Prognostication and Treatment-Related Outcomes in Secondary Central Nervous System Involvement of Large B-Cell Lymphoma (SCNSL): Evidence from a Large International Cohort
Authors: Alderuccio Juan Pablo , Khwaja Jahanzaib , Han Sunwoo , Ghione Paola , Nizamuddin Imran A. , Saha Aditi , Dong Ning , Wang Yucai , Cherng Hua-Jay J , Tolu Seda S. , Wagner-Johnston Nina , Olszewski Adam J. , Grover Natalie , Koff Jean L. , Desai Amrita , Ramakrishnan Geethakumari Praveen , Moyo Tamara K , Sandoval-Sus Jose , Epperla Narendranath , Wallace Danielle S , Kamdar Manali , Danilov Alexey , Tun Han W. , Munoz Javier , Narkhede Mayur S. , Rhodes Joanna M. , Prica Anca , Kuhnl Andrea , Maraj Adrian , Okosun Jessica , Smith Jeffery , Osborne Wendy , Calvert Victoria , el-Sharkawi Dima , Hilali Ammar , Collins Graham P. , Linton Kim , Elmusharaf Nagah , Santarsieri Anna , Karim Farheen , Ollila Thomas , Monick Sarah , Trutzer Iris Margalit , Ghosh Nilanjan , Can Jones , Ayers Amy , Calabrese De Feo Jacopo , Sharp John , Treitman Rachel , Kallam Avyakta , Okcu Izel , Deshani Vismay , Baidoun Firas , Abeyakoon Chathuri , Hann William , Barrett Aisling , Kahl Brad , Chavez Julio C. , Cwynarski Kate 
Published: December 2024

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 &gt;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 &gt;2 lines of Tx (6.5 & 9.7 mos); P&lt;0.0001. Factors associated with significantly shorter OS in UVA across all presentations were age &gt;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 &gt;60, male sex, MYC-R, ECOG PS ≥2, and failure to achieve response to 1L remained significant in MVA.
In de novo cases, age &gt;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 &gt;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&lt;.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.