Max S Topp1, Nicola Gökbuget2, Anthony S Stein3, Gerhard Zugmaier4, Susan O'Brien5, Ralf C Bargou6, Hervé Dombret7, Adele K Fielding8, Leonard Heffner9, Richard A Larson10, Svenja Neumann11, Robin Foà12, Mark Litzow13, Josep-Maria Ribera14, Alessandro Rambaldi15, Gary Schiller16, Monika Brüggemann17, Heinz A Horst17, Chris Holland18, Catherine Jia19, Tapan Maniar20, Birgit Huber4, Dirk Nagorsen20, Stephen J Forman3, Hagop M Kantarjian5. 1. Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany. Electronic address: topp_m@ukw.de. 2. Department of Medicine II, Goethe University, Frankfurt, Germany. 3. City of Hope, Duarte, CA, USA. 4. Amgen Research (Munich) GmbH, Munich, Germany. 5. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6. Comprehensive Cancer Center Mainfranken, Universitätsklinikum Würzburg, Würzburg, Germany. 7. University Paris, Hôpital Saint Louis, Paris, France. 8. Department of Haematology, University College London Medical School, London, UK. 9. Winship Cancer Institute, Emory University, Atlanta, GA, USA. 10. University of Chicago, Chicago, IL, USA. 11. Medizinische Klinik und Poliklinik, Städtischen Krankenhaus Kiel GmbH, Kiel, Germany. 12. Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy. 13. Department of Hematology, Mayo Clinic, Rochester, MN, USA. 14. ICO-Hospital Germans Trias i Pujol, Jose Carreras Research Institute, UAB, Badalona, Spain. 15. Department of Hematology, Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. 16. David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 17. University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany. 18. Amgen Rockville, Rockville, MD, USA. 19. Amgen South San Francisco, San Francisco, CA, USA. 20. Amgen, Thousand Oaks, CA, USA.
Abstract
BACKGROUND: Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. METHODS: In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. FINDINGS: Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. INTERPRETATION: Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. FUNDING: Amgen.
BACKGROUND: Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. METHODS: In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. FINDINGS: Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. INTERPRETATION: Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. FUNDING: Amgen.
Authors: José Baselga; Nina Bhardwaj; Lewis C Cantley; Ronald DeMatteo; Raymond N DuBois; Margaret Foti; Susan M Gapstur; William C Hahn; Lee J Helman; Roy A Jensen; Electra D Paskett; Theodore S Lawrence; Stuart G Lutzker; Eva Szabo Journal: Clin Cancer Res Date: 2015-10-01 Impact factor: 12.531
Authors: Don S Dizon; Lada Krilov; Ezra Cohen; Tara Gangadhar; Patricia A Ganz; Thomas A Hensing; Stephen Hunger; Smitha S Krishnamurthi; Andrew B Lassman; Merry Jennifer Markham; Erica Mayer; Michael Neuss; Sumanta Kumar Pal; Lisa C Richardson; Richard Schilsky; Gary K Schwartz; David R Spriggs; Miguel Angel Villalona-Calero; Gina Villani; Gregory Masters Journal: J Clin Oncol Date: 2016-02-04 Impact factor: 44.544
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