Impact of Choice of Platinum-Based Salvage Therapy on CNS Relapse in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Authors: Buege Michael J , Dao Phuong , Dematteo Raymond G , LeVoir Andréa , Pak Terry , Batlevi Connie Lee , Hamilton Audrey , Hamlin Paul A. , Horwitz Steven M. , Joffe Erel , Johnson William T , Khan Niloufer , Kumar Anita , Lee Christina Y. , Matasar Matthew J. , Moskowitz Alison J. , Noy Ariela , Owens Colette , Palomba M. Lia , Straus David J. , von Keudell Gottfried , Zelenetz Andrew D. , Grommes Christian , Sauter Craig S. , Salles Gilles , Falchi Lorenzo 
Published: November 2021

Abstract
Introduction
Risk of central nervous system (CNS) relapse and its management in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) have been extensively studied. However, similar data in patients with relapsed or refractory (R/R) disease are lacking. Specifically, it is unknown whether choice of treatment in this setting may influence the CNS risk. A number of commonly used platinum-based regimens do not contain agents that consistently penetrate the CNS at therapeutic concentrations. High-dose cytarabine, used in standard salvage therapy alongside rituximab, dexamethasone, and either cisplatin (R-DHAP) or oxaliplatin (R-DHAX), is known to cross the blood-brain barrier. Therefore, we asked whether the use of R-DHAP/R-DHAX may be associated with lower risk of CNS relapse than other platinum-based regimens in patients with R/R DLBCL.
Methods
We reviewed consecutive adult patients who initiated a standard platinum regimen (R-ICE, R-GDP, R-GemOx, R-DHAP, or R-DHAX) for the treatment of DLBCL in first relapse at MSKCC. Patients with evidence of CNS involvement prior to, or at initiation of salvage, history of human immunodeficiency virus, or whose front-line treatment included a platinum agent were excluded. The primary objective of the analysis was to compare the cumulative incidence of CNS relapse in patients receiving R-DHAP/R-DHAX versus other salvage regimens (OSR). Death without relapse was treated as a competing risk.
Results
Between April 1996 and September 2020, we identified 302 eligible patients (Table 1), of whom 51 received R-DHAP/R-DHAX and 251 received OSR. Median age at the time of R/R disease was 61 years (range, 19 to 92 years). Patients who received R-DHAP/R-DHAX were significantly more likely to have germinal center B-cell-like phenotype by Hans algorithm (61% vs 24%, p &lt; 0.001) and to have double- or triple-hit lymphoma (DHL/THL; 22% vs 2%, p &lt; 0.001). A higher proportion of patients who received R-DHAP/R-DHAX received CNS prophylaxis during front-line treatment (37% vs 21%, p = 0.01), possibly owing to the number of patients with DHL/THL. Intrathecal methotrexate was used in 68% of patients receiving R-DHAP/R-DHAX and 17% of patients receiving OSR; high-dose methotrexate was used in 5% of the R-DHAP/R-DHAX group and 2% of OSR. A higher proportion of patients who received R-DHAP/R-DHAX underwent consolidative chimeric antigen receptor T-cell therapy (CAR-T) for residual disease (33% vs 5%, p &lt; 0.001), but fewer underwent consolidative autologous hematopoietic cell transplantation (HCT; 33% vs 54%; p = 0.008).
After median overall follow-up of 68 months (34 months for R-DHAP/R-DHAX vs 79 months for OSR, p &lt; 0.001), CNS relapse was observed in 20 patients: 2 in the R-DHAP/R-DHAX group and 18 in the OSR group (Table 2). CNS relapse occurred as leptomeningeal disease only in both patients who received R-DHAP/R-DHAX; all brain parenchyma relapses occurred in patients who received OSR. This numerical difference did not translate into a statistically significant difference in cumulative incidence of CNS relapse (p = 0.52, Figure 1). No independent predictors of CNS relapse were identified in multivariate analysis, and cumulative incidence of CNS relapse was similar when the OSR group was restricted to patients who received R-ICE (n = 198). Median progression-free survival (PFS) was shorter in patients who received R-DHAP/R-DHAX compared to those who received OSR (5.4 months vs 24 months; p = 0.008). However, in Cox regression analysis controlling for effects of salvage regimen (R-DHAP/R-DHAX vs OSR), international prognostic index, DHL/THL biology, and consolidative use of either CAR-T or autologous HCT, only autologous HCT appeared to be an independent predictor of longer PFS (p &lt; 0.001). There was no significant difference in median overall survival (38 months vs 58 months; p = 0.5).
Conclusion
In patients with R/R DLBCL receiving platinum-based salvage therapy, the cumulative incidence of CNS relapse after salvage initiation was not significantly different between patients who received R-DHAP/R-DHAX and those who received other salvage regimens. The lower number of CNS relapses and absence of brain parenchyma relapses in the R-DHAP/R-DHAX group, despite a greater proportion of patients with DHL/THL, suggests that parenchymal penetration by cytarabine may influence the pattern of relapse, warranting study in a larger cohort.
Figure 1 Figure 1.

Disclosures
Batlevi: Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Bayer: Research Funding; Dava Oncology: Honoraria; Life Sciences: Consultancy; GLG Pharma: Consultancy; Juno/Celgene: Consultancy; Kite Pharma: Consultancy; TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; ADC Therapeutics: Consultancy; Viatris: Current holder of individual stocks in a privately-held company; Memorial Sloan Kettering Cancer Center: Current Employment; Medscape: Honoraria; Karyopharm: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Hamlin: Incyte, Janssen, Molecular Templates: Research Funding; Alexion, AstraZeneca Rare Disease (formerly Portola Pharmaceuticals): Other: Study investigator, Research Funding; Kite, Karyopharm, Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Abbvie Pharmaceuticals: Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding. Lee: Intellisphere, LLC: Consultancy. Matasar: Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Teva: Consultancy; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Merck: Consultancy. Moskowitz: ADC Therapeutics: Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Seattle Genetics: Consultancy, Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Takeda: Consultancy; Incyte: Research Funding; Beigene: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding. Noy: Epizyme: Consultancy; Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria. Palomba: Notch: Honoraria, Other: Stock; PCYC: Consultancy; Pluto: Honoraria; Nektar: Honoraria; WindMIL: Honoraria; Lygenesis: Honoraria; Priothera: Honoraria; Ceramedix: Honoraria; Wolters Kluwer: Patents & Royalties; BeiGene: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Rheos: Honoraria; Juno: Patents & Royalties; Magenta: Honoraria; Kite: Consultancy; Novartis: Consultancy. von Keudell: Incyte: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; AbbVie: Research Funding; Merck: Research Funding; BMS: Research Funding; Janssen: Research Funding. Zelenetz: Abbvie: Honoraria, Research Funding; MethylGene: Research Funding; Beigene: Honoraria, Other, Research Funding; MorphoSys: Honoraria; LFR: Other; Gilead: Honoraria, Research Funding; Janssen: Honoraria; NCCN: Other; AstraZeneca: Honoraria; Pharmacyclics: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; MEI Pharma: Honoraria, Research Funding; Genentech/Roche: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria; Verastem: Honoraria; SecuraBio: Honoraria; Novartis: Honoraria. Sauter: Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Genmab: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Gamida Cell: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Salles: Novartis: Consultancy; Kite/Gilead: Consultancy; Morphosys: Consultancy, Honoraria; Miltneiy: Consultancy; Regeneron: Consultancy, Honoraria; Incyte: Consultancy; Rapt: Consultancy; Takeda: Consultancy; Ipsen: Consultancy; Loxo: Consultancy; Genmab: Consultancy; Epizyme: Consultancy, Honoraria; Genentech/Roche: Consultancy; Janssen: Consultancy; Velosbio: Consultancy; Allogene: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Falchi: Roche: Research Funding; Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Genetech: Research Funding.