Biomarkers for Risk Stratification in Patients With Previously Untreated Follicular Lymphoma Receiving Anti-CD20-based Biological Therapy.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti-CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.

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Conflicts of Interest and Source of Funding: Supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821, U10CA180882, and U24CA196171 (to the Alliance for Clinical Trials in Oncology), UG1CA233180, UG1CA233329, and UG1CA233339 (https://acknowledgments.alliancefound.org). Also supported in part by funds from Celgene (CALGB 50803) and GlaxoSmithKline (CALGB 50901). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.R.S. served in expert consultancy at Seeger Salvas & Devine LLP, Levin Papantonio PA, Arnold & Itkin LLP. M.J.M. served in consultancy and advisory boards in Pfizer, MorphoSys, Kite; received research funding from Celgene/BMS, Nanostring. M.S.C. was an employee at Celgene; served in consultancy at MorphoSys; in advisory boards at Immunogen, Boehringer-Ingelheim. P.M. served in consultancy at Bayer, Beigene, Celgene, Cellectar, Janssen, Karyopharm, Kite, MorphoSys, Regeneron, Teneobio; Research Funding (institutional): Karyopharm. J.P.L. served in consultancy at Sutro, Miltenyi, AstraZeneca, Epizyme, Roche/Genentech, BMS/Celgene, Regeneron, ADC Therapeutics, MEI Pharma, Bayer, Gilead/Kite. B.D.C. served in consultancy at BMS, Pharmacyclics, AstraZeneca, Symbios, MorphoSys, Abbvie; received research funding (to former institution) from Roche/Genentech, Celgene, Kite, Pharmacyclics, AstraZeneca, Trillium, Abbvie, TG Therapeutics. E.D.H. received research funding from Abbvie, Eli Lilly and Co.; serves in advisory board at Seattle Genetics, Miletnyi. For the remaining authors none were declared.