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1629 Subsets of Follicular Lymphoma (FL) 3B Have Divergent Biological Behavior and Clinical Outcome: Results from the Prospective Multicenter MER and LEO Cohorts

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Adult, Lymphomas, Non-Hodgkin lymphoma, Clinical Research, B Cell lymphoma, Diseases, Lymphoid Malignancies, Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Patrizia Mondello, MD, PhD, MSc1, Brianna J Negaard, MS2*, Andrew L. Feldman, MD3, Brian K. Link, MD4*, Carla Casulo, MD5, Dai Chihara, MD, PhD6, David A Russler-Germain, MD, PhD7, Jason Romancik8*, Caitlin Gribbin, MD9*, Sara Haddadi10*, Eric Mou, MD4*, Ivana N. Micallef1*, Patrick B. Johnston, MD, PhD11*, Anne J. Novak, PhD1, Yucai Wang, MD, PhD1, Rebecca L. King, MD3*, Thomas M. Habermann, MD1, Peter Martin, MD9, Grzegorz S. Nowakowski, MD11, Loretta Nastoupil6*, James R. Cerhan, MD, PhD12, Christopher R. Flowers, MD, MS6, Izidore S. Lossos, MD10, Richard Burack, MD, PhD13, Matthew J. Maurer, DSc2* and Stephen M. Ansell, MD, PhD1

1Division of Hematology, Mayo Clinic, Rochester, MN
2Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
4Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa, Iowa City, IA
5Division of Hematology and Medical Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY
6Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
7Siteman Cancer Center, Division of Oncology, Washington University School of Medicine, Saint Louis, MO
8Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, Georgia
9Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY
10Division of Hematology, Sylvester Comprehensive Cancer Center, Miami, FL
11Mayo Clinic, Rochester, MN
12Division of Epidemiology / Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
13Pathology and Laboratory Medicine, University of Rochester, Rochester, NY

Background: FL3B is the least common among FL subtypes, accounting for 5-10% of cases. Almost half of FL3B tumors have concurrent diffuse large B cell lymphoma (DLBCL) in the diagnostic tissue biopsy, while FL3B rarely coexists with FL1-2 or FL3A. Several lines of evidence suggest that FL3B displays distinct biological and clinical characteristics resembling aggressive DLBCL rather than the indolent FL1-3A. Accordingly, DLBCL anthracycline-containing regimens, such as R-CHOP, are the mainstay of therapy for FL3B with or without coexisting DLBCL. However, while some studies show that R-CHOP therapy in FL3B was associated with 5-year overall survival (OS) rate of 54%, others report outcomes comparable to FL3A with 79-90% survival. Additional controversy involves the clinical implication of pure FL3B (FL3Bp) vs FL3B with concurrent DLBCL (FL3Bc). Thus, it remains unclear if FL3B clinically resembles DLBCL or lower-grade FL and whether FL3Bp has a different prognosis from FL3Bc. To address these questions, we performed a pooled study of two large prospective multicenter study cohorts to compare the clinical characteristics and outcomes of newly diagnosed FL3B with FL1-2, FL3A and DLBCL patients, all of whom were uniformly treated with frontline R-CHOP.

Patients and Methods: We evaluated 469 newly diagnosed patients with FL1-2 (n=216), FL3A (n=170) and FL3B (n=83) who received R-CHOP within 6 months of diagnosis and 739 de novo DLBCL (GCB n=455 and non-GCB n=284) who were prospectively enrolled into the Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts between 2002 and 2021. FL3B cases were designated as FL3Bc and FL3Bp based on the presence or absence of coexisting DLBCL, respectively. Histologic diagnosis was determined by an expert pathologist at each participating center and centrally reviewed. Event free survival (EFS) and OS were defined as time from diagnosis to progression, relapse, retreatment or death, and early progression defined as failing to achieve EFS at 24 months (EFS24). Associations between clinical features and EFS or OS were evaluated using Kaplan Meier curves and Cox proportional hazards models unadjusted and adjusted for age and FLIPI (comparisons with FL1-2 and FL3A) or IPI (comparisons with DLBCL).

Results: The median age was 61 years (range, 18-94 years). Among FL3B patients, 21 (25%) had FL3Bc and 62 (75%) FL3Bp. Baseline characteristics and outcomes were broadly similar between the two FL3B subtypes. We then compared all FL3B patients to those with lower-grade FL. Patients with FL3B showed similar clinical features to those with FL1-2 and FL3A, with exception for a lower tumor burden. After R-CHOP, FL1-2 patients had an inferior EFS (HR 2.13 95%CI 1.31-3.46) than those with FL3B, whereas there was no difference compared to FL3A. OS was similar across all FL grades. Although FL1-2 patients failed to achieve EFS24 more frequently than FL3B and FL3A (34% vs 18% and 15%, p<0.001), FL3B patients who did fail EFS24 had almost three folds higher risk of subsequent mortality (HR 2.84 95%CI 1.35-6.01) than other FLs. At 5-year follow-up, FL3B patients had twice the risk of relapse with an aggressive subtype (i.e., DLBCL, high-grade B-cell lymphoma) than those with FL1-2 and FL3A, who instead often recurred with indolent disease (i.e., FL1-2, FL3A; p<0.001). We further compared FL3B patients to those with DLBCL classified based on cell-of-origin into GCB and non-GCB subtypes. At diagnosis, patients with FL3B had more favorable clinical features than those with GCB and non-GCB DLBCL. Compared to FL3B, patients with non-GCB DLBCL had an inferior EFS (HR 1.73 95%CI 1.07-2.79) and OS (HR 2.04 95%CI 1.11-3.75), while those with GCB DLBCL did not show a significant difference in EFS (HR 1.41 95%CI 0.88-2.25) or OS (HR 1.69, 95%CI 0.93-3.06) likely due to insufficient statistical power. Patients with FL3B failed EFS24 less frequently than patients with GCB or non-GCB DLBCL (17% vs 25% and 32%; p=0.01). Among patients who failed EFS24, those with FL3B had a similar subsequent OS as both GCB (HR 1.41 95%CI 0.73-2.72) and non-GCB DLBCL (HR 1.27 95%CI 0.65-2.47).

Conclusions: We report that FL3Bp and FL3Bc appear clinically similar. While most FL3B patients have a prognosis comparable to FL1-2 and FL3A, 18% exhibit aggressive behavior with poor outcome reminiscent of DLBCL. Future studies with a larger population will be needed to confirm our findings.

Disclosures: Feldman: Seattle Genetics: Research Funding; Zeno Pharmaceuticals: Patents & Royalties. Link: Genentech: Research Funding. Casulo: AbbVie: Consultancy, Honoraria; Gilead Sciences, Secura Bio: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Genmab: Research Funding; Verastem: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chihara: BeiGene: Honoraria; BMS: Research Funding; Ono pharmaceutical: Research Funding; Genmab: Research Funding; Genentech: Research Funding; SymBio pharmaceutical: Honoraria. Russler-Germain: Regeneron: Consultancy; Genentech: Research Funding; AstraZeneca: Consultancy. Johnston: Miltenyi: Consultancy, Other: Honoaria paid to Mayo Clinic. Novak: Bristol Myers Squibb: Research Funding. Wang: InnoCare, AbbVie: Consultancy; Kite: Honoraria; Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, Genmab, AbbVie: Other: Advisory Board; Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, AbbVie, BeiGene, Merck: Research Funding. Habermann: Lilly: Other: Data Monitoring Committee. Martin: AbbVie, AstraZeneca, Beigene, Daiichi Sankyo, Genentech, Janssen, Merck, Pepromene: Consultancy. Nowakowski: Zai Laboratory: Consultancy; MorphoSys AG: Consultancy, Research Funding; F. Hoffmann-La Roche Limited: Consultancy; Fate Therapeutics: Consultancy; Incyte Corporation: Consultancy; Genentech: Consultancy; Constellation Pharmaceuticals: Consultancy; AbbVie Inc.: Consultancy; Celgene Corporation: Consultancy, Research Funding; Selvita Inc: Consultancy; MEI Pharma: Consultancy; TG Therapeutics Inc: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Segen: Consultancy; Daiichi Sankyo: Consultancy; ADC Therapeutics: Consultancy; Ryvu Therapeutics: Consultancy; Blueprint Medicines Corporation: Consultancy; Karyopharm Therapeutics: Consultancy; Debiopharm: Consultancy; Bantam Pharmaceutical, LLC: Consultancy; Kymera Therapeutics: Consultancy; Curis: Consultancy, Research Funding. Nastoupil: Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Caribou Biosciences: Honoraria, Research Funding; Denovo Biopharma: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; AbbVie: Honoraria; ADC Therapeutics: Honoraria; Genmab: Honoraria, Research Funding; Gilead Sciences/Kite Pharma: Honoraria, Research Funding; Incyte Corporation: Honoraria; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Abbvie, BMS, Caribou Biosciences, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Regeneron, Takeda: Consultancy; BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Takeda: Research Funding; Abbvie, BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Novartis, Takeda: Honoraria. Cerhan: BMS: Research Funding; Protagonist Therapeutics: Other: SMC; GenMab: Research Funding; Genentech: Research Funding. Flowers: Eastern Cooperative Oncology Group: Research Funding; Iovance: Research Funding; EMD Serono: Research Funding; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Seagen: Consultancy; Morphosys: Research Funding; Pfizer: Research Funding; Bayer: Consultancy, Research Funding; Kite: Research Funding; 4D: Research Funding; Allogene: Research Funding; Takeda: Research Funding; Cellectis: Research Funding; Genentech/Roche: Consultancy, Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Nektar: Research Funding; Burroughs Wellcome Fund: Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Adaptimmune: Research Funding; Acerta: Research Funding; Amgen: Research Funding; Janssen Pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Denovo Biopharma: Consultancy; Sanofi: Research Funding; BeiGene: Consultancy; Guardant: Research Funding; BostonGene: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Bristol Myers Squibb: Consultancy; Ziopharm National Cancer Institute: Research Funding; Spectrum: Consultancy; Karyopharm: Consultancy; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Pharmacyclics / Janssen: Consultancy; Xencor: Research Funding; AstraZeneca: Consultancy; Bio Ascend: Consultancy; AbbVie: Consultancy, Research Funding. Lossos: Not specified: Patents & Royalties; ADCT: Research Funding; University of Miami: Current Employment. Ansell: Regeneron Pharmaceuticals, Inc.: Research Funding; SeaGen: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding; AstraZeneca: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Takeda: Research Funding.

*signifies non-member of ASH