Journal article
Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial
The lancet oncology, Vol.20(1), pp.31-42
01/01/2019
DOI: 10.1016/S1470-2045(18)30864-7
PMCID: PMC6733402
PMID: 30518502
Abstract
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 2x10(6) CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m(2) body-surface area) and cyclophosphamide (500 mg/m(2) 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.
Copyright (C) 2018 Elsevier Ltd. All rights reserved.
Details
- Title: Subtitle
- Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial
- Creators
- Frederick L. Locke - University of South FloridaArmin Ghobadi - Washington University in St. LouisCaron A. Jacobson - Dana-Farber Cancer InstituteDavid B. Miklos - Stanford UniversityLazaros J. Lekakis - University of Miami Health SystemOlalekan O. Oluwole - Vanderbilt UniversityYi Lin - Mayo CLinic, Rochester, MN, USA,Ira Braunschweig - Albert Einstein College of MedicineBrian T. Hill - Cleveland ClinicJohn M. Timmerman - University of California, Los AngelesAbhinav Deol - Wayne State UniversityPatrick M. Reagan - University of Rochester Medical CenterPatrick Stiff - Loyola University ChicagoIan W. Flinn - Sarah CannonUmar Farooq - University of IowaAndre Goy - Hackensack University Medical CenterPeter A. McSweeney - Colorado Blood Cancer InstituteJavier Munoz - The University of Texas MD Anderson Cancer CenterTanya Siddiqi - City Of Hope National Medical CenterJulio C. Chavez - University of South FloridaAlex F. Herrera - City Of Hope National Medical CenterNancy L. Bartlett - Washington University in St. LouisJeffrey S. Wiezorek - KiteLynn Navale - KiteAllen Xue - KiteYizhou Jiang - KiteAdrian Bot - KiteJohn M. Rossi - KiteJenny J. Kim - KiteWilliam Y. Go - KiteSattva S. Neelapu - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- The lancet oncology, Vol.20(1), pp.31-42
- Publisher
- Elsevier
- DOI
- 10.1016/S1470-2045(18)30864-7
- PMID
- 30518502
- PMCID
- PMC6733402
- ISSN
- 1470-2045
- eISSN
- 1474-5488
- Number of pages
- 12
- Grant note
- Kite Leukemia AMP; Lymphoma Society Therapy Acceleration Program; Leukemia and Lymphoma Society P30CA086862; K23CA201594 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 01/01/2019
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359839902771
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