OBJECTIVE: To characterize the incidence and clinical characteristics of neurotoxicity in the month following CTL019 infusion in children and young adults, to define the relationship between neurotoxicity and cytokine release syndrome (CRS), and to identify predictive biomarkers for development of neurotoxicity following CTL019 infusion. METHODS: We analyzed data on 51 subjects, 4 to 22 years old, who received CTL019, a chimeric antigen receptor-modified T-cell therapy against CD19, between January 1, 2010 and December 1, 2015 through a safety/feasibility clinical trial (NCT01626495) at our institution. We recorded incidence of significant neurotoxicity (encephalopathy, seizures, and focal deficits) and CRS, and compared serum cytokine levels in the first month postinfusion between subjects who did and did not develop neurotoxicity. RESULTS: Neurotoxicity occurred in 23 of 51 subjects (45%, 95% confidence interval = 31-60%) and was positively associated with higher CRS grade (p < 0.0001) but was not associated with demographic characteristics or prior oncologic treatment history. Serum interleukin (IL)-2, IL-15, soluble IL-4, and hepatocyte growth factor concentrations were higher in subjects with neurotoxicity than those with isolated CRS. Differences in peak levels of select cytokines including IL-12 and soluble tumor necrosis factor receptor-1 within the first 3 days were seen in subjects with neurotoxicity. INTERPRETATION: Neurotoxicity is common after CTL019 infusion in children and young adults, and is associated with higher CRS grade. Differences in serum cytokine profiles between subjects with neurotoxicity and those with isolated CRS suggest unique pathophysiological mechanisms. Serum cytokine profiles in the first 3 days postinfusion may help identify children and young adults at risk for neurotoxicity, and may provide a foundation for investigation into potential mitigation strategies. Ann Neurol 2018;84:537-546.
OBJECTIVE: To characterize the incidence and clinical characteristics of neurotoxicity in the month following CTL019 infusion in children and young adults, to define the relationship between neurotoxicity and cytokine release syndrome (CRS), and to identify predictive biomarkers for development of neurotoxicity following CTL019 infusion. METHODS: We analyzed data on 51 subjects, 4 to 22 years old, who received CTL019, a chimeric antigen receptor-modified T-cell therapy against CD19, between January 1, 2010 and December 1, 2015 through a safety/feasibility clinical trial (NCT01626495) at our institution. We recorded incidence of significant neurotoxicity (encephalopathy, seizures, and focal deficits) and CRS, and compared serum cytokine levels in the first month postinfusion between subjects who did and did not develop neurotoxicity. RESULTS:Neurotoxicity occurred in 23 of 51 subjects (45%, 95% confidence interval = 31-60%) and was positively associated with higher CRS grade (p < 0.0001) but was not associated with demographic characteristics or prior oncologic treatment history. Serum interleukin (IL)-2, IL-15, soluble IL-4, and hepatocyte growth factor concentrations were higher in subjects with neurotoxicity than those with isolated CRS. Differences in peak levels of select cytokines including IL-12 and soluble tumor necrosis factor receptor-1 within the first 3 days were seen in subjects with neurotoxicity. INTERPRETATION:Neurotoxicity is common after CTL019 infusion in children and young adults, and is associated with higher CRS grade. Differences in serum cytokine profiles between subjects with neurotoxicity and those with isolated CRS suggest unique pathophysiological mechanisms. Serum cytokine profiles in the first 3 days postinfusion may help identify children and young adults at risk for neurotoxicity, and may provide a foundation for investigation into potential mitigation strategies. Ann Neurol 2018;84:537-546.
Authors: Rebecca A Gardner; Olivia Finney; Colleen Annesley; Hannah Brakke; Corinne Summers; Kasey Leger; Marie Bleakley; Christopher Brown; Stephanie Mgebroff; Karen S Kelly-Spratt; Virginia Hoglund; Catherine Lindgren; Assaf P Oron; Daniel Li; Stanley R Riddell; Julie R Park; Michael C Jensen Journal: Blood Date: 2017-04-13 Impact factor: 22.113
Authors: Junwei Hao; Ruolan Liu; Wenhua Piao; Qinghua Zhou; Timothy L Vollmer; Denise I Campagnolo; Rong Xiang; Antonio La Cava; Luc Van Kaer; Fu-Dong Shi Journal: J Exp Med Date: 2010-08-09 Impact factor: 14.307
Authors: David T Teachey; Susan R Rheingold; Shannon L Maude; Gerhard Zugmaier; David M Barrett; Alix E Seif; Kim E Nichols; Erica K Suppa; Michael Kalos; Robert A Berg; Julie C Fitzgerald; Richard Aplenc; Lia Gore; Stephan A Grupp Journal: Blood Date: 2013-05-15 Impact factor: 22.113
Authors: Anna Lünemann; Jan D Lünemann; Susanne Roberts; Brady Messmer; Rosa Barreira da Silva; Cedric S Raine; Christian Münz Journal: J Immunol Date: 2008-11-01 Impact factor: 5.422
Authors: Rosalie M Sterner; Reona Sakemura; Michelle J Cox; Nan Yang; Roman H Khadka; Cynthia L Forsman; Michael J Hansen; Fang Jin; Katayoun Ayasoufi; Mehrdad Hefazi; Kendall J Schick; Denise K Walters; Omar Ahmed; Dale Chappell; Tarek Sahmoud; Cameron Durrant; Wendy K Nevala; Mrinal M Patnaik; Larry R Pease; Karen E Hedin; Neil E Kay; Aaron J Johnson; Saad S Kenderian Journal: Blood Date: 2018-11-21 Impact factor: 22.113
Authors: Caroline Diorio; Pamela A Shaw; Edward Pequignot; Alena Orlenko; Fang Chen; Richard Aplenc; David M Barrett; Hamid Bassiri; Edward Behrens; Amanda M DiNofia; Vanessa Gonzalez; Natalka Koterba; Bruce L Levine; Shannon L Maude; Nuala J Meyer; Jason H Moore; Michele Paessler; David L Porter; Jenny L Bush; Don L Siegel; Megan M Davis; Donglan Zhang; Carl H June; Stephan A Grupp; J Joseph Melenhorst; Simon F Lacey; Scott L Weiss; David T Teachey Journal: Blood Adv Date: 2020-10-27
Authors: Kevin R Parker; Denis Migliorini; Eric Perkey; Kathryn E Yost; Aparna Bhaduri; Puneet Bagga; Mohammad Haris; Neil E Wilson; Fang Liu; Khatuna Gabunia; John Scholler; Thomas J Montine; Vijay G Bhoj; Ravinder Reddy; Suyash Mohan; Ivan Maillard; Arnold R Kriegstein; Carl H June; Howard Y Chang; Avery D Posey; Ansuman T Satpathy Journal: Cell Date: 2020-09-21 Impact factor: 41.582
Authors: Haneen Shalabi; Juliane Gust; Agne Taraseviciute; Pamela L Wolters; Allison B Leahy; Carlos Sandi; Theodore W Laetsch; Lori Wiener; Rebecca A Gardner; Veronique Nussenblatt; Joshua A Hill; Kevin J Curran; Timothy S Olson; Colleen Annesley; Hao-Wei Wang; Javed Khan; Marcelo C Pasquini; Christine N Duncan; Stephan A Grupp; Michael A Pulsipher; Nirali N Shah Journal: Nat Rev Clin Oncol Date: 2021-01-25 Impact factor: 66.675