Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies

Chimeric antigen receptor T cells are a new and exciting immunotherapeutic approach to managing cancer, with impressive efficacy but potentially life-threatening inflammatory toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Patients with severe CRS may develop capillary leak syndrome and disseminated intravascular coagulation, with a cytokine signature similar to that of macrophage activation syndrome/hemophagocytic lymphohistiocytosis. Moderate-to-severe CRS is managed with the IL-6 receptor antagonist tocilizumab with or without corticosteroids, with questions remaining regarding the optimal management of nonresponders. ICANS is an inflammatory neurotoxicity typically occurring after CRS and characterized by impaired blood-brain barrier integrity. Symptoms of encephalopathy range from mild confusion and aphasia to somnolence, obtundation, and in some cases seizures and cerebral edema. ICANS is currently managed with corticosteroids; however, the optimal dose and duration remain to be determined. Little information is available to guide the management of patients with steroid-refractory ICANS. Numerous cytokine-targeted therapies have been proposed to manage these inflammatory toxicities, but few clinical data are available. Management of inflammatory toxicities of chimeric antigen receptor T cells often requires multidisciplinary management and intensive care, during which allergists and immunologists may encounter patients with these unique toxicities. Chimeric antigen receptor T cells are a new and exciting immunotherapeutic approach to managing cancer, with impressive efficacy but potentially life-threatening inflammatory toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Patients with severe CRS may develop capillary leak syndrome and disseminated intravascular coagulation, with a cytokine signature similar to that of macrophage activation syndrome/hemophagocytic lymphohistiocytosis. Moderate-to-severe CRS is managed with the IL-6 receptor antagonist tocilizumab with or without corticosteroids, with questions remaining regarding the optimal management of nonresponders. ICANS is an inflammatory neurotoxicity typically occurring after CRS and characterized by impaired blood-brain barrier integrity. Symptoms of encephalopathy range from mild confusion and aphasia to somnolence, obtundation, and in some cases seizures and cerebral edema. ICANS is currently managed with corticosteroids; however, the optimal dose and duration remain to be determined. Little information is available to guide the management of patients with steroid-refractory ICANS. Numerous cytokine-targeted therapies have been proposed to manage these inflammatory toxicities, but few clinical data are available. Management of inflammatory toxicities of chimeric antigen receptor T cells often requires multidisciplinary management and intensive care, during which allergists and immunologists may encounter patients with these unique toxicities. Clinicians have long sought to harness the immune system to eliminate cancer. It has been clear for many years that the success of allogeneic stem cell transplantation is dependent in part on the T-cell–mediated graft-versus-tumor response at the cost of graft-versus-host disease. Donor lymphocyte infusions after allogeneic stem cell transplantation can induce a direct graft-versus-tumor response and restore antitumor surveillance if relapse occurs, but responses are inconsistent and graft-versus-host disease is common.1Loren A.W. Porter D.L. Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation.Bone Marrow Transplant. 2008; 41: 483-493Crossref PubMed Scopus (84) Google Scholar Chimeric antigen receptor T cells (CAR T) may be the culmination of previous efforts to elicit T-cell antitumor response by using genetic rather than pharmacologic T-cell manipulation. CAR T therapy carries the risk of inflammatory toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), which are challenging to manage given the persistence of CAR T and the inability to easily reverse the resultant immune activation. These toxicities can be life-threatening and often require intensive care and multidisciplinary management, during which allergists and immunologists may encounter patients with these unique toxicities. CAR T are typically manufactured from autologous T cells collected via leukapheresis. In most cases, T cells are infected with a viral vector (lentivirus or retrovirus) containing the CAR DNA sequences: a single chain variable fragment, a costimulatory molecule (4-1BB or CD28), and a signal transduction molecule (CD3ζ). The sequences integrate into the T-cell genome, ultimately resulting in extracellular membrane CAR expression, which is able bind target antigen independent of HLA molecules. Genetically modified T cells are then expanded ex vivo to obtain the desired dose. CAR T manufacturing generally takes 2 to 4 weeks; however, given capacity issues, shipping, release testing, and other logistics, turnaround time may be closer to 3 to 6 weeks depending on the product. Some patients may receive bridging chemotherapy during CAR T manufacturing to ensure disease control in the interim. Patients then receive lymphodepleting chemotherapy (LDC) aimed at immunosuppression to reduce the risk of CAR T rejection and promote CAR T proliferation and ultimately persistence.2Fesnak A.D. June C.H. Levine B.L. Engineered T cells: the promise and challenges of cancer immunotherapy.Nat Rev Cancer. 2016; 16: 566-581Crossref PubMed Scopus (574) Google Scholar, 3June C.H. Sadelain M. Chimeric antigen receptor therapy.New Engl J Med. 2018; 379: 64-73Crossref PubMed Scopus (661) Google Scholar, 4Gill S. Maus M.V. Porter D.L. Chimeric antigen receptor T cell therapy: 25 years in the making.Blood Rev. 2016; 30: 157-167Crossref PubMed Scopus (136) Google Scholar Following infusion, CAR T bind their cognate antigen, resulting in CAR T activation, proliferation, immune activation, release of inflammatory cytokines, and—ultimately and it is hoped—tumor cell clearance. CAR T persistence for some period after infusion may be necessary to maintain antitumor surveillance to reduce the risk of relapse (Fig 1).4Gill S. Maus M.V. Porter D.L. Chimeric antigen receptor T cell therapy: 25 years in the making.Blood Rev. 2016; 30: 157-167Crossref PubMed Scopus (136) Google Scholar, 5Kenderian S.S. Porter D.L. Gill S.I. Chimeric antigen receptor T cells and hematopoietic cell transplantation: how not to put the CART before the horse.Biol Blood Marrow Transplant. 2017; 23: 235-246Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 6Frey N.V. Porter D.L. CAR T-cells merge into the fast lane of cancer care.Am J Hematol. 2016; 91: 146-150Crossref PubMed Scopus (29) Google Scholar An ideal target antigen for CAR T is expressed on tumor cells but not on normal tissue. Some of the most effective CAR T applications have targeted CD19 in B-cell malignancies. CD19 is an almost ideal target antigen, as its expression is limited largely to normal B cells and B-cell malignancies. The risks to patients from B-cell aplasia by targeting CD19 on normal B cells is low, and many patients have minimal long-term toxicities after other B-cell–targeted therapies such as rituximab or blinatumomab.7Witzens-Harig M. Foa R. Di Rocco A. van Hazel G. Chamone D.F.A. Rowe J.M. et al.Maintenance rituximab is safe and not associated with severe or uncommon infections in patients with follicular lymphoma: results from the phase IIIB MAXIMA study.Ann Hematol. 2014; 93: 1714-1724Google Scholar,8Zugmaier G. Topp M.S. Alekar S. Viardot A. Horst H.A. Neumann S. et al.Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with minimal residual disease-positive B-precursor acute lymphoblastic leukemia.Blood Cancer J. 2014; 4: 244Crossref PubMed Scopus (43) Google Scholar The approval of 2 CD19-targeted CAR T products, tisagenlecleucel (tisa-cel [Kymriah, Novartis Pharmaceuticals Corporation, East Hanover, NJ]) and axicabtagene ciloleucel (axi-cel [Yescarta, Kite Pharma, Santa Monica, Calif]), have marked the dawn of a new era in cancer therapeutics, offering unprecedented efficacy for patients with limited options. Tisa-cel, the first US Food and drug Administration (FDA)-approved CAR T therapy, contains a 4-1BB costimulatory domain and is manufactured using a lentiviral vector. Tisa-cel was initially approved for the treatment of relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in pediatric and young adult patients. Although ALL generally has a favorable prognosis with 5-year overall survival (OS) of 90% with chemotherapy,9Hunger S.P. Lu X. Devidas M. Camitta B.M. Gaynon P.S. Winick N.J. et al.Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the Children’s Oncology Group.J Clin Oncol. 2012; 30: 1663-1669Crossref PubMed Scopus (658) Google Scholar patients with R/R disease have a poor response to salvage chemotherapy and a 5-year OS of only 20%.10Nguyen K. Devidas M. Cheng S. La M. Raetz E.A. Carrol W.L. et al.Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group Study.Leukemia. 2008; 22: 2142-2150Crossref PubMed Scopus (339) Google Scholar Tisa-cel was later approved for the treatment of R/R large B-cell lymphoma (LBCL), which is the most common aggressive non-Hodgkin lymphoma seen in adults. Many patients with LBCL can be cured with a combination of rituximab and chemotherapy; however, patients with R/R LBCL have poor outcomes, with an OS of just 6 months.11Crump M. Neelapu S.S. Farooq U. Van Den Neste E. Kuruvilla J. Westin J. et al.Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study.Blood. 2017; 130: 1800-1808Crossref PubMed Scopus (479) Google Scholar Axi-cel is also approved for R/R LBCL; it is manufactured using a retroviral vector and contains a CD28 costimulatory domain. A summary of the FDA-approved indications and registration trial results for tisa-cel and axi-cel is shown in Table I.12Kymriah [prescribing information]. Novartis Pharmaceuticals Corporation, East Hanover, NJ2019Google Scholar, 13Maude S.L. Laetsch T.W. Buechner S. Rives S. Boyer M. Bittencourt H. et al.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.New Engl J Med. 2018; 378: 439-448Crossref PubMed Scopus (1676) Google Scholar, 14Schuster S.J. Bishop M.R. Tam C.S. Waller E.K. Borchmann P. Mcguirk J.P. et al.Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.New Engl J Med. 2019; 380: 45-56Crossref PubMed Scopus (958) Google Scholar, 15Yescarta [prescribing information]. Kite Pharma Inc, Santa Monica, CA2019Google Scholar, 16Neelapu S.S. Locke F.L. Bartlett N.L. Lekakis L.J. Miklos D.B. Jacobson C.A. et al.Axicabtagene ciloleucel CAR T-cell therapy in refractory Large B-cell lymphoma.New Engl J Med. 2017; 377: 2531-2544Crossref PubMed Scopus (1726) Google ScholarTable ILabeled indications and clinical data for tisa-cel and axi-celCAR T productFDA-approved indication(s)Registration trial resultsTisa-cel (Kymriah)B-cell ALL in patients up to 25 years old that is refractory or in second or later relapse12Kymriah [prescribing information]. Novartis Pharmaceuticals Corporation, East Hanover, NJ2019Google ScholarELIANA13Maude S.L. Laetsch T.W. Buechner S. Rives S. Boyer M. Bittencourt H. et al.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.New Engl J Med. 2018; 378: 439-448Crossref PubMed Scopus (1676) Google Scholar: N = 75CR/CRi: 81%12-mo OS: 76%Adult R/R LBCL∗LBCL includes diffuse LBCL not otherwise specified, high-grade B-cell lymphoma, and diffuse LBCL arising from follicular lymphoma. For axi-cel, primary mediastinal lymphoma is also included among the labeled indications. after ≥2 lines of systemic therapy12Kymriah [prescribing information]. Novartis Pharmaceuticals Corporation, East Hanover, NJ2019Google ScholarJULIET14Schuster S.J. Bishop M.R. Tam C.S. Waller E.K. Borchmann P. Mcguirk J.P. et al.Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.New Engl J Med. 2019; 380: 45-56Crossref PubMed Scopus (958) Google Scholar: N = 93ORR: 52%, CR: 40%12-mo OS: 65%Axi-cel (Yescarta)Adult R/R LBCL∗LBCL includes diffuse LBCL not otherwise specified, high-grade B-cell lymphoma, and diffuse LBCL arising from follicular lymphoma. For axi-cel, primary mediastinal lymphoma is also included among the labeled indications. after ≥2 lines of systemic therapy15Yescarta [prescribing information]. Kite Pharma Inc, Santa Monica, CA2019Google ScholarZUMA-116Neelapu S.S. Locke F.L. Bartlett N.L. Lekakis L.J. Miklos D.B. Jacobson C.A. et al.Axicabtagene ciloleucel CAR T-cell therapy in refractory Large B-cell lymphoma.New Engl J Med. 2017; 377: 2531-2544Crossref PubMed Scopus (1726) Google Scholar: N = 101ORR: 82%, CR: 54%18-mo OS: 52%CR, Complete remission; CRi, complete remission with incomplete blood count recovery; ORR, objective response rate or overall remission rate.∗ LBCL includes diffuse LBCL not otherwise specified, high-grade B-cell lymphoma, and diffuse LBCL arising from follicular lymphoma. For axi-cel, primary mediastinal lymphoma is also included among the labeled indications. Open table in a new tab CR, Complete remission; CRi, complete remission with incomplete blood count recovery; ORR, objective response rate or overall remission rate. CRS reflects antigen-nonspecific toxicity characterized by supraphysiologic immune activation following activation and expansion of CAR T binding their cognate antigen.17Lee D.W. Gardner R. Porter D.L. Louis C.U. Ahmed N. Jensen M. et al.Current concepts in the diagnosis and management of cytokine release syndrome.Blood. 2014; 124: 188-195Crossref PubMed Scopus (1231) Google Scholar, 18Frey N. Porter D. Cytokine release syndrome with chimeric antigen receptor T cell therapy.Biol Blood Marrow Transplant. 2019; 25: e123-e127Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 19Hay K.A. Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified T cell therapy.Br J Haematol. 2018; 183: 364-374Crossref PubMed Scopus (64) Google Scholar The median onset of CRS is 2 to 3 days following infusion—usually with mild symptoms that progress gradually over hours to days. The majority of CRS cases begin within 14 days of infusion and last 7 to 8 days.13Maude S.L. Laetsch T.W. Buechner S. Rives S. Boyer M. Bittencourt H. et al.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.New Engl J Med. 2018; 378: 439-448Crossref PubMed Scopus (1676) Google Scholar,14Schuster S.J. Bishop M.R. Tam C.S. Waller E.K. Borchmann P. Mcguirk J.P. et al.Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.New Engl J Med. 2019; 380: 45-56Crossref PubMed Scopus (958) Google Scholar,16Neelapu S.S. Locke F.L. Bartlett N.L. Lekakis L.J. Miklos D.B. Jacobson C.A. et al.Axicabtagene ciloleucel CAR T-cell therapy in refractory Large B-cell lymphoma.New Engl J Med. 2017; 377: 2531-2544Crossref PubMed Scopus (1726) Google Scholar Fever is almost always the initial sign, sometimes reaching 105°F (40.5°C) or even higher. Other symptoms mimic flu-like illness, including myalgias, headaches, rigors, malaise, and anorexia. Many cases of CRS are self-limiting; however, some progress to severe symptoms mirroring sepsis or capillary leak syndrome. Hypotension, tachycardia, pleural effusions, pulmonary edema, and hypoxia may progress to multiorgan failure and ultimately require intensive care.17Lee D.W. Gardner R. Porter D.L. Louis C.U. Ahmed N. Jensen M. et al.Current concepts in the diagnosis and management of cytokine release syndrome.Blood. 2014; 124: 188-195Crossref PubMed Scopus (1231) Google Scholar, 18Frey N. Porter D. Cytokine release syndrome with chimeric antigen receptor T cell therapy.Biol Blood Marrow Transplant. 2019; 25: e123-e127Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 19Hay K.A. Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified T cell therapy.Br J Haematol. 2018; 183: 364-374Crossref PubMed Scopus (64) Google Scholar Hypofibrinogenemia and disseminated intravascular coagulation may occur, particularly with more severe CRS.20Jiang H. Liu L. Guo T. Wu Y. Ai L. Deng J. et al.Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy.Ann Hematol. 2019; 98: 1721-1732Crossref PubMed Scopus (27) Google Scholar,21Buechner J. Grupp S.A. Maude S.L. Hiramatsu H. Teachey D.T. Wood P.A. et al.Management of coagulopathy associated with CTL019 CAR T-cell therapy.Blood. 2017; 130: 1276Google Scholar Troponin level elevations and decreased ejection fraction are also common in severe CRS.22Alvi R.M. Frigault M.J. Fradley M.G. Jain M.D. Mahmood S.S. Awadalla M. et al.Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T).J Am Coll Cardiol. 2019; 74: 3099-3108Crossref PubMed Scopus (83) Google Scholar Levels of markers of generalized inflammation, including C-reactive protein (CRP) and ferritin, can be extraordinarily elevated in severe CRS, which is consistent with findings observed in macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH).23Fitzgerald J.C. Weiss S.L. Maude S.L. Barrett D.M. Lacey S.F. Melenhorst J.J. et al.Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia.Crit Care Med. 2017; 45: e124-e131Crossref PubMed Scopus (215) Google Scholar, 24Teachey D.T. Lacey S.F. Shaw P.A. Melenhorst J.J. Maude S.L. Frey N. et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.Cancer Discov. 2016; 6: 664-679Crossref PubMed Scopus (475) Google Scholar, 25Hay K.A. Hanafi L.A. Li D. Gust J. Liles W.C. Wurfel M. et al.Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy.Blood. 2017; 130: 2295-2306Crossref PubMed Scopus (402) Google Scholar Levels of organ-specific markers such as hepatic aminotransferases, bilirubin, blood urea nitrogen, creatine phosphokinase, and creatinine are also commonly elevated.17Lee D.W. Gardner R. Porter D.L. Louis C.U. Ahmed N. Jensen M. et al.Current concepts in the diagnosis and management of cytokine release syndrome.Blood. 2014; 124: 188-195Crossref PubMed Scopus (1231) Google Scholar,18Frey N. Porter D. Cytokine release syndrome with chimeric antigen receptor T cell therapy.Biol Blood Marrow Transplant. 2019; 25: e123-e127Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar,23Fitzgerald J.C. Weiss S.L. Maude S.L. Barrett D.M. Lacey S.F. Melenhorst J.J. et al.Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia.Crit Care Med. 2017; 45: e124-e131Crossref PubMed Scopus (215) Google Scholar Although cytopenias are common following LDC, delayed cytopenias are common after severe CRS.26Fried S. Avigdor A. Bielorai B. Meir A. Besser M.J. Schachter J. et al.Early and late hematologic toxicity following CD19 CAR-T cells.Bone Marrow Transplant. 2019; 54: 1643-1650Crossref PubMed Scopus (69) Google Scholar Infections are also common, particularly in patients with ALL and severe CRS, and are associated with significant mortality.27Hill J.A. Li D. Hay K.A. Green M.L. Cherian S. Chen X. et al.Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy.Blood. 2018; 131: 121-130Crossref PubMed Scopus (159) Google Scholar, 28Park J.H. Romero F.A. Taur Y. Sadelain M. Brentjens R.J. Hohl T.M. et al.Cytokine release syndrome grade as a predictive marker for infections in patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with chimeric antigen receptor T cells.Clin Infect Dis. 2018; 67: 533-540Crossref PubMed Scopus (83) Google Scholar, 29Frey N.V. Shaw P.A. Hexner E.O. Pequignot E. Gill S. Luger S.M. et al.Optimizing chimeric antigen receptor T-cell therapy for adults with acute lymphoblastic leukemia.J Clin Oncol. 2020; 38: 415-422Crossref PubMed Scopus (45) Google Scholar The cytokine profile of CRS is the result of activation of numerous immune cells rather than a binary interaction between CD19+ cells and CAR T. IL-6 released by activated macrophages and monocytes appears to be the primary driver of CRS,30Singh N. Hofmann T.J. Gershenson Z. Levine B.L. Grupp S.A. Teachey D.T. et al.Monocyte lineage-derived IL-6 does not affect chimeric antigen receptor T-cell function.Cytotherapy. 2017; 19: 867-880Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar with higher levels observed in severe CRS.24Teachey D.T. Lacey S.F. Shaw P.A. Melenhorst J.J. Maude S.L. Frey N. et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.Cancer Discov. 2016; 6: 664-679Crossref PubMed Scopus (475) Google Scholar,25Hay K.A. Hanafi L.A. Li D. Gust J. Liles W.C. Wurfel M. et al.Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy.Blood. 2017; 130: 2295-2306Crossref PubMed Scopus (402) Google Scholar IL-1 is released from activated macrophages and monocytes, stimulating release of IL-6 and induction of nitric oxide synthetase.31Norelli M. Camisa B. Barbiera G. Falcone L. Purevdork A. Genua M. et al.Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells.Nat Med. 2018; 24: 739-748Crossref PubMed Scopus (467) Google Scholar,32Giavridis T. van der Stegen S.J.C. Eyquem J. Hamieh M. Piersigilli A. Sadelain M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.Nat Med. 2018; 24: 731-738Crossref PubMed Scopus (404) Google Scholar Serum elevations of IL-2, TNF-ɑ, IFN-ɣ, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1ɑ (MIP-1ɑ) occur, released from CAR T, other activated T cells, or activated myeloid cells. Increased serum levels of GM-CSF are observed in severe CRS,24Teachey D.T. Lacey S.F. Shaw P.A. Melenhorst J.J. Maude S.L. Frey N. et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.Cancer Discov. 2016; 6: 664-679Crossref PubMed Scopus (475) Google Scholar and activated CAR T have been shown to upregulate GM-CSF receptors.33Cox M.J. Kuhlmann C. Sterner R.M. Sakemura R. Sinha S. Hefazi M. et al.Improved anti-tumor response of chimeric antigen receptor T cell (CART) therapy after GM-CSF inhibition is mechanistically supported by a novel direct interaction of GM-CSF with activated Carts.Biol Blood Marrow Transplant. 2020; 26: S60Abstract Full Text Full Text PDF Google Scholar In severe CRS, cytokine patterns mimicking that observed in MAS/HLH are observed. Endothelial activation, with increased levels of von Willebrand factor and angiopoietin-2 (which promotes capillary leak), coupled with a decreased level of angiopoietin-1 (which promotes endothelial stability), may contribute to capillary leak.24Teachey D.T. Lacey S.F. Shaw P.A. Melenhorst J.J. Maude S.L. Frey N. et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.Cancer Discov. 2016; 6: 664-679Crossref PubMed Scopus (475) Google Scholar,25Hay K.A. Hanafi L.A. Li D. Gust J. Liles W.C. Wurfel M. et al.Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy.Blood. 2017; 130: 2295-2306Crossref PubMed Scopus (402) Google Scholar Results of cytokine assays may not be readily available at many centers; however, ferritin and CRP are surrogate markers that can be trended as a marker of CRS tempo and response to treatment.23Fitzgerald J.C. Weiss S.L. Maude S.L. Barrett D.M. Lacey S.F. Melenhorst J.J. et al.Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia.Crit Care Med. 2017; 45: e124-e131Crossref PubMed Scopus (215) Google Scholar, 24Teachey D.T. Lacey S.F. Shaw P.A. Melenhorst J.J. Maude S.L. Frey N. et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.Cancer Discov. 2016; 6: 664-679Crossref PubMed Scopus (475) Google Scholar, 25Hay K.A. Hanafi L.A. Li D. Gust J. Liles W.C. Wurfel M. et al.Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy.Blood. 2017; 130: 2295-2306Crossref PubMed Scopus (402) Google Scholar Although ferritin and CRP levels are higher in severe CRS than in mild or moderate CRS, early monitoring does not predict patients destined for severe CRS.24Teachey D.T. Lacey S.F. Shaw P.A. Melenhorst J.J. Maude S.L. Frey N. et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.Cancer Discov. 2016; 6: 664-679Crossref PubMed Scopus (475) Google Scholar Coagulopathy coincides with peak IL-6 levels and may be triggered by release of tissue factor and platelet endothelial cell adhesion molecule-1 (PECAM-1).20Jiang H. Liu L. Guo T. Wu Y. Ai L. Deng J. et al.Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy.Ann Hematol. 2019; 98: 1721-1732Crossref PubMed Scopus (27) Google Scholar Ultimately CRS is a clinical diagnosis, and although inflammatory and cytokine profiles can be useful confirmatory tests, these data are not used to determine grading or treatment of CRS. Importantly, in patients with ALL, the presence (although not the grade) of CRS correlates with CAR T efficacy (Fig 2).34Gofshteyn J.S. Shaw P.A. Teachey D.T. Grupp S.A. Maude S. Banwell B. et al.Neurotoxicity after CTL019 in a pediatric and young adult cohort.Ann Neurol. 2018; 84: 537-546Crossref PubMed Scopus (40) Google Scholar, 35Santomasso B.D. Park J.H. Salloum D. Riviere I. Flynn J. Mead E. et al.Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia.Cancer Discov. 2018; 8: 958-971Crossref PubMed Scopus (269) Google Scholar, 36Gust J. 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Feldman S.A. et al.T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.Lancet. 2015; 385: 517-528Abstract Full Text Full Text PDF PubMed Scopus (1657) Google Scholar In early CAR T trials it was realized that grading CRS by using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, was not practical. For example, Common Terminology Criteria for Adverse Events grading considered the need for infusion interruption, which cannot apply to cellular therapies.40U.S. Department of Health and Human ServicesCommon terminology criteria for adverse events (CTCAE) version 4.0.https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdfDate accessed: July 7, 2020Google Scholar Clinical trials with tisa-cel used the Penn scale for grading CRS,41Porter D.L. Hwang W.T. Frey N.V. Lacey S.F. Shaw P.A. Loren A.W. et al.Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia.Sci Transl Med. 2015; 7303ra139Crossref PubMed Scopus (936) Google Scholar,42Porter D. Frey N. Wood P.A. Weng Y. Grupp S.A. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel.J Hematol Oncol. 2018; 11: 35Crossref PubMed Scopus (185) Google Scholar whereas trials with axi-cel used the Lee scale,17Lee D.W. Gardner R. Porter D.L. Louis C.U. Ahmed N. Jensen M. et al.Current concepts in the diagnosis and management of cytokine release syndrome.Blood. 2014; 124: 188-195Crossref PubMed Scopus (1231) Google Scholar complicating toxicity comparisons between products. A standardized grading system proposed by the American Society of Transplant and Cellular Therapy (ASTCT) shown in Table II,43Lee D.W. Santomasso B.D. Locke F.L. Ghobadi A. Turtle C.J. Brudno J.N. et al.ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells.Biol Blood Marrow Transplant. 2019; 25: 625-638Abstract Full Text Full Text PDF PubMed Scopus (554)