Background: Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct
targeting CD3ε on T cells and CD19 on B cells. We describe the relationship between pharmacokinetics
(PK) of blinatumomab and pharmacodynamic (PD) changes in peripheral lymphocytes,
serum cytokines, and tumor size in patients with non-Hodgkin lymphoma (NHL).
Methods: In a phase 1 study, 76 patients with relapsed/refractory NHL received blinatumomab by
continuous intravenous infusion at various doses (0.5 to 90 µg/m2/day). PD changes were analyzed
with respect to dose, blinatumomab concentration at steady state (Css), and cumulative area under
the concentration-versus-time curve (AUCcum).
Results: B-cell depletion occurred within 48 hours at doses ≥5 µg/m2/day, followed first-order
kinetics, and was blinatumomab exposure-dependent. Change in tumor size depended on systemic
blinatumomab exposure and treatment duration and could be fitted to an Emax model, which predicted
a 50% reduction in tumor size at AUCcum of ≥1,340 h×µg/L and Css of ≥1,830 pg/mL, corresponding
to a blinatumomab dose of 47 µg/m2/day for 28 days. The magnitude of transient cytokine
elevation, observed within 1-2 days of infusion start, was dose-dependent, with less pronounced
elevation at low starting doses.
Conclusion: B-lymphocyte depletion following blinatumomab infusion was exposure-dependent.
Transient cytokine elevation increased with dose; it was less pronounced at low starting doses. Tumor
response was a function of exposure, suggesting utility for the PK/PD relationship in dose selection
for future studies, including NHL and other malignant settings.