Pharmacokinetic and Pharmacodynamic Relationship of Blinatumomab in Patients with Non-Hodgkin Lymphoma

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 concentra-tion 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 magni-tude 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 eleva-tion increased with dose; it was less pronounced at low starting doses. Tumor response was a function of exposure, suggest-ing utility for the PK/PD relationship in dose selection for future studies, including NHL and other malignant settings.