Emily Liang 1,2, Aya Albittar1, Andrew Portuguese1,2, Jennifer Huang1,2, Natalie Wuliji1,2, Qian Wu1, Joseph De Los Reyes1,2, Nikki Pin1, Aiko Torkelson1, Delaney Kirchmeier1, Abigail Chutnik1, Barbara Pender1, Joshua Hill1,2, Noam Kopmar1,2, Rahul Banerjee1,2, Andrew Cowan1,2, Damian Green1,2, Ajay Gopal1,2, Christina Poh1,2, Mazyar Shadman1,2, Alexandre Hirayama1,2, Brian Till1,2, Erik Kimble1,2, Lorenzo Iovino1,2, Aude Chapuis1,2, Folashade Otegbeye1,2, Ryan Cassaday1,2, Filippo Milano1,2, Cameron Turtle3, David Maloney1,2, Jordan Gauthier1,2 1Fred Hutchinson Cancer Center, Seattle, United States, 2University of Washington, Seattle, United States, 3University of Sydney, Sydney, Australia

Background: The observation that distinct patterns of hematologic toxicity are not adequately captured by CTCAE grading led to the recently developed EHA/EBMT immune effector cell-associated hematotoxicity (ICAHT) grading system (Rejeski et al, Blood, 2023). We applied the ICAHT grading system to patients undergoing CAR T-cell therapy at a large institution in the US and assess factors associated with grade ≥3 ICAHT.

Methods: Adults who underwent CAR T-cell therapy for hematologic malignancies with commercial or investigational products at our center between 2013 and 2023 were included (n = 454). Grading of early hematotoxicity (day-0-30 after CAR T-cell cell infusion) was automated using the heatwaveR package in R per ICAHT criteria detailed in Rejeski et al, Blood, 2023. Associations with 50 patient, disease-related, and laboratory factors, and ICAHT grade ≥3 were modeled using univariate and multivariable logistic regression.

Results: The most common disease types were aggressive non-Hodgkin lymphoma (n = 216; 48%), acute lymphoblastic leukemia (n = 82; 18%), and multiple myeloma / plasma cell leukemia (n = 61; 13%) (Table). The most common CAR T-cell products were investigational CD19 CAR T-cell products (n = 180; 40%), axicabtagene ciloleucel (n = 114; 25%), and lisocabtagene maraleucel (n = 58; 13%).

Incidences of early ICAHT grades 1, 2, 3, and 4 were 141 (31%), 177 (39%), 47 (10%), and 30 (7%), respectively. Patients with grades 3-4 ICAHT had worse overall survival compared to those with grade 0-2 ICAHT (median of 6 s. 18 months, p < 0.001).

Baseline patient factors associated with grade 3-4 ICAHT included ALL (reference: aggressive NHL, OR = 3.0, 95% CI, 1.7-5.6, p < 0.001) and age (OR = 0.97, 95% CI, 0.96-0.99, p = 0.003). Pre-lymphodepletion (LD) laboratory factors associated with grade 3-4 ICAHT included ANC (OR = 0.18 per log10, 95% CI, 0.10-0.30, p < 0.001), lactate dehydrogenase (OR = 7.4 per log10U/L, 95% CI, 3.3-17.4, p < 0.001), C-reactive protein (CRP; OR = 5.9 per log10mg/L, 95% CI, 2.8-14.0, p < 0.001), and ferritin (OR = 6.5 per log10mg/L, 95% CI, 3.0-16.0, p < 0.001). Peak CRP (OR = 12.8, 95% CI, 5.3-33.9, p < 0.001) and ferritin (OR = 5.6, 95% CI, 3.7-8.7, p < 0.001) after CAR T-cell infusion were strongly associated with grade 3-4 ICAHT. In a multivariable model including disease type, pre-LD ANC, pre-LD LDH, and peak CRP, pre-LD ANC (OR = 0.22, 95% CI, 0.11-0.42, p < 0.001), pre-LD LDH (OR = 5.0, 95% CI, 1.7-14.6, p = 0.003), and peak CRP (OR = 6.7, 95% CI, 2.7-18.4) remained independently associated with grade 3-4 ICAHT.

Table. Demographic, disease, and treatment characteristics (N = 454)

Age at infusion, median (range)

60 (50, 68)

Male sex

286 (63%)

Prior HCT

186 (41%)

Disease

 Aggressive NHL

216 (48%)

 ALL

82 (18%)

 MM/PCL

61 (13%)

 Indolent NHL

53 (12%)

 CLL

42 (9%)

CAR T-cell product

 Investigational CD19 CAR T-cell product

180 (40%)

 Commercial CD19 CAR T-cell product with CD28 costimulatory domain (axi-cel, brexu-cel)

143 (31%)

 Commercial CD19 CAR T-cell product with 4-1BB costimulatory domain (liso-cel, tisa-cel)

70 (15%)

 Commercial BCMA CAR T-cell product (cilta-cel, ide-cel)

61 (13%)

Conclusions: We found that 17% of patients undergoing CAR T-cell therapy at our center developed grade 3-4 hematotoxicity by EHA/EBMT ICAHT criteria. Grade 3-4 ICAHT was associated with worse OS. Multivariable logistic regression of factors associated with grade 3-4 ICAHT identified pre-LD ANC, pre-LD LDH, and peak CRP as independent predictors of grade 3-4 ICAHT.

Disclosure: Joshua Hill: allovir: Consultancy, Research Funding; moderna: Consultancy; deverra: Research Funding.

Rahul Banerjee: BMS: Consultancy; Janssen: Consultancy; Genentech: Consultancy; SparkCures: Consultancy; Sanofi: Consultancy; Caribou: Consultancy; Pfizer: Consultancy; Pack Health: Research Funding.

Andrew Cowan: BMS, Adaptive: Consultancy; Adaptive Biotechnologies, Harpoon, Nektar, BMS, Janssen, Sanofi, Abbvie: Research Funding.

Damian Green: Cellectar Biosciences: Research Funding; SpringWorks Therapeutics: Research Funding; Celgene: Consultancy; GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding; Janssen Biotech: Consultancy, Research Funding; Ensoma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Juno Therapeutics A BMS Company: Patents & Royalties, Research Funding.

Ajay Gopal: Compliment Corporation: Current holder of stock options in a privately-held company; Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi: Consultancy; Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab: Research Funding.

Christina Poh: BeiGene: Consultancy; Seattle Genetics: Consultancy; Incyte: Research Funding; Acrotech: Consultancy.

Mazyar Shadman: Fate Therapeutics: Consultancy; Genmab: Consultancy, Research Funding; Vincerx: Research Funding; MorphoSys/Incyte: Consultancy, Research Funding; Eli Lilly: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; AbbVie: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; ADC therapeutics: Consultancy; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy; Regeneron: Consultancy; TG Therapeutics: Research Funding.

Alexandre Hirayama: Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Nektar Therapeutics: Honoraria, Research Funding; Juno Therapeutics, a Bristol Myers Squibb Company: Research Funding.

Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding; BMS/Juno Therapeutics: Research Funding; Proteios Technology: Consultancy, Current holder of stock options in a privately-held company.

Kimble: Juno/BMS: Research Funding.

Lorenzo Iovino: Mustang Bio: Current equity holder in publicly-traded company.

Aude Chapuis: Juno Therapeutics: Research Funding.

Ryan Cassaday: Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Incyte: Research Funding; Autolus: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; Jazz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; PeproMene Bio: Membership on an entity’s Board of Directors or advisory committees; Seagen: Other: Spouse was employed by and owned stock in Seagen within the last 24 months.

Filippo Milano: ExCellThera Inc.: Research Funding.

David Maloney: A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Other: Member of the Scientific Advisory Board; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Rights to royalties from Fred Hutch for patents licensed to Juno Therapeutics/BMS, Research Funding; Janssen: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria, Research Funding; Mustang Bio: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Lyell Immunopharma: Other: Member, CAR T Steering Committee; Incyte: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Member, Scientific Review Committee, Research Scholars Program in Hematologic Malignancies; Kite, a Gilead Sciences: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board, Research Funding; Genentech: Consultancy, Honoraria, Other: Chair and Member of the Lymphoma Steering Committee; MorphoSys: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Other: Member of the JCAR017 EAP-001 Safety Review Committee and Member, CLL Strategic Council, Member of the JCAR017-BCM-03 Scientific Steering Committee under BMS, Research Funding; Amgen: Consultancy, Honoraria; Navan Technologies: Consultancy, Honoraria, Other: Member of the Scientific Advisory Board; Bioline Rx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board; Fred Hutch: Other: rights to royalties for patents licensed to Juno; Navan Technologies: Current holder of stock options in a privately-held company; Chimeric Therapeutics: Other: Member of the Scientific Advisory Board; ImmPACT Bio: Other: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program; Interius: Other: Member, Clinical Advisory Board.

Jordan Gauthier: Kite Pharma: Consultancy, Honoraria; MorphoSys: Consultancy, Research Funding; Angiocrine Bioscience: Research Funding; Century Therapeutics: Other: Independent data review committee; Celgene (a Bristol Myers Squibb company): Research Funding; Legend Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Juno Therapeutics (a Bristol Myers Squibb company): Research Funding; Sobi: Consultancy, Honoraria, Research Funding.

4: CAR-based Cellular Therapy – Clinical