Abstract 2049: Cytokines associated with prolonged Cytopenia after axicabtagene ciloleucel in patients with refractory large B-cell lymphoma
Authors: Strati Paolo , Puebla-Osorio Nahum , Han Guangchun , Westin Jason , Nastoupil Loretta , Samaniego Felipe , Fowler Nathan , Fayad Luis , Lee Hun Ju , Flowers Christopher , Srour Samer , Watson Grace , Wang Linghua , Green Michael , Neelapu Sattva 
Published: September 2020

Abstract
Introduction. Prolonged grade 3-4 (G3-4) cytopenias lasting beyond day 30 have been observed with various chimeric antigen receptor (CAR) T-cell products, suggesting a class effect. However, the mechanism(s) of prolonged cytopenias remains largely unknown, being unclear whether it is related to the effects of the conditioning regimen or due to CAR T-cell activity.
Methods. To investigate whether CAR T-cell activity is associated with prolonged cytopenia, we measured 29 analytes associated with CAR-T cell activity by multiplex assays (V-Plex, Meso Scale Diagnostics) in serial plasma samples at baseline and days 7, 14 and 30 (D30) after standard of care axicabtagene ciloleucel (axi-cel) therapy in patients with refractory large B-cell lymphoma treated at MD Anderson Cancer Center between March and August 2018. Patients with G3-4 cytopenia before conditioning, defined according to CTCAE v5, and those who progressed and/or died before D30 were excluded from the analysis. Unpaired t-test was used for area under the curve (AUC) comparison, independent sample t-test for mean peak comparison, and the Benjamini-Hochberg method for adjustment of false discovery rate (FDR).
Results. Of 19 patients included in the analysis, 9 (47%) had ongoing G3-4 cytopenia at D30. Baseline clinical characteristics were not significantly different between the 2 groups. Patients with D30 G3-4 cytopenia had a significantly higher AUC for the following cytokine levels: IFN-γ, FLT3-L, G-CSF, GM-CSF, CXCL1, IL-1Rα, IL-3, IL-8, IL-10, M-CSF, CCL2 (p≤0.05); IL-1β, IL-2Rα, IL-6, IL-15, TNF-α (p&lt;0.01); and VWF (p&lt;0.001). In contrast, a significantly lower AUC was observed for Ang-1 (p=0.0002) and EGF (p=0.05). After adjusting for FDR, the association was maintained only for the following cytokines: Ang-1, IL-10, IL-15, IL-1β, IL-2Rα, IL-6, IL-8, TNF-α and VWF. As the majority of cytokines outlined above showed a peak at day 7, the association between day 7 peak and D30 G3-4 cytopenia was evaluated. Patients with D30 G3-4 cytopenia showed a significantly higher peak at day 7 for the following cytokines: IFN-γ, G-CSF, GM-CSF, CXCL1, IL-1β, IL-2Rα, IL-3, IL-6, IL-8, IL-10, M-CSF, CCL2 (p≤0.05); and FLT3-L (p&lt;0.001); and a significantly lower peak for EGF (p=0.005). After adjusting for FDR, the only cytokine maintaining its association was FLT3-L.
Conclusions. Development of prolonged cytopenia after axi-cel in patients with large B-cell lymphoma is associated with significant increase in the levels of multiple inflammatory cytokines early after CAR T infusion, suggesting this may be due to CAR T-cell activity rather than to the myelosuppressive effect of conditioning regimen. The majority of these cytokines appear to be derived from myeloid cells and peak at day 7, providing potential targets for prophylactic intervention in these patients. Analysis of CAR-T expansion is ongoing and will be presented at the meeting.
Citation Format: Paolo Strati, Nahum Puebla-Osorio, Guangchun Han, Jason Westin, Loretta Nastoupil, Felipe Samaniego, Nathan Fowler, Luis Fayad, Hun Ju Lee, Christopher Flowers, Samer Srour, Grace Watson, Linghua Wang, Michael Green, Sattva Neelapu. Cytokines associated with prolonged Cytopenia after axicabtagene ciloleucel in patients with refractory large B-cell lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2049.