Background: Disease progression and relapse remain significant challenges to chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Using an unsupervised machine learning approach applied to pre-infusion labs and cytokines assessing organ function and inflammation, we previously identified unique signatures (inflammatory vs. non-inflammatory clusters). The inflammatory cluster was enriched for patients with elevated inflammatory markers, increased cell turnover, or end-organ sequelae of inflammation (e.g., hepatitis, bone marrow suppression) and was strongly associated with CAR-T treatment failure in the clinical setting (Raj S et al. ASH 2022).
Methods: Here, we validated the model, named InflaMix, and evaluated its utility in a large cohort of patients with LBCL (n=352) treated with axicabtagene ciloleucel (axi-cel) as part of the ZUMA-1 (NCT02348216; n=182, 52%) and ZUMA-7 (NCT03391466; n=170, 48%) registrational studies. InflaMix was applied using 14 pre-infusion, day 0 laboratory and cytokine (hemoglobin, platelets, white blood cells, CRP, ferritin, IL-6, IL-10, TNF∝, d-dimer, aspartate transaminase, alkaline phosphatase, total bilirubin, LDH, albumin) measurements.
Results: InflaMix assigned 46 % and 30% of patients to the inflammatory cluster in the ZUMA-1 and ZUMA-7 cohorts, respectively. Patients in the inflammatory clusters were more likely to have had more prior lines of therapy and higher baseline LDH than those in the non-inflammatory clusters ( p < 0.001). Assignment to the inflammatory cluster vs. non-inflammatory cluster was significantly associated with an increased risk of not achieving complete response (CR) by day 100 across both ZUMA-1 (odds ratio [OR] 1.68 [95% confidence interval (CI) 1.31 to 2.64) and ZUMA-7 (OR 1.57 [95% CI 1.25 to 2.53]) cohorts ( Figure A). Importantly, the inflammatory cluster was also significantly associated with inferior overall survival compared with the non-inflammatory cluster ( Figure B) in ZUMA-1 and ZUMA-7 (hazard ratio [HR] 1.65 [95% CI 1.38 to 2.14] and HR1.75 [95% CI 1.39 to 2.59], respectively), as well as decreased progression-free survival in ZUMA-1. All analyses were adjusted for age, pre-lymphodepletion LDH as a surrogate for baseline disease burden, and history of primary refractory disease, and adjustment for prophylactic steroid treatment in the ZUMA-1 cohort; prophylactic steroids were administered immediately before and after infusion in sub-cohort 6 of ZUMA-1.
Conclusion: InflaMix identifies a unique inflammatory biomarker signature that can be derived using a simple blood draw prior to CAR-T infusion. We show that the signature reproducibly stratifies patients with LBCL by risk for CAR-T treatment failure and inferior survival is valid in patients treated with axi-cel as second-line treatment or later. Potential clinical applications of InflaMix include prognostication and informed design of clinical trials to target high-risk populations.
Disclosures
Xie:Kite, a Gilead company: Current Employment. Song:Kite, a Gilead company: Current Employment. Kim:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current holder of stock options in a privately-held company. To:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current holder of stock options in a privately-held company, Other. van den Brink:Rheos Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seres Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: IP licensing , Research Funding; Frazier Healthcare Partners: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lygenesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Notch Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vor Biopharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Wolters Kluwer: Patents & Royalties; Thymofox: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Other: IP licensing; Ceramedix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Da Volterra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; DKMS (a non-profit organization): Membership on an entity's Board of Directors or advisory committees; Pluto Immunotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Perales:Adicet: Honoraria; Incyte: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Syncopation: Honoraria; DSMB: Other; Takeda: Consultancy, Honoraria; NexImmune: Consultancy, Current equity holder in publicly-traded company; AbbVie: Consultancy, Honoraria; Allovir: Consultancy; Exevir: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Omeros: Consultancy, Current equity holder in publicly-traded company, Honoraria; Astellas: Consultancy, Honoraria; Cidara Therapeutics: Consultancy, Other; Allogene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Honoraria; Vor Biopharma: Consultancy, Honoraria; Equillium: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Honoraria; Caribou: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Research Funding; Servier: Other; Medigene: Consultancy, Other; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; VectivBio AG: Consultancy, Honoraria; Orcabio: Consultancy, Current equity holder in publicly-traded company, Honoraria; Sellas Life Sciences: Consultancy. Mattie:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company.
