title: Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab.
abstract: T cell-engaging CD19/CD3-bispecific BiTE Ab blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD(+) B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B-cell counts dropped to < 1 B cell/μL within an average of 2 days and remained essentially undetectable for the entire treatment period. By contrast, T-cell counts in all patients declined to a nadir within < 1 day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline within 2-3 weeks under continued infusion of blinatumomab. A significant percentage of reappearing CD8(+) and CD4(+) T cells newly expressed activation marker CD69. Shortly after start of infusion, a transient release of cytokines dominated by IL-10, IL-6, and IFN-γ was observed, which no longer occurred on start of a second treatment cycle. The response of lymphocytes in leukemic patients to continuous infusion of blinatumomab helps to better understand the mode of action of this and other globally T cell-engaging Abs. The trial is registered with www.clinicaltrials.gov identifier NCT00560794.
authors.affiliation: Amgen Research (Munich) GmbH, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klinger
authors.forename: Christian
authors.initials: C
authors.lastname: Brandl
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zugmaier
authors.forename: Youssef
authors.initials: Y
authors.lastname: Hijazi
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Bargou
authors.forename: Max S
authors.initials: MS
authors.lastname: Topp
authors.forename: Nicola
authors.initials: N
authors.lastname: Gökbuget
authors.forename: Svenja
authors.initials: S
authors.lastname: Neumann
authors.forename: Mariele
authors.initials: M
authors.lastname: Goebeler
authors.forename: Andreas
authors.initials: A
authors.lastname: Viardot
authors.forename: Matthias
authors.initials: M
authors.lastname: Stelljes
authors.forename: Monika
authors.initials: M
authors.lastname: Brüggemann
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Evelyn
authors.initials: E
authors.lastname: Degenhard
authors.forename: Dirk
authors.initials: D
authors.lastname: Nagorsen
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: Andreas
authors.initials: A
authors.lastname: Wolf
authors.forename: Peter
authors.initials: P
authors.lastname: Kufer
mesh_terms: D000328:Adult; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018941:Antigens, CD19 / Q000276:immunology*; D000961:Antilymphocyte Serum / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects*; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods; D007260:Infusion Pumps; D008213:Lymphocyte Activation / Q000187:drug effects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000961:Antilymphocyte Serum; D017252:CD3 Complex; D007155:Immunologic Factors; C510808:blinatumomab