Ruxolitinib mitigates steroid‐refractory CRS during CAR T therapy

• Published in: Journal of cellular and molecular medicine 2021-01, Vol.25 (2), p.1089-1099
• Main Authors: Pan, Jing, Deng, Biping, Ling, Zhuojun, Song, Weiliang, Xu, Jinlong, Duan, Jiajia, Wang, Zelin, Chang, Alex H., Feng, Xiaoming, Tan, Yue
• Format: Article
• Language: English
• Subjects: acute lymphoblastic leukemia; Adolescent; Antibodies; Blood platelets; Bone marrow; CAR T cell therapy; CD19 antigen; CD22 antigen; Cell Proliferation - drug effects; Cell therapy; Child; Child, Preschool; Clinical trials; Cytokine Release Syndrome - drug therapy; Cytokine Release Syndrome - etiology; Cytokines; Cytokines - metabolism; Cytotoxicity; Data analysis; Dexamethasone - pharmacology; Disease; Dosage; Female; Flow cytometry; Graft versus host disease; hematology; Humans; immunology; Immunotherapy, Adoptive - adverse effects; Inflammatory diseases; Kinases; Leukemia; Lymphocytes; Lymphocytes T; Male; Medical treatment; Neurotoxicity; Nitriles; Original; Pilot Projects; Pyrazoles - adverse effects; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyrimidines; Remission; ruxolitinib; Steroid hormones; Steroids; Steroids - therapeutic use; Targeted cancer therapy; Transplants & implants; Treatment Outcome; Tumor necrosis factor-TNF
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.16176

Cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life‐threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B‐ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high‐dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti‐leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid‐refractory and even life‐threatening CRS.