Bijal D Shah1, Armin Ghobadi2, Olalekan O Oluwole3, Aaron C Logan4, Nicolas Boissel5, Ryan D Cassaday6, Thibaut Leguay7, Michael R Bishop8, Max S Topp9, Dimitrios Tzachanis10, Kristen M O'Dwyer11, Martha L Arellano12, Yi Lin13, Maria R Baer14, Gary J Schiller15, Jae H Park16, Marion Subklewe17, Mehrdad Abedi18, Monique C Minnema19, William G Wierda20, Daniel J DeAngelo21, Patrick Stiff22, Deepa Jeyakumar23, Chaoling Feng24, Jinghui Dong24, Tong Shen24, Francesca Milletti24, John M Rossi24, Remus Vezan24, Behzad Kharabi Masouleh24, Roch Houot25. 1. Moffitt Cancer Center, Tampa, FL, USA. Electronic address: bijal.shah@moffitt.org. 2. Washington University School of Medicine and Siteman Cancer Center, St Louis, MO, USA. 3. Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. 4. Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. 5. Hôpital Saint-Louis, Paris, France. 6. University of Washington School of Medicine, Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance, Seattle, WA, USA. 7. Centre Hospitalier Universitaire de Bordeaux, Pessac, France. 8. The University of Chicago Medicine, Chicago, IL, USA. 9. Universitätsklinikum Würzburg, Würzburg, Germany. 10. University of California, San Diego, La Jolla, CA, USA. 11. Wilmot Cancer Institute of University of Rochester, Rochester, NY, USA. 12. Winship Cancer Institute of Emory University, Atlanta, GA, USA. 13. Mayo Clinic, Rochester, MN, USA. 14. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA. 15. David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 16. Memorial Sloan Kettering Cancer Center, New York, NY, USA. 17. Ludwig-Maximilians-Universität München, Munich, Germany. 18. University of California-Davis Medical Center, Sacramento, CA, USA. 19. University Medical Center Utrecht, Utrecht, Netherlands. 20. The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 21. Dana-Farber Cancer Institute, Boston, MA, USA. 22. Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA. 23. University of California Irvine Medical Center, Irvine, CA, USA. 24. Kite, a Gilead Company, Santa Monica, CA, USA. 25. CHU Rennes, University of Rennes, INSERM U1236, EFS, Rennes, France.
Abstract
BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 106 CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p<0·0001) had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 12·8 months (95% CI 8·7-not estimable), median relapse-free survival was 11·6 months (2·7-15·5), and median overall survival was 18·2 months (15·9-not estimable). Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anaemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had infections of grade 3 or higher. Two grade 5 KTE-X19-related events occurred (brain herniation and septic shock). Cytokine release syndrome of grade 3 or higher occurred in 13 (24%) patients and neurological events of grade 3 or higher occurred in 14 (25%) patients. INTERPRETATION: KTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients. FUNDING: Kite, a Gilead Company.
BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 106 CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p<0·0001) had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 12·8 months (95% CI 8·7-not estimable), median relapse-free survival was 11·6 months (2·7-15·5), and median overall survival was 18·2 months (15·9-not estimable). Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anaemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had infections of grade 3 or higher. Two grade 5 KTE-X19-related events occurred (brain herniation and septic shock). Cytokine release syndrome of grade 3 or higher occurred in 13 (24%) patients and neurological events of grade 3 or higher occurred in 14 (25%) patients. INTERPRETATION: KTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients. FUNDING: Kite, a Gilead Company.
Authors: Astha Thakkar; Michelly Abreu; Ira Braunschweig; Mendel Goldfinger; Kith Pradhan; R Alejandro Sica; Aditi Shastri; Noah Kornblum; Nishi Shah; Ioannis Mantzaris; Kira Gritsman; Eric Feldman; Richard Elkind; Susan Green-Lorenzen; Amit Verma Journal: Bone Marrow Transplant Date: 2022-04-28 Impact factor: 5.174