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Cancer Biol Med 2023.doi:10.20892/j.issn.2095-3941.2022.0585CONSENSUS2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphomaPing Li1*,Yang Liu2*,Yun Liang3*,Jian Bo4,Sujun Gao5,Yongxian Hu6,Yu Hu7,He Huang6,Xiaojun Huang8,Hongmei Jing9,Xiaoyan Ke9,Jianyong Li10,Yuhua Li11,Qifa Liu12,Peihua Lu13,Heng Mei7,Ting Niu14,Yongping Song15,Yuqin Song16,Liping Su17,Sanfang Tu11,Jianxiang Wang18,Depei Wu19,Zhao Wang20,Kailin Xu21,Zhitao Ying16,Qingming Yang2,Yajing Zhang2,Fengxia Shi2,Bin Zhang22,Huilai Zhang23,Xi Zhang24,Mingfeng Zhao25,Weili Zhao26,Xiangyu Zhao8,Liang Huang27,Jun Zhu16,Wenbin Qian3,Weidong Han2,Aibin Liang11Department of Hematology,Shanghai Tongji Hospital,Tongji University School of Medicine,Shanghai 200065,China;2Department of Bio-therapeutic,Chinese PLA General Hospital,Beijing 100853,China;3Department of Hematology,The Second Affiliated Hospital,College of Medicine,Zhejiang University,Hangzhou 310009,China;4Department of Hematology,Chinese PLA General Hospital,Beijing 100853,China;5Department of Hematology,The First Hospital of Jilin University,Changchun 130012,China;6Center for Bone Marrow Transplantation,The First Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou 310058,China;7Institute of Hematology,Union Hospital of Tongji Medical College;Huazhong University of Science and Technology,Wuhan 430022,China;8Peking University Peoples Hospital&Peking University Institute of Hematology,Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation,Beijing 100044,China;9Department of Hematology,Lymphoma Research Center,Peking University Third Hospital,Beijing 100191,China;10Department of Hematology,The First Affiliated Hospital of Nanjing Medical University,Jiangsu Province Hospital,Nanjing 210029,China;11Department of Hematology,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China;12Department of Hematology,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China;13Lu Daopei Institute of Hematology,Beijing 101102,China;14Department of Hematology,West China Hospital,Sichuan University,Chengdu 610041,China;15The Affiliated Cancer Hospital of Zhengzhou University,Zhengzhou 450008,China;16Department of Lymphoma,Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Peking University Cancer Hospital and Institute,Beijing 100142,China;17Department of Hematology,Shanxi Cancer Hospital,Taiyuan 030013,China;18State Key Laboratory of Experimental Hematology,National Clinical Research Center for Blood Diseases,Division of Pediatric Blood Disease Center,Institute of Hematology&Blood Disease Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin 300020,China;19Department of Hematology,The First Affiliated Hospital of Soochow University,Jiangsu Institute of Hematology,National Clinical Research Center for Hematologic Diseases,Suzhou 215006,China;20Department of Hematology,Beijing Friendship Hospital,Capital Medical University,Beijing 100050,China;21Department of Hematology,The Affiliated Hospital of Xuzhou Medical University,Xuzhou 221006,China;22Institute of Blood and Marrow Transplantation,The Fifth Medical Center,Chinese PLA General Hospital,Beijing 100039,China;23Department of Lymphoma,Tianjin Medical University Cancer Institute&Hospital,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin,Tianjins Clinical Research Center for Cancer,Tianjin 300060,China;24Medical Center of Hematology,Xinqiao Hospital,State Key Laboratory of Trauma,Burn and Combined Injury,Army Medical University,Chongqing 400037,China;25Department of Hematology,Tianjin First Central Hospital,Tianjin 300192,China;26Department of Hematology,Shanghai Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;27Department of Hematology,Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,ChinaABSTRACT Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the 130 Li et al.Clinical management of CAR T-cell-associated toxicity for B-NHLprevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.KEYWORDS CAR T-cell therapy;B-cell non-Hodgkin lymphoma;toxicity;cytokine-release syndrome;clinical managementIntroductionCAR T-cell therapy is a novel treatment approach for hema-tological malignancies1-3.Multiple CD19-targeted CAR T-cell products have been approved for the treatment of relapsed and/or refractory(r/r)B-cell non-Hodgkin lymphoma(B-NHL),including large B-cell lymphoma,follicular lym-phoma,and mantle cell lymphoma,in the United States and Europe4-7.In China,2 CAR T-cell products,axicabtagene cilo-leucel8 and relmacabtagene autoleucel9,have been approved for use in adults with r/r large B-cell lymphoma.In addition,the number of registered clinical trials of CAR T cells in China has substantially increased in the past 5 years,and surpassed that in the United States.With the development of novel CAR T-cell products10-12 and innovative approaches,such as dual-target CAR T cells13-15 and sequential infusions of CAR T cells targeting different antigens16-18,CAR T-cell therapy is anticipated to be widely used to treat various tumors beyond B-NHL in the near future.With increased understanding of CAR T-cell properties and experience in treating patients with CAR T cells,clinicians are becoming more concerned about potentially life-threat-ening CAR T-cell-associated toxicities19-22.CAR T cells show dynamic differences among hematological malignancies23-26,and CAR T-cell-associated toxicities in B-NHL have distin-guishing features such as local cytokine-release syndrome(L-CRS)27.Nevertheless,previously published CRS grading and management guidelines have provided few specific recom-mendations for managing these toxicities28-30.This consensus aims to provide clinicians with a standardized guideline and recommendations for the diagnosis,prevention,and treat-ment of toxicities in patients with B-NHL treated with CAR T-cell therapy.The contents of the consensus are divided into 7 sections:the first section includes a workup and risk assessment for CAR T-cell-associated toxicities at baseline,and the other 6 sections outline various toxicities,including CRS,CAR-T-cell-associated encephalopathy syndrome(CRES),hemophago-cytic lymphohistiocytosis/macrophage activation syndrome(HLH/MAS),and other adverse events(AEs).Because CRS is the most commonly observed AE in CAR T-cell therapy,its clinical management is emphasized herein.Workup and risk assessment for toxicities at baselineEssential workup procedures before CAR T-cell therapy should include a complete medical history and physical examination,with attention paid to node-bearing areas,evaluation of performance status,documentation of lym-phoma classification and staging at diagnosis,previous treatments,and evaluation of opportunistic infections,as appropriate.Laboratory evaluations include complete blood count(CBC),urinalysis,blood chemistry profile,compre-hensive metabolic panel,serum ferritin and lactate dehy-drogenase,disseminated intravascular coagulation panel(including D-dimer,fibrinogen,prothrombin time,and partial thromboplastin time measurements),serum cytokine profile including measurements for serum interleukin(IL)6,tumor necrosis factor-(TNF-),and C-reactive pro-tein.Other recommended tests include hepatitis B/C virus,human immunodeficiency virus,and treponemia pallidum antibody evaluations.EpsteinBarr virus,cytomegalovirus and human herpes virus testing may be useful under cer-tain circumstances.Imaging and other studies include chest/abdomen/pelvic computed tomography(CT)with contrast and/or whole body positron emission tomography/CT,brain*These authors contributed equally to this work.Correspondence to:Aibin Liang,Weidong Han and Wenbin QianE-mail:, and Received September 23,2022;accepted December 13,2022Available at www.cancerbiomed.org2023 Cancer Biology&Medicine.Creative Commons Attribution-NonCommercial 4.0 International LicenseCancer Biol Med Vol 20,No 2 February 2023 131magnetic resonance imaging(MRI),electrocardiography,and echocardiography.If any extranodal involvement,par-ticularly in the bone marrow(BM),gastrointestinal(GI)tract,pleura/peritoneum,and central nervous system(CNS),is suspected,relevant examinations,including BM biopsy with aspirate,endoscopic ultrasound,and serosal and lum-bar puncture to analyze serosal effusion and cerebrospinal fluid(CSF),should be performed.Organ function tests are recommended for patients with vital organ involvement.Optional workup procedures include BM cytogenetics(kar-yotype analysis)and pulmonary function tests.The above workup is also designed to identify populations at higher risk of developing severe toxicities.These high-risk factors include the following:(1)ECOG 331;(2)age 70 years;(3)high tumor burden,i.e.,the sum of the product of the perpendicular diameters of multiple lesions(SPD)100 cm2 32;(4)a bulky mass with diameter 10 cm;(5)a mass located in the pharynx or around the trachea,with compres-sion symptoms;(6)a mass near luminal organs(e.g.,the GI tract or bile duct),which may induce organ dysfunction because of tumor compression and infiltration;(7)serosal involvement with massive serous effusion(pleural/abdomi-nal effusion);(8)hepatitis B antigen seropositivity,hepatitis B virus(HBV)DNA copy number above the upper limit of normal value,or active HBV infection without antiviral treat-ment;(9)involvement of vital organs(e.g.,lung,kidney,or bone marrow);and(10)tumor-associated fever.CRSCRS is defined as a supraphysiologic immune response after immunotherapy that leads to overactivation of endogenous or infused T cells and other immune effector cells29,33,34.The incidence rate of CRS among patients with B-NHL treated with CAR T cells is 23%93%.Among these patients,2%22%experience severe CRS(sCRS,grade 3 or higher)8,35,36.The mechanism of CRS remains elusive.Recent studies have indicated that activated monocytes/macrophages but not CAR T cells are major contributors to CRS37,38,and that endothe-lial activation and macrophage-released catecholamines may involve amplification of cytokine release and enhancement of inflammatory injury during CAR T-cell therapy39,40.Yuying Liu et al.41 have suggested that damage-associated molecular patterns released by pyroptotic cells may be upstream trig-gers of macrophage/macrophage activation.Direct contact between CAR T cells and macrophages through CD40-40 L42,CD6943,lymphocyte activation gene-344,and TNF-45 may also play important roles in this process.Classification and grading of CRSOwing to its physiological features,CRS in B-NHL exhibits unique features27,46.Therefore,the classification and grading of CRS in B-NHL must be refined to help clinicians identify and manage this AE effectively.CRS can be classified as acute CRS(13 weeks after infu-sion),late CRS(36 weeks after infusion),and chronic CRS(6 weeks after infusion)according to the onset time.CRS can also be classified as L-CRS or systemic CRS(S-CRS)according to the location and site,involved 27,47(Figure 1).During early stages of CAR T-cell therapy,the infused CAR T cells accumu-late in the tumor,expand locally,and release several cytokines that in turn trigger a local inflammatory response,which is defined as L-CRS.Subsequently,the locally expanded CAR T cells and cytokines“overflow”into the circulatory system,thereby promoting S-CRS(Figure 2).L-CRS is frequently observed in patients with a high tumor burden or bulky mass,and it manifests as redness/swelling/enlargement and exudation/effusion in or around the lesion,or even perforation or bleeding at the lesion site.Unlike those of L-CRS,the clinical manifestations of S-CRS are character-ized by fever,hypotension,and hypoxia,with or without organ dysfunction27,47-49.Given that the previously published CRS grading systems are based only on the severity of S-CRS symp-toms,which may not be fully applicable to B-NHL,we propose a new CRS grading system that incorporates the specific man-ifestations of L-CRS29.The grades are defined by the presence of fever(38 C),the severity of hemodynamic compromise,the severity of hypoxia and the severity of local inflamma-tory manifestations of lesions surrounding tissues and organs(Table 1).Monitoring and management of acute CRSThe peak window of CRS risk is typically the first 3 weeks after CAR T-cell infusion,which is a critical period for CRS management30.Thus,clinicians must closely monitor patients to ensure early diagnosis and prompt intervention for CRS.The workup includes a complete physical examination,with special attention to vital signs and lesion sites,assessment of 132 Li et al.Clinical management of CAR T-cell-associated toxicity for B-NHLSystematicCRSProceedingLocalCRSProceedingCytokinesCAR-T cellLesion of lymphomaCAR-T cellinfusionCAR-T cellinfiltration&proliferationCytokinesreleaseCytokines andCAR-T cellsreleaseCAR-T cellinfiltration andexpansionProgressionCAR-TTumor cellKilling proliferationInflammation:Inflammation:CAR-T cellexpansionCAR-T cellexpansionProgressionCAR-TKilling proliferationKilling proliferationInflammation:CAR-TTumor cellKilling proliferationInflammation:Lymphoma locationPeripheral bloodCAR-T cell&cytokinesreleasingCAR-T cell&cytokinesreleasingTumor cellCAR-TTumor cellRemissionRemissionFigure 2 Schematic diagram of the in vivo distribution of CAR T cells.Schematic procedures from local to systemic CRS after CAR T cell infusion.Duri