Shannon L Maude1, Theodore W Laetsch1, Jochen Buechner1, Susana Rives1, Michael Boyer1, Henrique Bittencourt1, Peter Bader1, Michael R Verneris1, Heather E Stefanski1, Gary D Myers1, Muna Qayed1, Barbara De Moerloose1, Hidefumi Hiramatsu1, Krysta Schlis1, Kara L Davis1, Paul L Martin1, Eneida R Nemecek1, Gregory A Yanik1, Christina Peters1, Andre Baruchel1, Nicolas Boissel1, Francoise Mechinaud1, Adriana Balduzzi1, Joerg Krueger1, Carl H June1, Bruce L Levine1, Patricia Wood1, Tetiana Taran1, Mimi Leung1, Karen T Mueller1, Yiyun Zhang1, Kapildeb Sen1, David Lebwohl1, Michael A Pulsipher1, Stephan A Grupp1. 1. From the Departments of Pediatrics (S.L.M., S.A.G.) and Pathology and Laboratory Medicine (C.H.J., B.L.L.), Perelman School of Medicine, and Abramson Cancer Center (C.H.J., B.L.L.), University of Pennsylvania, and the Division of Oncology, Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children's Hospital of Philadelphia (S.L.M., S.A.G.) - all in Philadelphia; the Department of Pediatrics and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, and the Pauline Allen Gill Center for Cancer and Blood Disorders, Children's Health, Dallas (T.W.L.); the Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo (J.B.); the Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu Barcelona, Barcelona (S.R.); the Department of Pediatrics and Internal Medicine, University of Utah, Salt Lake City (M.B.); the Department of Pediatrics, Faculty of Medicine, University of Montreal, and the Hematology Oncology Division and Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal (H.B.), and the Division of Haematology/Oncology/Bone Marrow Transplantation, Hospital for Sick Children, Toronto (J.K.) - all in Canada; the Division of Stem Cell Transplantation and Immunology, Hospital for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany (P.B.); the Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis (M.R.V., H.E.S.); Children's Mercy Hospital and Clinics, Kansas City, MO (G.D.M.); Aflac Cancer and Blood Disorders Center, Emory University, Atlanta (M.Q.); the Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, and the Cancer Research Institute Ghent (CRIG), Ghent, Belgium (B.D.M.); the Department of Pediatrics, Graduate School of Medicine Kyoto University, Kyoto, Japan (H.H.); the Department of Pediatrics, Stanford University School of Medicine, Stanford (K. Schlis, K.L.D.), and the Division of Hematology, Oncology, Blood and Marrow Transplant, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles (M.A.P.) - all in California; the Division of Pediatric Blood and Marrow Transplant, Duke University Medical Center, Durham, NC (P.L.M.); Oregon Health and Science University, Portland (E.R.N.); C.S. Mott Children's Hospital, Ann Arbor, MI (G.A.Y.); the Stem Cell Transplantation Unit, St. Anna Children's Hospital, Vienna (C.P.); University Hospital Robert Debré and University Paris Diderot (A. Baruchel), and Saint-Louis Hospital and University Paris Diderot (N.B.), Paris; the Royal Children's Hospital, Melbourne, VIC, Australia (F.M.); Clinica Pediatrica Universita degli Studi di Milano Bicocca, Monza, Italy (A. Balduzzi); and Novartis Pharmaceuticals (P.W., T.T., M.L., Y.Z., K. Sen, D.L.) and Novartis Institutes for Biomedical Research (K.T.M.) - both in East Hanover, NJ.
Abstract
BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).
BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).
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: Sima Jeha; Paul S Gaynon; Bassem I Razzouk; Janet Franklin; Richard Kadota; Violet Shen; Lori Luchtman-Jones; Michael Rytting; Lisa R Bomgaars; Susan Rheingold; Kim Ritchey; Edythe Albano; Robert J Arceci; Stewart Goldman; Timothy Griffin; Arnold Altman; Bruce Gordon; Laurel Steinherz; Steven Weitman; Peter Steinherz Journal: J Clin Oncol Date: 2006-04-20 Impact factor: 44.544
Authors: Daniel W Lee; James N Kochenderfer; Maryalice Stetler-Stevenson; Yongzhi K Cui; Cindy Delbrook; Steven A Feldman; Terry J Fry; Rimas Orentas; Marianna Sabatino; Nirali N Shah; Seth M Steinberg; Dave Stroncek; Nick Tschernia; Constance Yuan; Hua Zhang; Ling Zhang; Steven A Rosenberg; Alan S Wayne; Crystal L Mackall Journal: Lancet Date: 2014-10-13 Impact factor: 79.321
Authors: Cameron J Turtle; Laïla-Aïcha Hanafi; Carolina Berger; Theodore A Gooley; Sindhu Cherian; Michael Hudecek; Daniel Sommermeyer; Katherine Melville; Barbara Pender; Tanya M Budiarto; Emily Robinson; Natalia N Steevens; Colette Chaney; Lorinda Soma; Xueyan Chen; Cecilia Yeung; Brent Wood; Daniel Li; Jianhong Cao; Shelly Heimfeld; Michael C Jensen; Stanley R Riddell; David G Maloney Journal: J Clin Invest Date: 2016-04-25 Impact factor: 14.808
Authors: Arend von Stackelberg; Franco Locatelli; Gerhard Zugmaier; Rupert Handgretinger; Tanya M Trippett; Carmelo Rizzari; Peter Bader; Maureen M O'Brien; Benoît Brethon; Deepa Bhojwani; Paul Gerhardt Schlegel; Arndt Borkhardt; Susan R Rheingold; Todd Michael Cooper; Christian M Zwaan; Phillip Barnette; Chiara Messina; Gérard Michel; Steven G DuBois; Kuolung Hu; Min Zhu; James A Whitlock; Lia Gore Journal: J Clin Oncol Date: 2016-10-31 Impact factor: 44.544
Authors: Stephan A Grupp; Michael Kalos; David Barrett; Richard Aplenc; David L Porter; Susan R Rheingold; David T Teachey; Anne Chew; Bernd Hauck; J Fraser Wright; Michael C Milone; Bruce L Levine; Carl H June Journal: N Engl J Med Date: 2013-03-25 Impact factor: 91.245
Authors: Michael C Milone; Jonathan D Fish; Carmine Carpenito; Richard G Carroll; Gwendolyn K Binder; David Teachey; Minu Samanta; Mehdi Lakhal; Brian Gloss; Gwenn Danet-Desnoyers; Dario Campana; James L Riley; Stephan A Grupp; Carl H June Journal: Mol Ther Date: 2009-04-21 Impact factor: 11.454
Authors: David L Porter; Wei-Ting Hwang; Noelle V Frey; Simon F Lacey; Pamela A Shaw; Alison W Loren; Adam Bagg; Katherine T Marcucci; Angela Shen; Vanessa Gonzalez; David Ambrose; Stephan A Grupp; Anne Chew; Zhaohui Zheng; Michael C Milone; Bruce L Levine; Jan J Melenhorst; Carl H June Journal: Sci Transl Med Date: 2015-09-02 Impact factor: 17.956
Authors: Adrienne H Long; Waleed M Haso; Jack F Shern; Kelsey M Wanhainen; Meera Murgai; Maria Ingaramo; Jillian P Smith; Alec J Walker; M Eric Kohler; Vikas R Venkateshwara; Rosandra N Kaplan; George H Patterson; Terry J Fry; Rimas J Orentas; Crystal L Mackall Journal: Nat Med Date: 2015-05-04 Impact factor: 53.440
Authors: Andrew H Ko; Alexander C Jordan; Evan Tooker; Simon F Lacey; Renee B Chang; Yan Li; Alan P Venook; Margaret Tempero; Lloyd Damon; Lawrence Fong; Mark H O'Hara; Bruce L Levine; J Joseph Melenhorst; Gabriela Plesa; Carl H June; Gregory L Beatty Journal: Mol Ther Date: 2020-07-21 Impact factor: 11.454
Authors: Sonia Guedan; Aviv Madar; Victoria Casado-Medrano; Carolyn Shaw; Anna Wing; Fang Liu; Regina M Young; Carl H June; Avery D Posey Journal: J Clin Invest Date: 2020-06-01 Impact factor: 14.808