High Grade B-Cell Lymphoma with MYC/BCL6-Rearrangements (R) May Have Inferior Outcomes Compared to BCL2-R Disease

Introduction: High grade B-cell lymphomas with MYC, BCL2 and/or BCL6 rearrangements (R) are a group of aggressive lymphomas with poor prognosis when treated with R-CHOP and generally present at advanced stage with a high risk of CNS relapse. Recent data suggests MYC/BCL6-R may not portend the same inferior outcomes as MYC/BCL2-R. In addition, the genetic basis of HGBCL remains incompletely understood. Herein, we describe the clinicopathologic characteristics of a large cohort of pts with advanced stage HGBCL focusing on translocation status and CNS involvement. We also explore the genetic characteristics of a subset of pts with targeted sequencing via MSK-IMPACT HEME.

Methods: We performed a retrospective analysis of pts with newly diagnosed HGBCL MYC/BCL2-R and/or BCL6-R at MSKCC from 1/2013 to 9/2022 with pathological confirmation at MSKCC. Demographics, disease/treatment history, and treatment response were extracted from the electronic medical record. IPI and CNS-IPI were calculated. PFS and OS were estimated using the Kaplan-Meier method, and comparisons were made using log-rank test. Associations between survival outcomes, clinical, and treatment characteristics were evaluated using Fischer exact test. Forty three tumors were sequenced via MSK-IMPACT HEME.

Results: A total of 182 pts were identified with HGBCL MYC/BCL2 +/- BCL6-R. One hundred twenty eight pts had advanced stage with sufficient follow-up. Median age at diagnosis was 63y (26-88y), 24% had stage III disease and 76% had stage IV disease; 75% of pts had extranodal involvement, 50% had bulky disease (> 7cm). Transformed disease was present in 39% with the majority (92%) arising from FL; 38% of pts with transformed disease received therapy prior to transformation. Fifty-five % (n=71) of pts had MYC/BCL2-R, 17% (n=22) were MYC/BCL6-R and 28% (n=36) of pts were MYC/BCL2/BCL6-R. The majority of pts received first-line therapy with DA-R-EPOCH (64%), with the remainder receiving R-CHOP (23%) or other therapies (13%). At diagnosis, 5 pts had CNS involvement (n=2 MYC/BCL6-R; n=3 MYC/BCL2-R with or without BCL6-R). Baseline CNS IPI were: 1-2 (n=51, 40%), 3-4 (n=70, 55%), 5-6 (n=8, 6%). Fifty-two % of pts received CNS prophylaxis with IT-chemotherapy alone being the most common (58.2%); there were 13 CNS relapses, most of which (10/13) occurred within 1 year of treatment. Median CNS-IPI among these patients was 3 (range: 1-4). CNS relapses were not impacted by mode of CNS prophylaxis nor systemic therapy (prophylaxis n=6, no prophylaxis n=7; R-CHOP n=6, DA-R-EPOCH n=6; other n=1). Prophylaxis in CNS relapses were: IT alone (n=3), IT plus HD-MTX (n=1) and HD-MTX alone (n=3).

At a median follow up of 18 months, the median PFS was 9.9 months (95% CI 8.0-15.7) and the median OS was 33.1 months (95% CI 26.4-NR). The CR rate was 44.5%. Among pts with relapsed or refractory disease, primary refractory predominated (58/71). Of those pts who had relapsed/refractory disease, 34% were subsequently treated with CAR-T therapy and 8.5% of pts underwent ASCT. At time of censoring, 56% and 50% of pts who received CAR-T and ASCT, respectively, were alive.

Age, IPI and treatment regimens did not differ significantly between BCL6-R and BCL2-R cases. Pts who received R-CHOP had inferior OS compared to those who received DA-R-EPOCH (median OS 19 and 35 months, respectively, p=0.03). MYC/BCL6-R pts had inferior OS compared to MYC/BCL2-R or MYC/BCL2/BCL6-R (median OS of 16, 44 and 47 months, respectively, p=0.02 BCL2-R vs BCL6-R cases). In our cohort, pts with MYC/BCL6-R had a higher rate of CNS relapse compared to BCL2-R cases (6/20 vs 7/106, p=0.008). CNS prophylaxis was similar in both groups (10/19 in MYC/BCL6-R vs 56/104 in BCL2-R cases, p=0.8). Analysis of mutational data from MSK-IMPACT is ongoing.

Conclusions: Our series reinforces the poor prognosis of advanced stage HGBCL with less intensive regimens such as R-CHOP. In contrast to several other series, MYC/BCL6-R are associated with inferior OS in our cohort, which may be secondary to a higher frequency of CNS relapse despite similar administration of CNS prophylaxis. Indeed, there was no clear impact of CNS prophylaxis/IT-chemotherapy as relapses were distributed equally between those who did or did not receive prophylaxis. Larger multicenter studies dedicated to this unique population is warranted and our study supports the ongoing separation of MYC/BCL6-R for further research purposes.

Boardman:Bristol Myers Squibb: Consultancy; OncLive: Honoraria; Cancer Study Group, LLC: Consultancy. Epstein-Peterson:Viracta: Research Funding; Amgen: Research Funding; OncLive: Honoraria; Genmab: Consultancy; Kymera: Research Funding. Falchi:Taylor Francis: Other: Journal Editor; Genentech, Roche, Genmab, AbbVie, Innate, BeiGene: Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Kaplan: Other: CME Presentation: Projects in Knowledge; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Genentech, ADC Therapeutics, Seagen, Ipsen: Membership on an entity's Board of Directors or advisory committees; Genentech, Roche, Genmab, Abbvie, Sanofi, EvolveImmune: Honoraria; Roche: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Consultancy, Research Funding; EvolveImmune: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Horwitz:Auxilius Pharma, Abcuro Inc., Corvus, CTI BioPharma Corp, Daiichi Sankyo, DrenBio, Kyowa Hakko Kirin, March Bio, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio and Takeda Pharmaceuticals.: Honoraria; Auxilius Pharma, Abcuro Inc., Corvus, Daiichi Sankyo, DrenBio, Farallon Capital Management, L.L.C., Kyowa Hakko Kirin, March Bio, Neovii Pharmaceuticals AG, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio, Treeline Bio and Takeda Pharmaceuticals.: Consultancy; ADC Therapeutics, Affimed, Celgene, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio.: Research Funding. Johnson:Electra Therapeutics: Other: Advisory Board; Sobi: Other: Advisory Board; BioNTech: Consultancy. Kumar:Genentech, Inc.: Consultancy, Honoraria, Research Funding; Loxo Oncology/Lily Pharmaceuticals: Honoraria, Research Funding; Astra Zeneca: Honoraria, Research Funding; Kite Pharmaceuticals, Janssen: Honoraria; BridgeBio Pharmaceuticals: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding; Adaptive Biotechnologies, Celgene, Pharmacyclics: Research Funding; Abbvie Pharmaceuticals: Research Funding. Moskowitz:Tessa Therapeutics: Honoraria; Seattle Genetics: Honoraria, Research Funding; Miragen Therapeutics: Honoraria; ADC therapeutics: Research Funding; Takeda Therapeutics: Honoraria; Merck: Research Funding; Secura Bio: Research Funding; Incyte: Research Funding; Brystal-Meyers Squibb: Research Funding; Beigene: Research Funding. Noy:EUSA: Consultancy; epizyme: Consultancy; Cornerstone Pharma: Honoraria, Research Funding; clearview: Consultancy; AstraZeneca: Consultancy; guidepoint global: Consultancy; health advance: Consultancy; janssen Global: Consultancy, Other: drug provided for research; Medallion Healthcare: Honoraria; NSCI: Honoraria; OncLIve: Honoraria; PER: Honoraria; ADC therapeutics: Consultancy; Beigene: Consultancy. Palomba:Cellectar: Consultancy; Novartis: Consultancy; Synthekine: Consultancy; Bristo Meyer Squibb: Consultancy. Steiner:Seagen: Research Funding; BMS: Research Funding; Rafael Pharmaceuticals: Research Funding; GSK: Research Funding. Stuver:Pfizer: Research Funding. Torka:Abbvie: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Lilly Oncology: Consultancy; Genmab: Consultancy; Genentech: Consultancy; Seagen: Consultancy. Zelenetz:Abbvie: Consultancy; Janssen: Consultancy; MorphoSys: Consultancy; Gilead/Kite: Consultancy; MEI Pharma: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; BMS/Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy. Galera:PAIGE.AI: Research Funding. Dogan:AstraZeneca: Research Funding. Salles:BMS/Celgene: Consultancy; Genmab: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Merck: Consultancy; Kite/Gilead: Consultancy; Ipsen: Consultancy, Research Funding; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Incyte: Consultancy; Molecular Partners: Consultancy; Nurix: Research Funding.