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4814 Clonal Hematopoiesis Is Associated with Severe Cytokine Release Syndrome in Patients Treated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Program: Oral and Poster Abstracts
Session: 703. Cellular Immunotherapies: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Biological therapies, Translational Research, Lymphomas, non-Hodgkin lymphoma, CHIP, B Cell lymphoma, Plasma Cell Disorders, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, indolent lymphoma, aggressive lymphoma, Therapies, Lymphoid Malignancies, Adverse Events, Biological Processes
Monday, December 11, 2023, 6:00 PM-8:00 PM

Scott R. Goldsmith1, Geoffrey P. Shouse, PhD, DO2, F. Lennie Wong, PhD3, Alysia Bosworth4*, Aleksi Iujuridze4*, Sitong Chen, MPH4*, June-Wha Rhee4*, Matthew G. Mei, MD4, Murali Janakiram, MD, MS5, Myo Htut, MD6, Stephen J. Forman, MD, FACP7, Raju Pillai, MD8*, Elizabeth Lihua Elizabeth Budde, MD, PhD9 and Saro Armenian, DO, MPH4

1Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA
2Hematology/HCT, City of Hope National Medical Center, Duarte, CA
3City of Hope, Duarte, CA
4City of Hope National Medical Center, Duarte, CA
5Division of Myeloma, Department of Hematology, City of Hope National Medical Center, Duarte, CA
6City of Hope Comprehensive Cancer Center, Duarte, CA
7Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, CA
8Department of Pathology, City of Hope National Comprehensive Cancer Center, Duarte, CA
9Department of Hematology and HCT, City of Hope, Duarte, CA

Background: Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR-T therapy, inflammation pre- and post-CAR-T infusion is attributed in the development of toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells with somatic mutations, has been associated with inflammatory disorders such as rheumatoid arthritis and graft-versus-host disease, as well as clonal cytopenias of undetermined significance. In the setting of CAR-T, others have reported an association between CH and both ICANS and treatment-associated myeloid neoplasms. Herein, we examined the prevalence of pre-CAR-T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between CH and CAR-T related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS).

Methods: This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR-T therapy from 2017 to 2022 at City of Hope and had available pre-CAR-T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected <30d of CAR-T infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH (Yes/No) and absolute neutrophil count (ANC) recovery at day +60 (Y/N), maximum grade CRS and ICANS, grade <2 vs 2+, and OS and PFS at 1y. Covariables considered were age at CAR-T, baseline ANC, sex, race, CAR-HEMATOTOX (Rejeski et al. 2021), bridging therapy (Y/N), and number of prior lines of therapy. ANC recovery was defined as grade 2 or better for 3 measurements without growth factor support >2 weeks. Those without ANC recovery and who started new treatment before day +60 were excluded from that analysis.

Results: Overall, the median age was 64y (range 21y-85y); 37 (60%) had de novo diffuse large B-cell lymphoma, 17 (27%) had transformed follicular lymphoma, 2 (3%) had MM, 2 (3%) had mantle cell lymphoma, and the remaining patients had other transformed indolent lymphomas. Median prior lines of therapy was 3 (1-12), and only 6% had previously undergone autologous hematopoietic cell transplantation. Systemic bridging therapy prior to CAR-T was required in 27 (44%), and 8 (13%) received radiation as bridging. All received fludarabine and cyclophosphamide for lymphodepleting chemotherapy. Axicabtagene ciloleucel was the most common (76%) CAR-T product, followed by tisagenlecleucel in 16% of patients. Overall, 51 (82%) and 29 (47%) patients experienced CRS and ICANS, respectively. had delayed ANC recovery. One-year PFS was 50% and 1y OS was 73%. Clonal hematopoiesis: 15 (24%) patients had at least one pathogenic CH mutation; 4 (6.5%) had ≥2 CH mutations. Of the 28 CH mutations identified, the most common were DNMT3A (18%), CHEK2 (11%), PMS2 (7%) and ASXL1 (7%); 29% of mutations had VAFs >10%. Outcomes after CAR-T: Patients with CH were significantly more likely to develop grade ≥2 CRS (60% vs. 28%, p=0.03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p=0.027). Accounting for baseline ANC (which was unexpectedly higher among the CH cohort and associated with delayed ANC recovery, p=0.02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p=0.17). There was no association between CH and ICANS, nor with 1y PFS and OS.

Conclusion: CH was frequent (24%) in this cohort of CAR-T recipients and was associated with a higher risk of ≥2 CRS after CAR-T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR-T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis

Acknowledgements: Funding through the CoH Hematological Malignancies Program Pilot Project Award. The authors acknowledge the work provided by CoH Center for Informatics, notably Research Informatics, and the utilization of the POSEIDON platform and the Honest Broker process.

Disclosures: Goldsmith: Oncovalent: Consultancy; Wugen Inc.: Consultancy; Sanofi-Genzyme: Consultancy; Janssen Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Bristol Myers Squibb: Research Funding. Shouse: Beigene, Inc.: Speakers Bureau; Kite Pharmaceuticals: Consultancy, Speakers Bureau. Rhee: Pfizer: Research Funding. Mei: Seagen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys: Research Funding; Beigene: Research Funding; EUSA: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Budde: MustangBio: Research Funding; Merck: Research Funding; Novartis, Gilead, F. Hoffmann-La Roche Ltd, BeiGene, Genentech, Inc.: Consultancy; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; Roche: Consultancy; Amgen: Research Funding.

*signifies non-member of ASH