Timing of Tocilizumab Administration Under the Guidance of IL-6 in CAR-T Therapy for R/R Acute Lymphoblastic Leukemia

Abstract

Chimeric antigen receptor T (CAR-T) cells targeting CD19 have achieved great clinical responses in patients with relapsed or refractory (R/R) acute B lymphoblastic leukemia. However, severe adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome restrict it to further application. Tocilizumab is the corner stone for the treatment of severe CRS. It has been used to treat mild CRS in recent years, whereas some statistical supports clarifying the suitable timing of its administration are lacking. Sixty-seven patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated with CD19-CART and enrolled in the study, of which 33 patients received Tocilizumab. Application of Tocilizumab in patients with grade 2 CRS in American Society for Transplantation and Cellular Therapy (ASTCT) criteria can significantly shorten the duration of CRS without affecting side effects and long-term efficacy. However, a number of patients still developed severe CRS with early use of Tocilizumab, indicating the significance of the introduction of clinical laboratories to assist medications. Statistically, patients with less than fourfold increase in IL-6 levels had a higher incidence of severe CRS after receiving Tocilizumab (37.5% versus. 0%, p=0.0125), which provided a basis for refining CRS intervention strategies under the guidance of IL-6.

Clinical trial registration: www.clinicaltrials.gov, NCT02965092 and NCT04008251.

Keywords: acute lymphoblastic leukemia; chimeric antigen receptor T cell; cytokine release syndrome; interleukin-6; tocilizumab.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CL declared a shared parent affiliation with the authors to the handling editor at the time of review.

Copyright © 2022 Zhang, Zhou, Wu, Li, Li, Du, Luo, Kou, Lu and Mei.

Figures

Figure 1

Tocilizumab shortened the duration of CRS. The grading of CRS and whether to use Tocilizumab were the basis for grouping. (A) Duration of CRS; (B) objective response rate; (C) incidence of severe infection; (D) incidence of ICANS; (E) overall survival rate in patients with grade 2 CRS; (F) progression-free survival in patients with grade 2 CRS. *p < 0.05; ***p < 0.001.

Figure 2

Two Cases With Severe CRS. Progression and treatment of two typical patients with severe CRS. MP, methylprednisolone; DXM, dexamethasone.

Figure 3

Cutoffs of IL-6, IL-10, CRP, FER. IL-6 (A), IL-10 (B), CRP (C), FER (D) were analyzed by ROC curve using GraphPad Prism, and the best cutoffs were determined according to the coordinates of the ROC curve. Youden index=sensitivity+specificity−1. Its maximum value corresponds to the optimal cutoff.

Figure 4

Tocilizumab induced severe CRS in low level group. There was no significantly difference between patients with toci and without toci except for one. (A) Duration of CRS, incidence of severe infection and ICANS, objective response rate in short-term, overall survival and progression-free survival in long term were compared between patients with or without toci in high level group of IL-6; (B) Duration of CRS, incidence of severe infection and ICANS, objective response rate in short-term, overall survival, and progression-free survival in the long term were compared between patients with or without toci in low level group of IL-6.

Figure 5

The flowchart of guidelines for the treatment of CRS. According to the ASTCT grading system and level of IL-6, patients were recommended for different treatment options.