Treatment Patterns and Outcomes Following Progression of Disease Post-CAR-T Therapy in Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter Analysis

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL.

Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes.

Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%).

Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD.

After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%.

The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P < 0.001).

Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.

Epstein-Peterson:Viracta: Research Funding; Genmab: Consultancy; Kymera: Research Funding; OncLive: Honoraria; Amgen: Research Funding. Chong:Nurix: Research Funding; CARGO: Research Funding; Genentech/Roche: Research Funding; AbbVie: Research Funding; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Genmab: Research Funding. Frank:BRVLH: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Cargo Therapeutics: Consultancy, Other: Travel Support; Allogene Therapeutics: Consultancy, Research Funding; Gilead: Consultancy, Other: Travel Support; Roche/Genentech: Current holder of stock options in a privately-held company; EcoR1: Consultancy; Kite-Pharma-Gilead: Consultancy, Research Funding. Iqbal:Sanofi US: Consultancy. Jacobson:Pfizer: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Instil Bio: Consultancy; ADC Therapeutics: Consultancy; Abintus Bio: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Caribou Biosciences: Consultancy; MorphoSys: Consultancy; Miltenyi: Consultancy; Ipsen: Consultancy; ImmPACT Bio: Consultancy; Synthekine: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Kamdar:Celgene: Other: Data Monitoring Committee; Beigene: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Genentech: Other: Data Monitoring Committee; Novartis: Research Funding; SeaGen: Speakers Bureau. Karmali:AstraZeneca: Speakers Bureau; Ipsen: Speakers Bureau; Genmab: Honoraria; Genentech/Roche: Honoraria; BeiGene: Speakers Bureau; Incyte: Speakers Bureau; BMS: Honoraria; Abbvie: Honoraria. Maddocks:ADC Therapeutics: Consultancy; Genmab: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy; Incyte: Consultancy; Genentech: Consultancy; Gilead/KITE: Consultancy; Lilly: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Matasar:Genmab: Membership on an entity's Board of Directors or advisory committees; IMV Therapeutics: Honoraria; AstraZeneca: Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria; Epizyme: Honoraria; Takeda: Honoraria; BMS/Celgene: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Merck: Current equity holder in publicly-traded company; GM Biosciences: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Honoraria; Pfizer: Honoraria; Kite: Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Immunovaccine Technologies: Research Funding; Allogene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Merryman:Genmab: Consultancy, Honoraria, 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; DG Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Merck: Research Funding. Munoz:Eli Lilly: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Consultancy; MEI: Consultancy; Morphosys/Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Epizyme: Consultancy; ADC Therapeutics: Consultancy; Genentech/Roche: Consultancy, Research Funding; Genzyme: Consultancy; Genmab: Consultancy; Verastem: Consultancy, Research Funding; Aurobindo: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Research Funding; Fosunkite: Consultancy; Alexion: Consultancy; Kyowa: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding; Pharmacyclics/Abbvie: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Merck: Research Funding; Portola: Research Funding; Curio: Honoraria; OncView: Honoraria; Physicians' Education Resource: Honoraria; Targeted Oncology: Honoraria; Alexion: Consultancy; BeiGene: Consultancy; Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, Beigene.: Research Funding; 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, OncView, Curio, Genzyme, and Physicians' Education Resource.: Honoraria. Riedell:Cargo Therapeutics: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; CVS Caremark: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Calibr: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CRISPR Therapeutics: Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sana Biotechnology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria. Ryan:AstraZeneca Brazil: Honoraria; Genentech: Other: Research Funding to institution. Salles:Merck: Consultancy; Kite/Gilead: Consultancy; Ipsen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; BMS/Celgene: Consultancy; Genmab: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Incyte: Consultancy; BeiGene: Consultancy; Molecular Partners: Consultancy; Nurix: Research Funding. Sauter:Cargo Therapeutics: Research Funding; Celgene/BMS: Consultancy; Gamida Cell: Consultancy; Karyopharm Therapeutics: Consultancy; MorphoSys: Consultancy; NKARTA: Consultancy; Ipsen Biopharmaceuticals: Consultancy; Juno Therapeutics: Research Funding; CSL Behring: Consultancy; Precision Biosciences: Research Funding; Actinium Pharmaceuticals: Research Funding; Syncopation Life Sciences: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene/BMS: Research Funding; Affimed: Research Funding; Kite/a Gilead Company: Consultancy; Ono Pharmaceuticals: Consultancy; NKARTA: Research Funding; Sanofi-Genzyme: Research Funding; CRISPR Therapeutics: Consultancy. Sawalha:Beigene: Research Funding; AbbVie: Research Funding; Genmab: Honoraria, Research Funding; ADC: Consultancy. Wang:Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, Genmab, AbbVie: Other: Advisory Board; Kite: Honoraria; Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, AbbVie, BeiGene, Merck: Research Funding; InnoCare, AbbVie: Consultancy. Yamshon:Kite: Consultancy; BMS: Consultancy. Zelenetz:BMS/Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy; MEI Pharma: Consultancy, Research Funding; Abbvie: Consultancy; Janssen: Consultancy; Adaptive Biotechnology: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; Genentech/Roche: Consultancy, Research Funding; Gilead/Kite: Consultancy. Palomba:Cellectar: Consultancy; Synthekine: Consultancy; Novartis: Consultancy; Bristo Meyer Squibb: Consultancy. Kumar:Genentech, Inc.: Consultancy, Honoraria, Research Funding; Kite Pharmaceuticals, Janssen: Honoraria; BridgeBio Pharmaceuticals: Current equity holder in publicly-traded company; Loxo Oncology/Lily Pharmaceuticals: Honoraria, Research Funding; Astra Zeneca: Honoraria, Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies, Celgene, Pharmacyclics: Research Funding; Abbvie Pharmaceuticals: Research Funding.