Prognostication and Treatment-Related Outcomes in Secondary Central Nervous System Involvement of Large B-Cell Lymphoma (SCNSL): Evidence from a Large International Cohort

Introduction: Scant data exist on prognostic factors, survival and treatment (Tx)-related outcomes in SCNSL. We conducted a multicenter international analysis to identify prognostic factors and outcomes in SCNSL at diagnosis (de novo), or after frontline Tx (1L) either with (concomitant) or without (isolated) systemic (syst) relapse.

Methods: This study collected data from patients (pts) treated between 2001-2023 at 35 centers. Overall (OS) and progression-free survival (PFS) were calculated from SCNSL diagnosis to first event (death for OS, relapse/death for PFS) or last follow-up. Uni- (UVA) and multivariable (MVA) Cox analyses were performed to assess prognostic factors; Kaplan-Meier method was used to estimate survival.

Results: 1173 (US: 863, UK: 273, Canada: 37) pts with SCNSL were included. Baseline characteristics were median age: 62 years (interquartile range 52.5-69), male sex: 58.7%, elevated LDH: 71.1%, stage III/IV: 88.6%, HIV: 3%, transformed LBCL (tLBCL): 13.8%, non-germinal center B-cell like (non-GCB) subtype: 52.3%, double expressor (DE): 40%, MYC rearrangement (MYC-R): 28.3%, MYC/BCL2 double hit: 16.6%, MYC/BCL2/BCL6 triple hit (TH): 6.1%.

Among 522 pts with de novo SCNSL, 84.2% had involvement of a single CNS compartment (44.7% brain parenchyma; 40.4% leptomeningeal [lepto]). 1L regimens included 36.2% R-CHOP with high-dose methotrexate (HD-MTX), 12.5% MARIETTA-type, and 9.8% R-CODOX-M/IVAC; 54.6% received intrathecal chemotherapy. Consolidation Thiotepa-based autologous stem cell transplant (TT-ASCT) occurred in 15.3%. The majority of pts who underwent TT-ASCT had previously achieved CR or PR in syst (92.5%) and CNS (72.5%) compartments. At median follow-up 25.7 months (mos), subsequent relapse was observed in 27.5% TT-ASCT recipients: 36.3% had isolated CNS, 27.4% syst, and 36.3% concomitant.

588 pts presented with SCNS after 1L (66.2% isolated, 33.8% concomitant). Brain parenchyma involvement was observed in 56.8%, lepto in 22.6%. Tx included 31.6% HD-MTX combination (eg, R-MPV, MTR); 18.4% HD-MTX +/- rituximab; 16.2% MARIETTA-type; and 9.4% platinum-based regimen. Consolidation TT-ASCT occurred in 22.4% (n=132), and 13.8% (n=81) received CAR-T cell therapy (excluding subsequent relapses in de novo group). Syst (65.1%) & CNS (69.1%) responses (CR/PR) were higher before TT-ASCT compared to CAR-T cell (49.5% & 54.5%, respectively). After TT-ASCT, 52 pts (39.3%) relapsed, mainly in the CNS (n=30, 57.7%), with only 4 (7.7%) concomitant. After CAR-T, 48 pts (59.3%) relapsed: 15 (31.2%) isolated in CNS and 15 (31.2%) concomitant. 12-month cumulative incidence of relapse (with death as competing risk) was 21.1% after TT-ASCT and 55.8% after CAR-T. In 63 pts (5.4%), the first CNS event occurred >2 lines of Tx.

With median follow-up of the entire cohort of 24.6 mos, median PFS and OS were 11 and 21 mos, respectively. mPFS and mOS were significantly better in pts with de novo SCNSL (13.4 & 47.4 mos) compared to SCNSL after 1L (10.4 & 14.2 mos) and >2 lines of Tx (6.5 & 9.7 mos); P<0.0001. Factors associated with significantly shorter OS in UVA across all presentations were age >60, male sex, GCB subtype, MYC-R, tLBCL, DE, TH, elevated LDH, ECOG PS ≥2, SCNSL after 1L (vs. de novo), and failure to achieve syst/CNS response to 1L. Of these, age >60, male sex, MYC-R, ECOG PS ≥2, and failure to achieve response to 1L remained significant in MVA.

In de novo cases, age >60, DE, ECOG PS≥2, and failure to achieve syst/CNS response to 1L were associated with poorer OS; for pts with SCNSL after 1L, age >60, GCB subtype, and ECOG PS ≥2 were significant. Pts treated with HD-MTX-based regimens after 1L experienced longer OS than those treated with platinum regimens or high-dose cytarabine. In de novo cases, TT-ASCT was significantly associated with longer OS (HR=0.58; P=0.025) in MVA after adjusting for significant factors, 1L type, and response. For SCNSL at relapse, TT-ASCT (HR=0.34; P<.0001) and isolated SCNSL presentation (vs. concomitant HR=0.70, P=0.007) were associated with longer OS, adjusting for significant factors, type of second-line Tx, & site of CNS relapse.

Conclusions: This study represents the largest analysis of SCNSL inclusive of all modes of presentation. Concomitant SCNSL at relapse was associated with poor outcomes, while TT-ASCT consolidation was associated with improved OS in de novo & relapsed disease. Despite advances in LBCL SCNSL remains an unmet therapeutic need.

Alderuccio:BeiGene: Research Funding; Genmab: Research Funding; AbbVie: Consultancy; Regeneron: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Genentech: Consultancy. Wang:Kite: Honoraria; InnoCare, AbbVie: Consultancy; 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. Wagner-Johnston:Beigene: Consultancy; Merck: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding. Olszewski:Genmab, Schrodinger, ADC Therapeutics, BeiGene, Bristol-Myers Squibb: Consultancy; Genmab, Schrodinger, Genentech, Inc., Precision Biosciences, Artiva, Pfizer, Kymera Therapeutics: Research Funding. Grover:Sangamo: Current holder of stock options in a privately-held company; Novartis: Honoraria; Regeneron: Honoraria, Research Funding; ADC Therapeutics: Honoraria; BMS: Honoraria, Research Funding; Caribou: Honoraria; Ono Pharma: Honoraria; Genentech: Honoraria; Cabaletta: Research Funding; Janssen: Honoraria; Kite: Honoraria; Seagen: Honoraria. Koff:BeiGene: Consultancy; Viracta Therapeutics: Research Funding; AbbVie: Consultancy. Ramakrishnan Geethakumari:Ipsen Biopharma: Membership on an entity's Board of Directors or advisory committees; Ono Pharma: Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy; Bristol Myers Squibb: Consultancy; Regeneron Pharma: Membership on an entity's Board of Directors or advisory committees. Moyo:Genmab: Research Funding; J&J: Research Funding; Century Therapeutics: Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Epperla:Incyte Corporation: Research Funding; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding. Wallace:Integrity CME: Honoraria. Kamdar:Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Novartis: Research Funding; SeaGen: Speakers Bureau; TG Therapeutics: Research Funding. Danilov:Cyclacel: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; ADCT: Consultancy; MEI Pharma: Research Funding; Takeda: Research Funding; Bayer: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Incyte: Consultancy; MorphoSys: Consultancy; Nurix: Consultancy, Research Funding; Genentech: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; GenMab: Consultancy, Research Funding; Janssen: Consultancy. Tun:Curis: Consultancy; Gossamerbio: Research Funding. Munoz:Pharmacyclics/Abbvie: Consultancy, Honoraria, Research Funding; Kyowa: Consultancy; Alexion: Consultancy; Fosunkite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; Aurobindo: Consultancy; Genmab: Consultancy; Genzyme: Consultancy; Genentech/Roche: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Epizyme: Consultancy; Bayer: Consultancy, Research Funding; Merck: Research Funding; Portola: Research Funding; Curio: Honoraria; OncView: Honoraria; Physicians' Education Resource: Honoraria; Eli Lilly: Consultancy; Pharmacyclics/Abbvie, Bayer, Gilead/Kite, Beigene, Pfizer, Janssen, Celgene/Bristol Myers Squibb, Kyowa, Alexion, Fosunkite, Seattle Genetics, Karyopharm, Aurobindo, Verastem, Genmab, Genzyme, Genentech/Roche, ADC Therapeutics, Epizyme, Beigene, Novartis,: Consultancy; Targeted Oncology: Honoraria; Alexion: Consultancy; BeiGene: Consultancy; Bayer: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MEI: Consultancy; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Targeted Oncology, OncView, Curio, Genzyme, and Physicians' Education Resource.: Honoraria; Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, Beigene.: Research Funding. Narkhede:Lilly Oncology: Speakers Bureau; Natera: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Cullinan Oncology: Research Funding; Adaptive Biotechnologies: Speakers Bureau; Genmab: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Beigene: Consultancy, Honoraria, Research Funding, Speakers Bureau; EUSA/Recordati Disease: Research Funding; Genentech-Roche: Speakers Bureau. Rhodes:AbbVie: Consultancy, Research Funding; Oncternal Therapeutics: Research Funding; Loxo Oncology: Research Funding; Janssen: Research Funding; TG Therapeutics: Consultancy; Seagen: Consultancy; Pharmacyclics: Consultancy, Research Funding; MorphoSys: Consultancy; Epizyme: Consultancy; Johnson and Johnson: Consultancy; Acerta: Research Funding; Verastem: Consultancy; ADC Therapeutics: Consultancy; Genentech: Consultancy; VelosBio: Research Funding; Beigene: Consultancy. Kuhnl:Astra Zeneca: Honoraria, Other: Travel grant; Abbvie: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy, Honoraria; BMS: Consultancy. Okosun:Incyte: Consultancy; Genmab: 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; BeiGene: Research Funding. Smith:MSD: Honoraria; Roche: Honoraria; Gilead: Honoraria; Beigene: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria. Osborne:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Kite Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria; Novartis: Honoraria; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Syneos: Membership on an entity's Board of Directors or advisory committees. el-Sharkawi:SOBI: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Conference/travel support; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Membership on an entity's Board of Directors or advisory committees; Nurix: Honoraria; Takeda: Honoraria; Roche: Honoraria, Other: Conference/travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Conference/travel support; Adaptive: Honoraria; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Collins:Sobi: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Pfizer: Research Funding; Amgen: Research Funding; BMS: Research Funding; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Linton:Viracta: Research Funding; Regeneron: Research Funding; AbbVie: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding; BMS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Nurix: Research Funding; Celgene: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Step Pharma: Research Funding; Kite/Gilead: Consultancy, Research Funding; Genmab: Consultancy, Other: Member of the Epcoritamab Global Council, Research Funding; MSD: Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; CellCentric: Research Funding; AstraZeneca: Research Funding; ADC Therapeutics: Research Funding; Roche: Consultancy, Research Funding. Ollila:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Lilly: Research Funding; Ono Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghosh:Seagen, TG Therapeutics, AstraZeneca, Pharmacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Beigene, Incyte, Karyopharm, Roche/Genentech, Novartis, Loxo Oncology, Genmab, Adaptive Biotech, ADC Therapeutics and Syncopation: Consultancy; TG Therapeutics, Genentech/Roche, Bristol Myers Squibb, Gilead, Morphosys, AbbVie: Research Funding; Roche/Genentech, AbbVie, BMS: Research Funding; AstraZeneca, Pharmacyclics, Janssen, BMS, Kite Pharma, BeiGene, Incyte, Lava Therapeutics, Roche/Genentech, Novartis, Loxo Oncology, AbbVie, Genmab, Prepromene, and ADC Therapeutics, Ascentage and Ipsen.: Honoraria; AstraZeneca, Pharmacyclics, Janssen, BMS, Gilead Sciences, Kite Pharma, BeiGene, Incyte, Lava Therapeutics, Roche/Genentech, Novartis, Loxo Oncology, AbbVie, Genmab, Adaptive Biotech, Prepromene, Ascentage and Ipsen: Consultancy. Kahl:AstraZeneca, BeiGene, Roche: Research Funding; BMS, BeiGene, Lilly, Kite, AZ, AbbVie, Merck, Novartis, Genentech, Roche, ADCT: Consultancy. Chavez:Cellectis: Consultancy; Allogene: Consultancy; Lilly: Honoraria, Speakers Bureau; Janssen: Honoraria; Merck: Research Funding; ADC Therapeutics: Consultancy; Abbvie: Consultancy; GenMab: Consultancy, Research Funding; BeiGene: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Cwynarski:BMS: Consultancy; Incyte: Consultancy, Speakers Bureau; Kite: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie, Celgene, Atara, Janssen,: Consultancy; Roche, Takeda: Consultancy, Speakers Bureau.