Absolute Lymphocyte Count As a Predictor of Safety and Efficacy Post CART for Multiple Myeloma and B Cell Malignancies

Background:

Absolute lymphocyte count (ALC) has previously been investigated as a prognostic factor for patients with relapsed/refractory (R/R) multiple myeloma due to its association with host immune status and the ability to successfully manufacture autologous chimeric antigen receptor T-cell (CAR-T). As such, ALC may also be useful for predicting the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which are caused by overstimulation of the immune system and cytokine release by CAR-T cells. The present study performed a retrospective review of patients receiving BCMA/CD19 CAR-T products at the University of Kansas Medical Center to identify whether incidence of CRS and ICANS could be associated with ALC at infusion day 0 of therapy in patients with multiple myeloma (MM), non-Hodgkins's lymphoma (NHL), and acute lymphoblastic leukemia (ALL).

Methods:

347 patients receiving CAR-T Therapy for MM, NHL, and ALL at the University of Kansas Medical Center from Dec 2017-Dec 2023 were included in the study. ALC was measured in cells/µL were recorded on Day 0 of CAR-T infusion. ALC was analyzed as a continuous variable and used to compare the incidence of CRS and ICANS, and to investigate overall survival (OS) and progression-free survival (PFS) at 180 days.

Results:

Patients with multiple myeloma comprised 23.6% of the study population (n=83). The median age of patients in this cohort was 69 years (range:44-82). 70% of the population had IgG MM, 15% had IgA MM, and 15% had light chain MM. 48% of the cohort received Idecabtagene vicleucel (ide-cel), 36% received ciltacabtagene autoleucel (cilta-cel), and 16% received investigational CAR-T therapies.

Patients with non-Hodgkin's lymphoma comprised 70.6% of the study population (n=246). The median age of patients in this cohort was 66 years (range: 28-91). 82% of the population had diffuse large B-cell lymphoma (DLBCL), 11% had follicular lymphoma, 6% had mantle cell lymphoma, and 1% had other malignancy. 60% of the cohort received Axicabtagene ciloleucel (axi-cel), 17% received Tisagenlecleucel (tisa-cel), 10% received investigational CAR-T therapies, 7% received Lisocabtagene maraleucel (liso-cel), and 6% received Brexucabtagene autoleucel (brexu-cel).

Patients with acute lymphoblastic leukemia comprised 5% of the study population (n=18). The median age of this cohort was 39 years (range: 21-70). 56% of the cohort received Brexucabtagene autoleucel (brexu-cel), 39% received Tisagenlecleucel (tisa-cel), and 5% received investigational CAR-T therapies.

Median ALC at infusion for patients with either CRS or ICANS in the total cohort was 10.0 cells/µL (IQR 0.0-30.0), while it was 30 cells/µL (IQR 10.0-60.0) in patients without CRS or ICANS. This suggests patients with either CRS or ICANS had a significantly lower median ALC at infusion (p=0.001).

When looking only at the NHL population, the median ALC for patients with either CRS or ICANS was 10.0 (IQR 0.0 to 30.0), which was significantly lower than the median ALC of 30.0 (IQR 10.0 to 60.0) in patients without CRS or ICANS (p=0.001). For the MM population, no significant difference in the median of ALC was found between patients with and without ICANS or CRS (p=0.061).

No significant difference in Day 0 ALC was found between patients who were alive at Day 180 and those who were not (p=0.166). No significant difference in ALC was found between patients who progressed by 180-days compared to and those who did not (p=0.236).

Conclusion:

Higher ALC on day 0 of infusion is associated with decreased risk of ICANS and CRS in the NHL cohort, and not in the MM cohort. These results are surprising because the findings are contrary to the conventional idea that low ALC at infusion is associated with lower risk of CRS and ICANS. While the mechanism of this finding is unknown, it may be the case that decreased ALC at time of infusion, following lymphodepleting chemotherapy, may indicate more pronounced lymphodepletion and allow for faster and more robust CAR-T cell expansion leading to increased toxicity. Moreover, the prognostic value of ALC may differ based on the immune environments of different malignancies and warrants further investigation. These findings suggest ALC on day 0 may have clinical use as a risk assessment tool to stratify patients. Further analysis and prospective multicenter data will be needed to evaluate the effect of other factors.

Tun:The University of Kansas: Current Employment. Hoffmann:ADC, Janssen, Pharmacyclics, BeiGene, Novartis, Astra-Zeneca, Abbvie, Kite, TG: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Other: Travel. McGuirk:Kite: Consultancy; Sana technologies: Consultancy; Legend biotech: Consultancy; Caribou bio: Consultancy; CRISPR therapeutics: Consultancy; NEKTAR therapeutics: Consultancy; Novartis: Consultancy; Allo Vir: Consultancy; Envision: Consultancy; Autolus: Consultancy; BMS: Consultancy. Ahmed:Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Lutfi:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees.