Absolute Lymphocyte Count after CAR-T Therapy Has Different Kinetics and Predicts Better Outcomes in B-Cell Malignancies

Introduction:

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 and BCMA antigens are now a valuable option for patients with relapsed or refractory (R/R) B-Cell malignancies Commercially available products consist of an antigen binding domain against CD19 or BCMA and one of two main co-stimulatory molecules, CD28 (Axi-Cel , Brexu-Cel ) and 41-BB (Tisa-Cel, Liso-Cel, Cilta-cel, and Ide-cel). We have previously shown that the absolute lymphocyte count (ALC) is a prognostic marker in R/R multiple myeloma (MM) and a surrogate of CAR-T cell expansion associated with improved response and progression free survival (PFS). In this study, we hypothesize that ALC in R/R B-Cell malignancies treated with CAR-T therapy correlates with longer PFS. We also investigate the differences in ALC kinetics between different products and co-stimulatory molecules.

Methods:

We analyzed data from patients with R/R B-Cell malignancies treated with CAR-T therapy from 2017 to 2024 at our two institutions (Columbia University Medical Center (CUMC) and Weil Cornell Medicine (WCM)). Baseline characteristics including year of infusion, disease type, best response, and ALC were collected. ALC_max was defined as the highest ALC from day 0 through 15, not attributable to leukemic disease. The ALC values and its kinetics were compared between products and co-stimulatory molecules of the CAR_T product. Survival and Cox proportional hazards analyses were performed with PFS as an outcome.

Results:

We identified 229 patients with B cell malignancies (DLBCL, MCL, FL, ALL, CLL, and MM), 75 from CUMC and 154 from WCM. Most used product was Axi-cel 117 (69%) followed by Liso-cel 27 (16%) in the lymphoma cohort in comparison to cilta-cel in the MM cohort. The most common malignancy was DLBCL (62%) followed by MM (26%), FL and MCL (5.9%) each. The ALC max was significantly higher in Liso-Cel and Tisa-Cel compared with Axi-cel and Brexu-Cel (p = 0.006). ALCmax was also higher in CD19 and BCMA CAR- T products with the 4-1BB compared to CD19 CAR-T cells with the CD28 co-stimulatory domain (0.76 vs 1.28 vs 0.59 x 10³/uL respectively) (p < 0.001). In Univariate analysis of DLBCL alone and all lymphoma patients treated with the CD19 CAR-T products with the CD28 co-stimulatory domain, higher ALC_max was associated with improved PFS (HR: 0.46, 95% CI: 0.23 - 0.9), while an ALC_max < 0.5 x 10³/uL was associated with worse PFS (Hazzard ratio (HR) 1.93, CI 1.13 - 3.27). There was no significant difference in PFS for CD19 CAR-T with 41-BB products; however, ALC_max was associated with better PFS after accounting for lines of therapy and high-risk cytogenetics in MM patients treated with the BCMA-41-BB CAR-T products (HR: 0.42, 95% CI: 0.26 - 0.78, p = 0.001). In the lymphoma cohort, ALC_max was not significantly associated with depth of response for any of the CD19 CAR-T therapies, while it was significantly associated with deeper response in MM patients achieving very good partial response or better (p =0.007).

Conclusions:

We observed higher ALC_max in 4-1BB compared to CD28 co-stimulatory domain products, probably representing a molecular feature of these co-stimulatory domains. Nonetheless, ALC_max was associated with better PFS in DLBCL patients treated with CD19-CD28 products. Similarly, ALC_max was associated with deeper response and improved PFS in MM patients treated with BCMA-41-BB CAR-T products. This data suggests that ALC_max is a good marker for response and outcomes of CAR-T therapy in B-cell malignancies and encourages a better understanding of the factors influencing ALC levels between different CAR-T products and disease subtypes.

Bhutani:Sanofi: Consultancy, Research Funding. Chakraborty:Janssen: Consultancy; Sanofi: Consultancy; Adaptive: Consultancy. Lentzsch:Peerview: Speakers Bureau; Clinical Care Options (COO): Speakers Bureau; RedMed: Speakers Bureau; Aptitude: Speakers Bureau; Bio Ascend: Speakers Bureau; Medscape: Speakers Bureau; Pfizer: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; GSK: Consultancy; Sanofi: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Angitia: Consultancy; Alexion: Consultancy; Takeda: Consultancy; Adaptive: Consultancy; Magenta: Current holder of stock options in a privately-held company; Poseida: Current holder of stock options in a privately-held company; Sanofi: Research Funding; Zentalis: Research Funding; Caelum Bioscience: Patents & Royalties. Mapara:Bluebirdbio: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ossiumhealth: Consultancy. Niesvizky:Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Consultancy, Research Funding. Reshef:Allogene: Consultancy; Gilead Sciences: Consultancy, Research Funding; Orca Bio: Consultancy; TScan: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Quell Biotherapeutics: Consultancy; Sana Biotechnology: Consultancy; Autolus: Consultancy; Bayer: Consultancy; Atara Biotherapeutics: Research Funding; Sanofi: Research Funding; Immatics: Research Funding; Abbvie: Research Funding; TCR2: Research Funding; Takeda: Research Funding; BMS: Research Funding; CareDx: Research Funding; Cabaletta: Research Funding; Synthekine: Research Funding; J&J: Research Funding; Genentech: Research Funding; Precision Biosciences: Research Funding. Yamshon:Bristol Myers Squibb: Consultancy; Kite Pharma: Consultancy.