Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial
Frederick L. Locke,Armin Ghobadi,Caron A. Jacobson,David B. Miklos,Lazaros J. Lekakis,Olalekan O. Oluwole,Yi Lin,Ira Braunschweig,Brian T. Hill,John M. Timmerman,Abhinav Deol,Patrick M. Reagan,Patrick J. Stiff,Ian W. Flinn,Umar Farooq,Andre Goy,Peter A. McSweeney,Javier Munoz,Tanya Siddiqi,Julio C. Chavez,Alex F. Herrera,Nancy L. Bartlett,Jeffrey S. Wiezorek,Lynn Navale,Allen Xue,Yizhou Jiang,Adrian Bot,John M. Rossi,Jenny J. Kim,William Y. Go,Sattva S. Neelapu +30 more
TLDR
Long-term activity and safety outcomes of the ZUMA-1 study suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable relapsed or refractory disease or relapsed after autologous stem-cell transplantation.Abstract:
Summary Background Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. Methods ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov , number NCT02348216 . Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Findings Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3–15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. Interpretation These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. Funding Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.read more
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ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells
Daniel W. Lee,Bianca Santomasso,Frederick L. Locke,Armin Ghobadi,Cameron J. Turtle,Jennifer N. Brudno,Marcela V. Maus,Jae H. Park,Elena Mead,Steven Z. Pavletic,William Y. Go,Lamis K. Eldjerou,Rebecca Gardner,Noelle V. Frey,Kevin J. Curran,Karl S. Peggs,Marcelo C. Pasquini,John F. DiPersio,Marcel R.M. van den Brink,Krishna V. Komanduri,Stephan A. Grupp,Sattva S. Neelapu +21 more
TL;DR: 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.
Journal ArticleDOI
Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.
Jeremy S. Abramson,M. Lia Palomba,Leo I. Gordon,Matthew A. Lunning,Michael Wang,Jon E. Arnason,Amitkumar Mehta,Enkhtsetseg Purev,David G. Maloney,Charalambos Andreadis,Alison R. Sehgal,Scott R. Solomon,Nilanjan Ghosh,Tina Albertson,Jacob Garcia,Ana Kostic,Mary Mallaney,Ken Ogasawara,Kathryn Newhall,Yeonhee Kim,Daniel Li,Tanya Siddiqi +21 more
TL;DR: Overall safety and activity of liso-cel did not differ by dose level, with a high objective response rate, and a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas.
Journal ArticleDOI
KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma
Michael Wang,Javier Munoz,Andre Goy,Frederick L. Locke,Caron A. Jacobson,Brian T. Hill,John M. Timmerman,Houston Holmes,Samantha Jaglowski,Ian W. Flinn,Peter A. McSweeney,David B. Miklos,John M. Pagel,Marie José Kersten,Noel Milpied,Henry C. Fung,Max S. Topp,Roch Houot,Amer Beitinjaneh,Weimin Peng,Lianqing Zheng,John M. Rossi,Rajul K. Jain,Arati V. Rao,Patrick M. Reagan +24 more
TL;DR: KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma, and led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies.
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A review of cancer immunotherapy toxicity.
TL;DR: This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.
ASBMT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells
DW Lee,Bianca Santomasso,Frederick L. Locke,Armin Ghobadi,Cameron J. Turtle,Jennifer N. Brudno,Marcela V. Maus,JH Park,Elena Mead,Steven Z. Pavletic,WY Go,Lamis K. Eldjerou,Rebecca Gardner,Noelle V. Frey,Kevin J. Curran,Karl S. Peggs,Marcelo C. Pasquini,John F. DiPersio,Mrm van den Brink,Krishna V. Komanduri,Stephan A. Grupp,Sattva S. Neelapu +21 more
TL;DR: In 2018, the American Society for Blood and Marrow Transplantation (ASBMT) recognized the need to harmonize the definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity associated with CAR T cell therapies.
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Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
Sattva S. Neelapu,Frederick L. Locke,Nancy L. Bartlett,Lazaros J. Lekakis,David B. Miklos,Caron A. Jacobson,Ira Braunschweig,Olalekan O. Oluwole,Tanya Siddiqi,Yi Lin,John M. Timmerman,Patrick J. Stiff,Jonathan W. Friedberg,Ian W. Flinn,Andre Goy,Brian T. Hill,Mitchell R. Smith,Abhinav Deol,Umar Farooq,Peter A. McSweeney,Javier Munoz,Irit Avivi,Januario E. Castro,Jason R. Westin,Julio C. Chavez,Armin Ghobadi,Krishna V. Komanduri,Ronald Levy,Eric D. Jacobsen,Thomas E. Witzig,Patrick M. Reagan,Adrian Bot,John J. Rossi,Lynn Navale,Yizhou Jiang,Jeff Aycock,Meg Elias,David Z. Chang,Jeff Wiezorek,William Y. Go +39 more
TL;DR: Patients with refractory large B‐cell lymphoma who received CAR T‐cell therapy with axi‐cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events.
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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
TL;DR: 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.
Journal ArticleDOI
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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