Outcomes of Aggressive B Cell Lymphoma Patients with No Evidence of Measurable Disease at the Time of CD19 Chimeric Antigen Receptor T Cell Therapy: The Experience from the CAR T Cell Consortium

Abstract

Introduction: CD19 chimeric antigen receptor (CAR) T cells provide high response rates and durable disease remission for many patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). Pre-treatment disease burden has been identified as a potential determining factor for efficacy and toxicity of CAR T cells, with lower tumor burden being associated with improved survival and lower toxicity (Bishop et al. Blood Advances 2019, Dean et al. Blood Advances 2020). However, in-vivo expansion and persistence of CAR T cells are thought to be influenced by pre-treatment tumor burden and play a role in treatment outcomes. Here, we report the characteristics, outcomes and toxicity patterns of DLBCL patients with no measurable diseases at the time of commercial CD19 CAR T cell therapy.Methods: The CAR T cell Consortium includes 8 US academic institutions that have collected data on adult patients with R/R DLBCL who received axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between April 2018 and October 2019. This multicenter retrospective study included all patients with no evidence of disease as evaluated by PET/CT scan and other indicated investigations before CAR T cell infusion. Baseline demographic data, CAR T cell treatment characteristics, response to CAR T cell therapy, outcomes and adverse events were analyzed and reported. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were reviewed and re-graded using the American Society of Transplant Cellular Therapy Consensus Criteria (Lee et al. BBMT 2019).Results: A total of 236 patients with DLBCL had CD19 CAR T cell therapy during the study period (151 axi-cel, and 85 tisa-cel). Data on disease status before CAR T cell infusion was available in 199 patients. Of these 199 patients, 15 (7.5%) were in complete remission (CR), as per investigator assessment at the time of CAR T-cell infusion (4 received axi-cel and 11 received tisa-cel). The median age was 61.6 years (range, 38.1-75.5). The indications of CAR T cell treatments included 12 R/R de novo DLBCL, 2 high grade B cell lymphoma and 1 transformed DLBCL. The median time from leukapheresis to CAR T cell infusion was 48 days (range, 19-89). After leukapheresis, 13 patients (86.7%) received bridging therapy prior to CAR T cell infusion. Of the 13 patients who received bridging therapy, all had repeated PET/CT scan prior to CAR T cell infusion showing no evidence of measurable diseases. The median time from pre-infusion PET/CT scan to the day of CAR T infusion was 14 days (range, 6-77) with 7 and 8 patients having CAR T cells in the inpatient and outpatient settings, respectively. Baseline characteristics and details of CAR T cell therapy are summarized in the Table. CRS was observed in 3 patients (20.0%) (2 Grade 1, 1 Grade 2) with the median time to onset of 1 day (range, 0-5). Of the 3 patients who developed CRS, 1 received axi-cel and 2 received tisa-cel. Tocilizumab was provided in 1 patient and no patients developed ICANS. At day +100 after CAR T cell infusion, 12 of 15 patients remained in CR (3 patients relapsed at day +30, +64 and +88). The 100-day treatment related mortality was 0%. At a median follow-up duration of 20 months, 10 patients remained alive and progression free, while 5 patients relapsed (4 DLBCL, 1 HGBL) and 4 patients died (3 from progressive disease and 1 from non-relapse mortality). The 1-year event free survival and overall survival was 66.0% (95%CI 45.7-59.4%) and 73.3% (95%CI 54.0-99.5%), respectively (Figure). The 1-year cumulative incidence of relapse was 27.3% (95%CI 3.4-51.3%).Conclusion: Patients with DLBCL who had no residual disease at the time of commercial CD19 CAR T cell infusion had excellent outcomes with very low incidence of CAR T cell-associated complications. These patients may be managed and followed safely in the ambulatory setting. Our findings emphasize the importance of pre-treatment disease burden on efficacy and tolerability of CAR T cell therapy. Our findings suggest that patients in CR at the time of infusion may still benefit from CAR T cell therapies and could serve as an initiative to explore the role of CAR T cells as a consolidation for patients with high risk DLBCL achieving CR after conventional treatments in the prospective clinical trial setting. [Display omitted] DisclosuresBachanova: KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Maziarz: Artiva Therapeutics: Consultancy; CRISPR Therapeutics: Consultancy; Intellia: Honoraria; Omeros: Research Funding; Allovir: Consultancy, Research Funding; Bristol-Myers, Squibb/Celgene, Intellia, Kite: Honoraria; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties; Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Incyte Corporation: Consultancy, Honoraria; Vor Pharma: Other: Data and Safety Monitoring Board. McGuirk: Novartis: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Pluristem Therapeutics: Research Funding; EcoR1 Capital: Consultancy; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astelllas Pharma: Research Funding; Gamida Cell: Research Funding. Nastoupil: Epizyme: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Caribou Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; Bayer: Honoraria; TG Therapeutics: Honoraria, Research Funding; MorphoSys: Honoraria; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; ADC Therapeutics: Honoraria; IGM Biosciences: Research Funding; Pfizer: Honoraria, Research Funding. Porter: Janssen: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Unity: Patents & Royalties; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Society for Transplantation and Cellular Therapy: Honoraria; ASH: Membership on an entity's Board of Directors or advisory committees; Wiley and Sons Publishing: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; GenenTech: Current Employment, Current equity holder in publicly-traded company. Riedell: Kite/Gilead: Research Funding, Speakers Bureau; MorphoSys: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding; Xencor: Research Funding; Tessa Therapeutics: Research Funding. Perales: Cidara: Honoraria; Novartis: Honoraria, Other; Merck: Honoraria; Incyte: Honoraria, Other; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sellas Life Sciences: Honoraria; NexImmune: Honoraria; Karyopharm: Honoraria; Servier: Honoraria; Takeda: Honoraria; Equilium: Honoraria; Omeros: Honoraria; Kite/Gilead: Honoraria, Other; MorphoSys: Honoraria; Miltenyi Biotec: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; Medigene: Honoraria.