Elevated CD10ˉ G-MDSC-like Neutrophils Correlate with Non-Response and Poor Prognosis of CD19 CAR T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia

Objectives: To explore the levels of CD10^-CD14^-HLA-DR^-CD33⁺CD45⁺SSC⁺ (CD10^- G-MDSC-like neutrophils, referred to as CD10^- neuts) in patients with B-cell acute lymphoblastic leukemia(B-ALL) undergoing CD19 CAR T cell therapy ,and to assess their impact on the efficacy of CAR-T cell treatment. Methods: 44 B-ALL patients undergoing CD19 CAR T therapy and 47 healthy controls (HCs) were included. Peripheral blood sample before CAR T cells infusion was drawn to examine CD10^- neuts level by flow cytometry. Three indicators used to reflect CD10^- neuts levels including the percent of CD10^- neuts in neutrophils (CD10^- neuts/neutrophils), and in all nucleated cells (CD10^- neuts/nucleated cells), and the absolute count of CD10^- neuts. Then we analyzed the correlation of CD10^- neuts levels with therapeutic response, relapse-free survival (RFS), overall survival (OS), and CAR T cells persistence time. Results: CD10^- neuts/neutrophils, CD10^- neuts/nucleated cells, and the absolute count of CD10^- neuts were all higher than HCs (34.94% vs 3.07%, 12.18% vs 1.32%, 227.4/uL vs 82.79/uL, all p<0·01). Comparing CD10^- neuts levels in non-response patients to remission patients, non-response patients had higher CD10^- neuts/neutrophils (64.44% vs 25.43%, p=0·004), CD10^- neuts/nucleated cells (28.61% vs 9.81%, p=0·018), and the absolute count of CD10^- neuts (766.1/uL vs 152.9/uL, p=0.04). All three CD10^- neutrophil indices predicted treatment response (AUC=0.816, 0.774, and 0.733, respectively), with high CD10^- neuts/neutrophils (≥53.86%) identified as an independent risk factor. Otherwise, only CD10^- neuts/neutrophils predicted both relapse and survival. The ROC curve determined the cutoff point, with patients having high CD10^- neuts/neutrophils (≥21.57%) showing significantly shorter RFS compared to those with low CD10^- neuts/neutrophils (3.2 months vs 14.5 months, p=0.001). Similarly, high CD10^- neuts/neutrophils (≥21.57%) were significantly correlated with shorter OS, with the median OS for low CD10^- neuts/neutrophils not reached (p=0.0002). Furthermore, CD10^- neuts/neutrophils was an independent risk factor for both RFS and OS (HR=4.704, p=0.004; HR=6.417, p=0.001), and negatively correlated with CD19 CAR T-cell persistence time (r=-0·479, p=0·024). Conclusions: High frequency of CD10^- neuts is correlated with poor response, shorter RFS and OS in CAR T therapy. CD10^- neuts could influence the efficacy of CAR-T therapy and specific targeted CD10^- neuts may be a desirable intervention to improve the outcome.

No relevant conflicts of interest to declare.