Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia
Shannon L. Maude,Theodore W. Laetsch,Jochen Buechner,S. Rives,Michael Boyer,Henrique Bittencourt,Peter Bader,Michael R. Verneris,Heather E. Stefanski,G.D. Myers,Muna Qayed,B. De Moerloose,Hidefumi Hiramatsu,Krysta Schlis,Kara L. Davis,Paul L. Martin,Eneida R. Nemecek,Gregory A. Yanik,Christina Peters,André Baruchel,Nicolas Boissel,Francoise Mechinaud,Adriana Balduzzi,Joerg Krueger,Carl H. June,Bruce L. Levine,Patricia A. Wood,Tanya Taran,Mimi Leung,Karen Thudium Mueller,Yiyun Zhang,Kapildeb Sen,David Lebwohl,Michael A. Pulsipher,Stephan A. Grupp +34 more
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TLDR
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.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-fread more
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Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab, is highly effective in patients with Philadelphia chromosome–negative acute lymphoblastic leukemia in first salvage
Elias Jabbour,Koji Sasaki,Farhad Ravandi,Xuelin Huang,Nicholas J. Short,Maria Khouri,Partow Kebriaei,Jan A. Burger,Joseph D. Khoury,Jeffrey L. Jorgensen,Nitin Jain,Marina Konopleva,Guillermo Garcia-Manero,Tapan M. Kadia,Jorge E. Cortes,Jovitta Jacob,Kathryn S. Montalbano,Rebecca Garris,Susan O'Brien,Hagop M. Kantarjian +19 more
TL;DR: Inotuzumab ozogamicin and blinatumomab have single‐agent activity in R‐R ALL and their addition to low‐intensity chemotherapy may further improve the outcomes of patients with ALL in their first relapse.
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Comparing CAR T-cell toxicity grading systems: application of the ASTCT grading system and implications for management.
Martina Pennisi,Martina Pennisi,Tania Jain,Bianca Santomasso,Bianca Santomasso,Elena Mead,Kitsada Wudhikarn,Kitsada Wudhikarn,Mari Lynne Silverberg,Yakup Batlevi,Roni Shouval,Sean M. Devlin,Connie L Batlevi,Renier J. Brentjens,Renier J. Brentjens,Parastoo B. Dahi,Parastoo B. Dahi,Claudia Diamonte,Sergio Giralt,Sergio Giralt,Elizabeth Halton,Molly Maloy,Maria Lia Palomba,Miriam Sanchez-Escamilla,Craig S. Sauter,Craig S. Sauter,Michael Scordo,Michael Scordo,Gunjan L. Shah,Gunjan L. Shah,Jae H. Park,Jae H. Park,Miguel Perales,Miguel Perales +33 more
TL;DR: Investigation of possible management implications in DLBCL patients showed that different recommendations on tocilizumab and steroids across current guidelines potentially result in either overtreating or delaying treatment.
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Clinical trials of dual-target CAR T cells, donor-derived CAR T cells, and universal CAR T cells for acute lymphoid leukemia
TL;DR: New clinical trials and latest updates at the 2018 ASH Annual Meeting on CAR T therapy for ALL are summarized with a focus on dual-target CAR T and universal CAR T cell trials.
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T-cell-based immunotherapy of acute myeloid leukemia: current concepts and future developments
TL;DR: Several immunotherapies that harness the power of T cells to treat solid tumors and an improved understanding of the immune systems of patients with hematologic malignancies have led to major efforts to develop immunotherapy approaches for the treatment of patients suffering from acute myeloid leukemia (AML) as mentioned in this paper.
Journal ArticleDOI
Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells.
Andrew M. Stein,Stephan A. Grupp,Stephan A. Grupp,John E. Levine,John E. Levine,Theodore W. Laetsch,Michael A. Pulsipher,Michael Boyer,Keith J. August,Bruce L. Levine,Lori Tomassian,Sweta Shah,Mimi Leung,Pai Hsi Huang,Rakesh Awasthi,Karen Thudium Mueller,Patricia A. Wood,Carl H. June +17 more
TL;DR: This work represents the first mixed‐effect model‐based analysis of chimeric antigen receptor–T cell therapy and may be clinically impactful as future studies examine prophylactic interventions in patients at risk of higher grade cytokine release syndrome and the effects of these interventions on chimeric receptor– T cell expansion.
References
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Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
Stephan A. Grupp,Michael Kalos,David M. 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 +12 more
TL;DR: The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
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T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial
Daniel W. Lee,James N. Kochenderfer,Maryalice Stetler-Stevenson,Yongzhi K Cui,Cindy Delbrook,Steven A. Feldman,Terry J. Fry,Rimas J. Orentas,Marianna Sabatino,Nirali N. Shah,Seth M. Steinberg,Dave Stroncek,Nick Tschernia,Constance M. Yuan,Hua Zhang,Ling Zhang,Steven A. Rosenberg,Alan S. Wayne,Crystal L. Mackall +18 more
TL;DR: CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia and non-Hodgkin lymphoma.
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CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia
Renier J. Brentjens,Marco L. Davila,Isabelle Riviere,Jae H. Park,Xiuyan Wang,Lindsay G. Cowell,Shirley Bartido,Jolanta Stefanski,Clare Taylor,Malgorzata Olszewska,Oriana Borquez-Ojeda,Jinrong Qu,Teresa Wasielewska,Qing He,Yvette Bernal,Ivelise Rijo,Cyrus V. Hedvat,Rachel Kobos,Kevin J. Curran,Peter G. Steinherz,Joseph G. Jurcic,Todd L. Rosenblat,Peter Maslak,Mark G. Frattini,Michel Sadelain +24 more
TL;DR: The results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.
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CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
Cameron J. Turtle,Laïla Aïcha Hanafi,Carolina Berger,Ted Gooley,Sindhu Cherian,Michael Hudecek,Daniel Sommermeyer,Katherine Melville,Barbara S. Pender,Tanya M Budiarto,Emily Robinson,Natalia N Steevens,Colette Chaney,Lorinda Soma,Xueyan Chen,Cecilia Yeung,Brent L. Wood,Daniel Li,Jianhong Cao,Shelly Heimfeld,Michael C. Jensen,Stanley R. Riddell,David G. Maloney +22 more
TL;DR: It is established that high CAR-T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity, and serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity are identified.
Journal ArticleDOI
Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia
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 E. Gonzalez,David E Ambrose,Stephan A. Grupp,Anne Chew,Zhaohui Zheng,Michael C. Milone,Bruce L. Levine,J. Joseph Melenhorst,Carl H. June +17 more
TL;DR: The in vivo expansion of theCAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR, suggesting that disease eradication may be possible in some patients with advanced CLL.
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