therapeutics: Research Funding; GenMab: Consultancy; ADC Therapeutics: Consultancy; Lumanity: Consultancy; Merck Pharmaceuticals: Consultancy. Matasar:Takeda: Honoraria; Immunovaccine Technologies: Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Epizyme: Honoraria; Roche: Consultancy, Honoraria, Research Funding; GM Biosciences: Consultancy, Research Funding; Pfizer: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria; IMV Therapeutics: Honoraria; Kite: Honoraria; BMS/Celgene: Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Merck: Current equity holder in publicly-traded company; Bayer: Consultancy, Honoraria, Research Funding. Palomba:Novartis: Consultancy; Synthekine: Consultancy; Bristo Meyer Squibb: Consultancy; Cellectar: Consultancy. Zelenetz:Genentech/Roche: Consultancy, Research Funding; Gilead/Kite: Consultancy; BMS/Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; MorphoSys: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; MEI Pharma: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding. Salles:AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; Incyte: Consultancy; Genmab: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; BMS/Celgene: Consultancy; Merck: Consultancy; Kite/Gilead: Consultancy; Janssen: Consultancy, Research Funding; Ipsen: Consultancy, Research Funding; Molecular Partners: Consultancy; Nurix: Research Funding.

Ibrutinib is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase. Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. NCCN lists ibrutinib as an “other recommended” MZL treatment beyond first line.