title: Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival.
abstract: OBJECTIVE
  Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.
  
  
  METHODS
  Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours.
  
  
  RESULTS
  Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events.
  
  
  CONCLUSIONS
  Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.
authors.affiliation: Comprehensive Cancer Center Mainfranken, University Wuerzburg, Germany.
authors.forename: Max S
authors.initials: MS
authors.lastname: Topp
authors.forename: Peter
authors.initials: P
authors.lastname: Kufer
authors.forename: Nicola
authors.initials: N
authors.lastname: Gökbuget
authors.forename: Mariele
authors.initials: M
authors.lastname: Goebeler
authors.forename: Matthias
authors.initials: M
authors.lastname: Klinger
authors.forename: Svenja
authors.initials: S
authors.lastname: Neumann
authors.forename: Heinz-A
authors.initials: HA
authors.lastname: Horst
authors.forename: Thorsten
authors.initials: T
authors.lastname: Raff
authors.forename: Andreas
authors.initials: A
authors.lastname: Viardot
authors.forename: Mathias
authors.initials: M
authors.lastname: Schmid
authors.forename: Matthias
authors.initials: M
authors.lastname: Stelljes
authors.forename: Markus
authors.initials: M
authors.lastname: Schaich
authors.forename: Evelyn
authors.initials: E
authors.lastname: Degenhard
authors.forename: Rudolf
authors.initials: R
authors.lastname: Köhne-Volland
authors.forename: Monika
authors.initials: M
authors.lastname: Brüggemann
authors.forename: Oliver
authors.initials: O
authors.lastname: Ottmann
authors.forename: Heike
authors.initials: H
authors.lastname: Pfeifer
authors.forename: Thomas
authors.initials: T
authors.lastname: Burmeister
authors.forename: Dirk
authors.initials: D
authors.lastname: Nagorsen
authors.forename: Margit
authors.initials: M
authors.lastname: Schmidt
authors.forename: Ralf
authors.initials: R
authors.lastname: Lutterbuese
authors.forename: Carsten
authors.initials: C
authors.lastname: Reinhardt
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Gert
authors.initials: G
authors.lastname: Riethmüller
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zugmaier
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Bargou
mesh_terms: D000328:Adult; D000361:Agammaglobulinemia / Q000139:chemically induced; D000368:Aged; D000369:Aged, 80 and over; D018033:Antibodies, Bispecific / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000918:Antibody Specificity; D018941:Antigens, CD19 / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001853:Bone Marrow / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology; D019070:Cell Lineage; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D018365:Neoplasm, Residual; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000628:therapy*; D012074:Remission Induction; D037182:T-Cell Antigen Receptor Specificity / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D055815:Young Adult
chemical_list: D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000951:Antigens, Neoplasm; D017252:CD3 Complex; C510808:blinatumomab