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263 Inflammatory Biomarker Clusters Are Predictive of Response and Toxicity in Large B-Cell Lymphoma Treated with CD19 CAR-T Cell Therapy

Program: Oral and Poster Abstracts
Type: Oral
Session: 705. Cellular Immunotherapies: Novel Predictors of Response or Toxicity to Cellular Therapies
Hematology Disease Topics & Pathways:
Research, Biological therapies, artificial intelligence (AI), adult, Lymphomas, non-Hodgkin lymphoma, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Therapies, Lymphoid Malignancies, Technology and Procedures, Study Population, Human, machine learning
Saturday, December 10, 2022: 3:00 PM

Sandeep Raj, MD1, Miguel-Angel Perales, MD2, Joshua A Fein, MD3, Ana Alarcon Tomas1*, Connie Lee Batlevi, MD, PhD4, Magdalena Corona De Lapuerta, MD5*, Parastoo B Dahi, MD2*, Ivetta Danylesko6*, Shalev Fried, BSc7*, Tyler Funnell, PhD8*, Sergio A. Giralt, MD, FACP, FASTCT9*, Elad Jacoby, MD10, Meirav Kedmi6*, Richard J. Lin, MD2, Arnon Nagler, MD11, Karthik Nath, MBBS, PhD1*, Allison Parascondola, BA1*, M.Lia Palomba, MD12, Gilles Salles, MD, PhD13, Michael Scordo, MD14, Gunjan L. Shah, MD15*, Noga Shem-Tov, MD6*, Avichai Shimoni, MD6*, John Slingerland16*, Moneeza Walji, MD, BSc, MPH1, Ronit Yerushalmi, MD6, Abraham Avigdor, MD7, Marcel R M van den Brink, MD, PhD15 and Roni Shouval, MD, PhD2

1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
2Adult Bone Marrow Transplant Service, Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
3Weill Cornell Medical College, New York, NY
4Lymphoma Service, Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, NEW YORK, NY
5Servicio de Hematología, Hospital 12 de Octubre, Madrid, Spain
6Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat Gan, Israel
7Chaim Sheba Medical Center, Ramat Gan, Israel
8Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
9Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY
10Pediatric Hematology and Oncology Department, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
11Hematology and Bone Marrow Transplant Unit, Chaim Sheba Medical Center, Tel Hashomer, Israel
12Lymphoma Service, Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
13Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
14Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center/New York, New York, NY
15Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
16Memorial Sloan Kettering Cancer Center, New York, NY

Disease recurrence and toxicity are common sequelae of CD19-directed chimeric antigen T-cell (CAR-T) cell therapy in large B-cell lymphoma (LBCL). We have developed a machine learning approach that is informative of adverse CAR-T outcomes and can support personalized treatment approaches.

In a single-center cohort of 198 LBCL patients treated with CD19-CAR-T cells (axicabtagene ciloleucel [axi-cel] 50%, tisagenlecleucel [tisa-cel] 32%, lisocabtagene maraleucel [liso-cel] 18%), we applied unsupervised k-means clustering on standard laboratory and cytokine measurements collected within the day prior to CAR-T infusion. Three distinct biomarker clusters emerged (Fig. A) – inflammatory (n=27, 14%), neutral (n=121, 61%), and favorable (n=50, 25%). The inflammatory subgroup was enriched for patients with high levels of inflammatory markers such as IL-6, TNFa, and ferritin, while the favorable cluster tended to have higher complete blood counts and albumin; intermediate values were characteristic of the neutral subgroup.

To determine the clinical implications of these subgroups, we studied their association with day 100 best response to CAR-T, significant toxicity by day 30 (defined as life-threatening complications such as immune toxicities requiring intervention, bloodstream infections, or early death), and overall survival (OS) after multivariate adjustment for CAR-T costimulatory domain (CD28 vs 41BB), patient age, primary refractory disease, and pre-lymphodepletion LDH. Compared to those in the favorable biomarker cluster, patients in the inflammatory cluster (Fig. A) had increased odds of not achieving CR by day 100 (odds ratio [OR] 4.23, 95% confidence interval [CI] 1.37-14.4, p < 0.05) and a high toxicity profile (OR 12.5, 95% CI 3.66-49.5, p < 0.001). OS was also reduced with the inflammatory subgroup in univariable analysis (Fig. B) and a multivariable Cox regression model (hazard ratio [HR] 4.03, 95% CI 1.99-8.16, p < 0.001). Patients in the neutral subgroup, compared to those in the favorable group, had reduced overall survival (HR 1.80, 95% CI 1.00-3.24, p < 0.05) and increased odds of high toxicity (OR 3.40, 95% CI 1.56-7.79, p <0.01).

Serial assessment of the uncommon biomarkers and cytokines in our day 0 panel may not be readily available to many centers. We developed a random forest prediction model for cluster type based on patient, disease, and widely available pre-lymphodepletion laboratory features. Our random forest model outperformed gradient boosting and logistic regression model alternatives and achieved a high discrimination (AUC 0.81) for cluster prediction. Next, we applied the random forest model to pre-lymphodepletion data from an independent LBCL cohort (n=155) from a different center (Fig. B). Most patients were assigned to the neutral subgroup (n=108, 70%) followed by the inflammatory (21%) and favorable (9%) subgroup. Assignment to the inflammatory cluster was strongly associated with inferior OS compared to the favorable subgroup (HR 2.89, 95% CI 1.12-7.48, p < 0.05) after multivariate adjustment for CAR-T costimulatory domain (CD28 vs 41BB), patient age, primary refractory disease, and pre-lymphodepletion LDH.

In conclusion, we identified three pre-infusion (day 0) biomarker clusters, which are tightly associated with CAR-T outcomes. These clusters could guide decision-making regarding hospitalization after CAR-T infusion and to preempt early inflammation and disease relapse in high-risk subgroups. Finally, to improve accessibility to cluster assignment, we developed a prediction model for cluster type based on readily available pre-lymphodepletion data and applied it towards an external center cohort as a proof-of-principle.

Disclosures: Perales: Astellas: Honoraria; AbbVie: Honoraria; Sellas Life Sciences: Consultancy; Kite, a Gilead Company: Honoraria, Research Funding; Merck: Consultancy; Miltenyi Biotec: Consultancy, Honoraria; Novartis: Honoraria; Nektar Therapeutics: Consultancy, Honoraria; Omeros: Consultancy; Vor Biopharma: Honoraria; VectivBio AG: Honoraria; Orca Bio: Consultancy; Karyopharm: Honoraria; Celgene: Honoraria; MorphoSys: Consultancy, Honoraria; Cidara Therapeutics: Consultancy; Takeda: Honoraria; Medigene: Consultancy; Servier: Consultancy; Bellicum: Honoraria; DSMB: Other; Incyte: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Batlevi: ADC Therapeutics: Other: Provision of Services; Bristol-Myers Squibb: Other: Ownership / Equity Interests; Provision of Services; Dava Oncology: Other: Provision of Services; Autolus: Research Funding; Bayer: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Roche/Genentech: Research Funding; Xynomic: Research Funding; GLG Pharma: Consultancy; Juno/Celgene: Consultancy; Kite Pharma: Consultancy; Life Sciences: Consultancy; Seattle Genetics: Consultancy. Giralt: Amgen, Actinium, Celgene, Kite, Janssen, Jazz Pharma, Johnson & Johnson, Novartis, Spectrum Pharma, Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen, Actinium, Celgene, Johnson & Johnson, Miltenyi, Omeros, Takeda: Research Funding; BMS, Sanofi, Pfizer, GSK: Membership on an entity's Board of Directors or advisory committees. Jacoby: Novartis: Membership on an entity's Board of Directors or advisory committees. Lin: Magenta Therapeutics: Consultancy; Kite, A Gilead Company: Consultancy. Palomba: BeiGene: Consultancy; Ceramedix: Consultancy. Salles: Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys AG, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, Bristol Myers Squibb, BeiGene, Incyte, Miltenyi Biotec, Ipsen, Kite, a Gilead Company, Loxo, Rapt: Consultancy; Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSys AG, Amgen, Bayer, Epizyme, Regeneron, Kite, a Gilead Company: Honoraria; AbbVie, BeiGene, Bristol Myers Squibb, Celgene, Debiopharm, Epizyme, Genentech/Roche, Genmab, Incyte, Kite, a Gilead Company, Miltenyi, MorphoSys, Takeda, and VelosBio: Membership on an entity's Board of Directors or advisory committees. Scordo: Medscape, LCC (CME): Honoraria; i3Health (CME): Honoraria; Amgen, Inc.: Research Funding; Omeros Corporation: Consultancy, Research Funding; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Kite - A Gilead Company: Other: Ad-hoc advisory board (past); McKinsey & Company: Consultancy. Shah: Amgen: Research Funding; Beyond Spring: Research Funding; Janssen: Research Funding. Slingerland: Seres Therapeutics: Other: salary support through a sponsored agreement. Avigdor: Takeda, Gilead, Novartis, Roche, BMS: Consultancy; AbbVie: Honoraria. van den Brink: Rheos Medicines: Honoraria; Vor Biopharma: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Honoraria; Notch Therapeutics: Current holder of stock options in a privately-held company, Honoraria; Frazier Healthcare Partners: Honoraria; Nektar Therapeutics: Honoraria; Ceramedix: Honoraria; Lygenesis: Honoraria; GlaskoSmithKline: Honoraria; Da Volterra: Honoraria; Thymofox: Honoraria; Garuda: Honoraria; Novartis (Spouse): Honoraria; Synthekine (Spouse): Honoraria; Beigene (Spouse): Honoraria; Kite (Spouse): Honoraria; Juno Therapeutics: Other: IP Licensing ; DKMS: Other: fiduciary role on the Foundation Board ; Wolters Kluwer: Patents & Royalties; Seres Therapeutics: Current holder of stock options in a privately-held company, Honoraria, Other: IP Licensing , Research Funding. Shouval: Medexus: Consultancy, Ended employment in the past 24 months; MyBiotics: Consultancy.

*signifies non-member of ASH