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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2019, Vol. 13 Issue (5) : 610-617    https://doi.org/10.1007/s11684-019-0714-8
RESEARCH ARTICLE
Management of cytokine release syndrome related to CAR-T cell therapy
Hongli Chen1, Fangxia Wang1, Pengyu Zhang1, Yilin Zhang1, Yinxia Chen1, Xiaohu Fan2, Xingmei Cao1, Jie Liu1, Yun Yang1, Baiyan Wang1, Bo Lei1, Liufang Gu1, Ju Bai1, Lili Wei1, Ruili Zhang1, Qiuchuan Zhuang2, Wanggang Zhang1(), Wanhong Zhao1(), Aili He1()
1. Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
2. Nanjing Legend Biotech Inc., Nanjing 210000, China
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Abstract

Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5–10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.
Keywords chimeric antigen receptor T cell      cytokine release syndrome      tocilizumab     
Corresponding Author(s): Wanggang Zhang,Wanhong Zhao,Aili He   
Just Accepted Date: 30 August 2019   Online First Date: 29 September 2019    Issue Date: 14 October 2019
 Cite this article:   
Hongli Chen,Fangxia Wang,Pengyu Zhang, et al. Management of cytokine release syndrome related to CAR-T cell therapy[J]. Front. Med., 2019, 13(5): 610-617.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0714-8
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I5/610
Grade Toxicity
I Symptoms, e.g., fever, nausea, fatigue, headache, myalgia, and malaise, requiring only symptomatic management
II Symptoms responding to moderate intervention, including oxygen requirement<40%, grade 2 organ toxicity, or hypotension responding to IV fluids or low doses of one vasopressor (e.g.,<20 mg/min of norepinephrine)
III Oxygen requirement>40%, hypotension requiring high-dose or multiple vasopressors, grade 4 transaminitis, and grade 3 organ toxicity at other sites
IV Life-threatening symptoms requiring ventilator support or grade 4 organ toxicity other than transaminitis
V Death
Tab.1  CRS grading system
Fig.1  Cytokine changes in case 1 with grade 3 CRS. IL-2R, IL-6, IL-8, IL-10, and TNF-α were significantly elevated through days 8 to 13 (IL-6>123-fold and IL-10>89-fold over baseline levels). Tocilizumab was given at a dose of 8 mg/kg on day 10.
Fig.2  Cytokine changes in case 2 with grade 3 CRS. IL-2R, IL-6, IL-8, IL-10, and TNF-α were significantly elevated through days 10 to 17 (IL-6>294-fold, IL-8>20-fold, and IL-10>20-fold over baseline levels). Tocilizumab was administered at a dose of 4 mg/kg on days 13 and 14.
Fig.3  Cytokine changes in case 3 with grade 3 CRS. IL-2R, IL-6, IL-8, IL-10, and TNF-α were significantly elevated on days 11 to 15 (IL-6>294-fold and IL-10>109-fold over baseline levels). Tocilizumab was administered at a dose of 4 mg/kg on days 11 and 12. Dexamethasone was provided at a dose of 10 mg/day on days 10, 13, and 14.
Fig.4  Cytokine changes in case 4 with grade 2 CRS. IL-2R, IL-6, IL-8, IL-10, and TNF-α were significantly elevated through days 9 to 15 (IL-6>185-fold and IL-10>36-fold). Tocilizumab was administered at a dose of 4 mg/kg on days 12 and 13. Dexamethasone was administered at a dose of 10 mg/day on day 16.
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