Introduction

Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients.

Methods

This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion.

Results

Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1)

Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively.

ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%).

Conclusion

In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.

Riedell:Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees; Celgene/ Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CVS Caremark: Consultancy; Sana Biotechnology: Consultancy; CRISPR Therapeutics: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding; Fate Therapeutics: Research Funding; Nkarta: Research Funding; Pharmacyclics: Consultancy; Genmab: Consultancy; Janssen: Consultancy; Intellia Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; Nektar Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Tessa Therapeutics: Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Xencor: Research Funding; Karyopharm Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Awan:Pharmacyclics LLC, an AbbVie Company.: Other: Contracted Research; Janssen, Gilead, Kite pharmaceuticals, Karyopharm, MEI Pharma, Verastem, Incyte, Johnson and Johnson, Merck, Epizyme, Loxo Oncology, Adaptive Biotechnologies, Genmab: Other: Consulting Agreements; AstraZeneca Pharmaceuticals LP: Other: Advisory Committee; AbbVie Inc, ADC Therapeutics, AstraZeneca Pharmaceuticals LP, BeiGene Ltd, Bristol-Myers Squibb Company, Cardinal Health, Caribou Biosciences Inc, Celgene Corporation, Cellectar Biosciences Inc, DAVA Oncology, Epizyme Inc, Genentech, a member of the Roche: Other: Consulting Agreements. Shadman:Pharmacyclics: Consultancy, Research Funding; MEI Pharma: Consultancy; TG Therapeutics: Research Funding; Mustang Bio: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; Vincerx: Research Funding; ADC therapeutics: Consultancy; Janssen: Consultancy; Fate Therapeutics: Consultancy; MorphoSys/Incyte: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Eli Lilly: Consultancy; Genmab: Consultancy, Research Funding; Regeneron: Consultancy. Hu:AbbVie: Membership on an entity's Board of Directors or advisory committees. Bachanova:Gamida Cell: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; ADC: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Other: DSMB; BMS: Research Funding; Citius: Research Funding; Incyte: Research Funding. Ahmed:BMS: Consultancy; Kite: Consultancy, Research Funding. Scordo:Angiocrine Bioscience, Inc.: Research Funding; CancertNetwork (Intellisphere LLC): Honoraria; Medscape, LLC: Honoraria; Omeros Corporation: Consultancy, Research Funding; Amgen, Inc.: Research Funding. Johnson:Abbvie: Consultancy; ADC Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Seagen: Consultancy; Medically Home: Research Funding. Ito:Horizon Therapeutics: Other: Clinical trial drug supply ; BlueSphere Bio: Patents & Royalties: Patent , Research Funding. Hamadani:SeaGen: Consultancy; BeiGene: Speakers Bureau; Myeloid Therapeutics: Honoraria; Sanofi Genzyme: Speakers Bureau; Astellas: Research Funding; Spectrum Pharmaceuticals: Research Funding; Takeda: Research Funding; Astra Zeneca: Speakers Bureau; Genentech: Honoraria; Novartis: Consultancy; MorphoSys: Consultancy; Legend Biotech: Consultancy; Kadmon: Consultancy; Genmab: Consultancy; Caribou: Consultancy; AstraZeneca: Speakers Bureau; Kite, a Gilead Company: Consultancy, Speakers Bureau; BeiGene: Speakers Bureau; Incyte: Consultancy; Bristol Myers Squibb: Consultancy; Gamida Cell: Consultancy; Genmab: Consultancy; CRISPR: Consultancy; Omeros: Consultancy; Abbvie: Consultancy; ADC therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau. Frigault:Arcellx: Research Funding; Covance: Consultancy; Kite: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy, Research Funding.

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2023
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