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Immunopharmacological response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab

Matthias Klinger, Christian Brandl, Gerhard Zugmaier, Youssef Hijazi, Ralf C. Bargou, Max S. Topp, Nicola Gökbuget, Svenja Neumann, Mariele Goebeler, Andreas Viardot, Matthias Stelljes, Monika Brüggemann, Dieter Hoelzer, Evelyn Degenhard, Dirk Nagorsen, Patrick A. Baeuerle, Andreas Wolf and Peter Kufer

Abstract

T cell-engaging CD19/CD3-bispecific BiTE antibody 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 less than one B cell/µl within an average of two days and remained essentially undetectable for the entire treatment period. By contrast, T cell counts in all patients declined to a nadir within less than one 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 upon 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 antibodies. The trial is registered with www.ClinicalTrials.gov Identifier NCT00560794.

  • Submitted January 5, 2012.
  • Accepted May 6, 2012.