TNF‐α increases the risk of bleeding in patients after CAR T‐cell therapy: A bleeding model based on a real‐world study of Chinese CAR T Working Party

Abstract

Chimeric antigen receptor (CAR) T‐cell therapy has shown excellent clinical efficacy in patients with hematologic malignancies. However, severe bleeding after this treatment is a life‐threatening complication for most patients. This study evaluated the risk factors associated with bleeding in CAR T treatment and developed a predictive model for this complication. Analysis performed in the First Affiliated Hospital of Suzhou University and external validation launched in Suzhou Hongci Hematology Hospital (Jiangsu, China). We conducted a real‐world study incorporating data from 400 patients with hematologic malignancies treated with CAR T between 1 November 2015 and 1 September 2019. Also, 39 patients from another hospital were selected for external validation. Patients with severe bleeding (hazard ratio [HR] 13.04, 95% confidence interval 5.82–29.18; p < 0.001) had a higher risk of death after CAR T. Stage III and IV cytokine release syndrome (CRS) (odds ratio [OR] 6.07, 95% CI 2.35–16.76; p < 0.001) and higher tumor necrosis factor‐α (TNF‐α) levels (OR 4.00, 95% CI 1.53–11.35; p < 0.001) were independent factors of bleeding in patients after CAR‐T treatment. The predictive model developed by Lasso regression, which selected factors such as CRS period, transfusion volume, platelet percentage, platelet count, thrombinogen time, interleukin 6, and TNF‐α levels, and showed Nomogram, yielded excellent agreement (C‐statistics = 0.905) with the calibration curve, which improved clinical benefit with respect to established bleeding scores such as outpatient bleeding risk index (MOBRI). External validation was performed using 39 patients from another hospital with an AUC of 0.700. Patients with severe bleeding after Car‐T therapy had increased the risk of death. A cross‐validated bleeding risk score based on CRS stages and TNF‐α level show significant prognostic value in patients undergoing CAR‐T treatment.

Biophysical and biochemical aspects of immune cell–tumor microenvironment interactions

“…Unfortunately, higher endogenous TNF-α levels after CAR-T therapy have been associated with severe bleeding. 126 Therefore, safer avenues to normalize interstitial pressure could be promising.…”

Small-Molecule Compounds Boost CAR-T Cell Therapy in Hematological Malignancies

“…These cytokines can promote T cell growth, survival, and expansion while providing resistance to immune suppression. So far, IL-2, IL-7 [127], IL-9 [128], IL-12 [129], IL-13 [130], IL-15 [131], IL-18 [132], IL-21 [133], IL-23 [134], IL-33 [135], and other cytokines have been used in pre-clinical studies in conjugations with CAR-T cells, while some cytokines, such as IL-1 [136,137], IL-6 [138,139], IL-10 [140], TNF-α [136,141], IFN-γ [138], and GM-CSF [142], have some negative effects on CAR-T cell therapy participating in the development of CRS during CAR-T cell therapy. Due to further research on the mechanisms of CRS and ICANS, as well as the continuous exploitation and validation of related cytokine inhibitors, concrete results have been achieved in the treatment of adverse reactions during CAR-T cell therapy.…”

Management of haemostatic complications of chimaeric antigen receptor T‐cell therapy

“…A retrospective review of 400 patients identified severe CRS and elevated (TNF‐α) levels as independent predictors of bleeding following CAR‐T‐cell treatment. The authors created a predictive model, which may be of use in risk‐stratifying patients, but requires validation against a larger patient set 66 …”

“…The authors created a predictive model, which may be of use in risk-stratifying patients, but requires validation against a larger patient set. 66 Treatment of CRS itself with corticosteroids and the anti-IL6 receptor antibody tocilizumab, following international guidelines, is likely ameliorate the prothombotic and haemorrhagic phenotype that may accompany severe CRS. 18,20 Preclinical studies using TNF-α and IL-1 antagonists have shown the ability to dampen endothelial activation and features of CRS and ICANS, which may be of clinical utility pending results of future clinical trials.…”