Abstract
Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.
Original language | English |
---|---|
Pages (from-to) | 625-638 |
Number of pages | 14 |
Journal | Biology of Blood and Marrow Transplantation |
Volume | 25 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2019 |
Keywords
- CAR T cell therapy
- Cellular immunotherapy
- Consensus grading
- Cytokine release syndrome
- Immune effector cell
- Neurotoxicity
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In: Biology of Blood and Marrow Transplantation, Vol. 25, No. 4, 04.2019, p. 625-638.
Research output: Contribution to journal › Review article › peer-review
TY - JOUR
T1 - ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells
AU - Lee, Daniel W.
AU - Santomasso, Bianca D.
AU - Locke, Frederick L.
AU - Ghobadi, Armin
AU - Turtle, Cameron J.
AU - Brudno, Jennifer N.
AU - Maus, Marcela V.
AU - Park, Jae H.
AU - Mead, Elena
AU - Pavletic, Steven
AU - Go, William Y.
AU - Eldjerou, Lamis
AU - Gardner, Rebecca A.
AU - Frey, Noelle
AU - Curran, Kevin J.
AU - Peggs, Karl
AU - Pasquini, Marcelo
AU - DiPersio, John F.
AU - van den Brink, Marcel R.M.
AU - Komanduri, Krishna V.
AU - Grupp, Stephan A.
AU - Neelapu, Sattva S.
N1 - Funding Information: Conflict of interest statement: D.W.L. has received clinical trial support from Kite/Gilead and serves as a consultant and advisory board member for Juno Therapeutics/ Celgene . B.D.S. has consulted or participated in advisory boards for Juno Therapeutics/ Celgene , Kite Pharma/Gilead, and Novartis . F.L.L. has served as a scientific advisor to Kite Pharma and Novartis and as a consultant to Cellular BioMedicine Group. A.G. has received research support from Kite Pharma and has served as a scientific advisor and speaker for Kite Pharma. C.J.T. has received research support from Juno Therapeutics and Nektar Therapeutics; has consulted or participated in advisory boards for Juno Therapeutics/Celgene, Nektar Therapeutics, Precision Biosciences, Eureka Therapeutics, Aptevo, Gilead, and Caribou Biosciences; and has option grants in Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences. M.V.M. has received research support from Novartis , Kite, Servier, TCR2, Agentus, and CRISPR Therapeutics and has participated in consulting or advisory boards for Agentus, Bluebird Bio, Cellectis, Juno, Kite, Novartis, Precision Biosciences, Takeda, and TCR2. J.H.P. has received research support from Juno Therapeutics, Genentech , and Amgen and has consulted or participated in advisory boards for Novartis, Kite, Juno Therapeutics, Shire, Amgen, Pfizer, Takeda, Adaptive Biotechnologies, TG Therapeutics, AstraZeneca, and Bayer. J.N.B., E.M., S.P., K.P., and J.F.D. have no conflicts of interest to report. W.Y.G. is employed by Kite, a Gilead Company, and has equity ownership in Gilead Sciences. L.E. is employed by Novartis Pharmaceuticals. R.A.G. has participated in advisory boards for Novartis. N.F. has consulted or participated in advisory boards for Novartis and Servier. K.J.C. has received research support from Juno Therapeutics and has consulted or participated in advisory boards for Juno Therapeutics and Novartis. M.C.P. has received honoraria from Pfizer and consulting fees from Medigene. M.R.M.V.D. has received research support from Seres Therapeutics; has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharmaceuticals, Therakos, Amgen, Merck & Co, Acute Leukemia Forum (ALF), and DKMS Medical Council (Board); and has IP Licensing with Seres Therapeutics and Juno Therapeutics. K.V.K. has received support for site participation in clinical trials from Kite, Adaptimmune, Atara, and Juno and has served as an ad hoc consultant to Kite/Gilead, Juno/Celgene, Novartis, Atara and Merck. S.A.G. has received research and/or clinical trial support from Novartis , Servier, and Kite and has served as a consultant, on study steering committees, or on scientific advisory boards for Novartis , Adaptimmune, Eureka, TCR2, Juno, GlaxoSmithKline , Cellectis, Vertex, Cure Genetics, and Roche . S.S.N. has received research support from Kite/Gilead, Celgene , Cellectis, Poseida, Merck , Acerta, Karus, and BMS and has served as a consultant and an advisory board member for Kite/Gilead, Celgene, Novartis, Unum Therapeutics, Pfizer, and Merck. Funding Information: Recognizing the disparity in published grading schemes and the need for harmonization of definitions and grading systems for immune effector cell-associated CRS and neurotoxicities seen after immune effector cell therapies including CAR T therapy, 49 experts from all aspects of the field met in Arlington, VA on June 20-21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT). Attendees included leaders from major academic centers involved in CAR T cell therapy research as well as representatives from industry, the Center for International Blood and Marrow Transplant Research (CIBMTR), the American Society of Hematology (ASH), and the National Cancer Institute (NCI). Key presentations regarding immune effector cell-associated CRS and neurotoxicity were followed by focused discussion of salient points. The writing group was then tasked with generating language encompassing a new consensus that is both easily applied at the bedside and easily verifiable during chart reviews. A full, iterative drafting and vetting process was undertaken. In addition, these guidelines were presented at the CIBMTR CT Registry Forum on October 25, 2018, for discussion and comment. The participation at this second meeting included a broad group of multiple stakeholders including investigators, industry, payors, and National Institutes of Health and other governmental agencies. Here we report the consensus and rationale of the group as related to grading and reporting of toxicities.The authors thank the following experts for their participation and contribution in developing this consensus document on grading of toxicities associated with CAR T cell therapy: Veronika Bachanova, University of Minnesota Medical Center, Songhai Barclift, Centers for Medicare & Medicaid Services, Michael Bishop, University of Chicago, Karen Chagin, Adaptimmune, Andrea Chassot Agostinho, Novartis, David Chonzi, Kite, a Gilead Company, Steven Devine, National Marrow Donor Program, Olivia Gardner, Bellicum, Dennis Gastineau, Mayo Clinic, Parameswaran Hari, Medical College of Wisconsin, Helen Heslop, Texas Children's Hospital, Mary Horwitz, Center for International Blood & Marrow Transplant Research, Ron Kline, Center for Medicare & Medicaid Innovation, Ana Kostic, Juno Therapeutics, a Celgene Company, Alice Kuaban, American Society of Hematology, Navneet Majhail, Cleveland Clinic, Shannon Maude, Children's Hospital of Philadelphia, Richard Maziarz, Oregon Health & Science University, Josh McFeesters, Centers for Medicare & Medicaid Services, William Merritt, National Cancer Institute, David Miklos, Stanford University Medical Center, Tonia Nesheiwat, Celgene, Sarah Nikiforow, Dana-Farber Cancer Institute, Miguel-Angel Perales, Memorial Sloan Kettering Cancer Center, David Porter, University of Pennsylvania Perelman School of Medicine, Travis Quigley, bluebird bio, Stephen Schuster, University of Pennsylvania Perelman School of Medicine, Elizabeth Shpall, M.D. Anderson Cancer Center, Patricia Steinert, Center for International Blood & Marrow Transplant Research, Sudhakar Tummala, M.D. Anderson Cancer Center, Conflict of interest statement: D.W.L. has received clinical trial support from Kite/Gilead and serves as a consultant and advisory board member for Juno Therapeutics/Celgene. B.D.S. has consulted or participated in advisory boards for Juno Therapeutics/Celgene, Kite Pharma/Gilead, and Novartis. F.L.L. has served as a scientific advisor to Kite Pharma and Novartis and as a consultant to Cellular BioMedicine Group. A.G. has received research support from Kite Pharma and has served as a scientific advisor and speaker for Kite Pharma. C.J.T. has received research support from Juno Therapeutics and Nektar Therapeutics; has consulted or participated in advisory boards for Juno Therapeutics/Celgene, Nektar Therapeutics, Precision Biosciences, Eureka Therapeutics, Aptevo, Gilead, and Caribou Biosciences; and has option grants in Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences. M.V.M. has received research support from Novartis, Kite, Servier, TCR2, Agentus, and CRISPR Therapeutics and has participated in consulting or advisory boards for Agentus, Bluebird Bio, Cellectis, Juno, Kite, Novartis, Precision Biosciences, Takeda, and TCR2. J.H.P. has received research support from Juno Therapeutics, Genentech, and Amgen and has consulted or participated in advisory boards for Novartis, Kite, Juno Therapeutics, Shire, Amgen, Pfizer, Takeda, Adaptive Biotechnologies, TG Therapeutics, AstraZeneca, and Bayer. J.N.B. E.M. S.P. K.P. and J.F.D. have no conflicts of interest to report. W.Y.G. is employed by Kite, a Gilead Company, and has equity ownership in Gilead Sciences. L.E. is employed by Novartis Pharmaceuticals. R.A.G. has participated in advisory boards for Novartis. N.F. has consulted or participated in advisory boards for Novartis and Servier. K.J.C. has received research support from Juno Therapeutics and has consulted or participated in advisory boards for Juno Therapeutics and Novartis. M.C.P. has received honoraria from Pfizer and consulting fees from Medigene. M.R.M.V.D. has received research support from Seres Therapeutics; has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharmaceuticals, Therakos, Amgen, Merck & Co, Acute Leukemia Forum (ALF), and DKMS Medical Council (Board); and has IP Licensing with Seres Therapeutics and Juno Therapeutics. K.V.K. has received support for site participation in clinical trials from Kite, Adaptimmune, Atara, and Juno and has served as an ad hoc consultant to Kite/Gilead, Juno/Celgene, Novartis, Atara and Merck. S.A.G. has received research and/or clinical trial support from Novartis, Servier, and Kite and has served as a consultant, on study steering committees, or on scientific advisory boards for Novartis, Adaptimmune, Eureka, TCR2, Juno, GlaxoSmithKline, Cellectis, Vertex, Cure Genetics, and Roche. S.S.N. has received research support from Kite/Gilead, Celgene, Cellectis, Poseida, Merck, Acerta, Karus, and BMS and has served as a consultant and an advisory board member for Kite/Gilead, Celgene, Novartis, Unum Therapeutics, Pfizer, and Merck. Funding Information: Recognizing the disparity in published grading schemes and the need for harmonization of definitions and grading systems for immune effector cell-associated CRS and neurotoxicities seen after immune effector cell therapies including CAR T therapy, 49 experts from all aspects of the field met in Arlington, VA on June 20-21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT). Attendees included leaders from major academic centers involved in CAR T cell therapy research as well as representatives from industry, the Center for International Blood and Marrow Transplant Research (CIBMTR), the American Society of Hematology (ASH), and the National Cancer Institute (NCI). Key presentations regarding immune effector cell-associated CRS and neurotoxicity were followed by focused discussion of salient points. The writing group was then tasked with generating language encompassing a new consensus that is both easily applied at the bedside and easily verifiable during chart reviews. A full, iterative drafting and vetting process was undertaken. In addition, these guidelines were presented at the CIBMTR CT Registry Forum on October 25, 2018, for discussion and comment. The participation at this second meeting included a broad group of multiple stakeholders including investigators, industry, payors, and National Institutes of Health and other governmental agencies. Here we report the consensus and rationale of the group as related to grading and reporting of toxicities.Conflict of interest statement: D.W.L. has received clinical trial support from Kite/Gilead and serves as a consultant and advisory board member for Juno Therapeutics/Celgene. B.D.S. has consulted or participated in advisory boards for Juno Therapeutics/Celgene, Kite Pharma/Gilead, and Novartis. F.L.L. has served as a scientific advisor to Kite Pharma and Novartis and as a consultant to Cellular BioMedicine Group. A.G. has received research support from Kite Pharma and has served as a scientific advisor and speaker for Kite Pharma. C.J.T. has received research support from Juno Therapeutics and Nektar Therapeutics; has consulted or participated in advisory boards for Juno Therapeutics/Celgene, Nektar Therapeutics, Precision Biosciences, Eureka Therapeutics, Aptevo, Gilead, and Caribou Biosciences; and has option grants in Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences. M.V.M. has received research support from Novartis, Kite, Servier, TCR2, Agentus, and CRISPR Therapeutics and has participated in consulting or advisory boards for Agentus, Bluebird Bio, Cellectis, Juno, Kite, Novartis, Precision Biosciences, Takeda, and TCR2. J.H.P. has received research support from Juno Therapeutics, Genentech, and Amgen and has consulted or participated in advisory boards for Novartis, Kite, Juno Therapeutics, Shire, Amgen, Pfizer, Takeda, Adaptive Biotechnologies, TG Therapeutics, AstraZeneca, and Bayer. J.N.B., E.M., S.P., K.P., and J.F.D. have no conflicts of interest to report. W.Y.G. is employed by Kite, a Gilead Company, and has equity ownership in Gilead Sciences. L.E. is employed by Novartis Pharmaceuticals. R.A.G. has participated in advisory boards for Novartis. N.F. has consulted or participated in advisory boards for Novartis and Servier. K.J.C. has received research support from Juno Therapeutics and has consulted or participated in advisory boards for Juno Therapeutics and Novartis. M.C.P. has received honoraria from Pfizer and consulting fees from Medigene. M.R.M.V.D. has received research support from Seres Therapeutics; has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharmaceuticals, Therakos, Amgen, Merck & Co, Acute Leukemia Forum (ALF), and DKMS Medical Council (Board); and has IP Licensing with Seres Therapeutics and Juno Therapeutics. K.V.K. has received support for site participation in clinical trials from Kite, Adaptimmune, Atara, and Juno and has served as an ad hoc consultant to Kite/Gilead, Juno/Celgene, Novartis, Atara and Merck. S.A.G. has received research and/or clinical trial support from Novartis, Servier, and Kite and has served as a consultant, on study steering committees, or on scientific advisory boards for Novartis, Adaptimmune, Eureka, TCR2, Juno, GlaxoSmithKline, Cellectis, Vertex, Cure Genetics, and Roche. S.S.N. has received research support from Kite/Gilead, Celgene, Cellectis, Poseida, Merck, Acerta, Karus, and BMS and has served as a consultant and an advisory board member for Kite/Gilead, Celgene, Novartis, Unum Therapeutics, Pfizer, and Merck. Financial disclosure: See Acknowledgments on page XXXX. Publisher Copyright: © 2018 American Society for Blood and Marrow Transplantation
PY - 2019/4
Y1 - 2019/4
N2 - Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.
AB - Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.
KW - CAR T cell therapy
KW - Cellular immunotherapy
KW - Consensus grading
KW - Cytokine release syndrome
KW - Immune effector cell
KW - Neurotoxicity
UR - http://www.scopus.com/inward/record.url?scp=85062342961&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2018.12.758
DO - 10.1016/j.bbmt.2018.12.758
M3 - Review article
C2 - 30592986
AN - SCOPUS:85062342961
SN - 1083-8791
VL - 25
SP - 625
EP - 638
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 4
ER -