title: Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Amgen.
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany. Electronic address: topp_m@ukw.de.
authors.forename: Max S
authors.initials: MS
authors.lastname: Topp
authors.affiliation: Department of Medicine II, Goethe University, Frankfurt, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Gökbuget
authors.affiliation: City of Hope, Duarte, CA, USA.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Stein
authors.affiliation: Amgen Research (Munich) GmbH, Munich, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zugmaier
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Comprehensive Cancer Center Mainfranken, Universitätsklinikum Würzburg, Würzburg, Germany.
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Bargou
authors.affiliation: University Paris, Hôpital Saint Louis, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Department of Haematology, University College London Medical School, London, UK.
authors.forename: Adele K
authors.initials: AK
authors.lastname: Fielding
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Heffner
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: Medizinische Klinik und Poliklinik, Städtischen Krankenhaus Kiel GmbH, Kiel, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Neumann
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.affiliation: Department of Hematology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Litzow
authors.affiliation: ICO-Hospital Germans Trias i Pujol, Jose Carreras Research Institute, UAB, Badalona, Spain.
authors.forename: Josep-Maria
authors.initials: JM
authors.lastname: Ribera
authors.affiliation: Department of Hematology, Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Schiller
authors.affiliation: University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Brüggemann
authors.affiliation: University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: Heinz A
authors.initials: HA
authors.lastname: Horst
authors.affiliation: Amgen Rockville, Rockville, MD, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Holland
authors.affiliation: Amgen South San Francisco, San Francisco, CA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Jia
authors.affiliation: Amgen, Thousand Oaks, CA, USA.
authors.forename: Tapan
authors.initials: T
authors.lastname: Maniar
authors.affiliation: Amgen Research (Munich) GmbH, Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Huber
authors.affiliation: Amgen, Thousand Oaks, CA, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Nagorsen
authors.affiliation: City of Hope, Duarte, CA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005060:Europe; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007262:Infusions, Intravenous; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012008:Recurrence; D012074:Remission Induction; D016879:Salvage Therapy; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; C510808:blinatumomab