Blinatumomab Pharmacodynamics and Exposure–Response Relationships in Relapsed/Refractory Acute Lymphoblastic Leukemia

Abstract

We evaluated blinatumomab pharmacokinetics, pharmacodynamics (CD3+ T-cell, CD19+ B-cell, and cytokine levels), and their associations with efficacy or safety in relapsed/refractory acute lymphoblastic leukemia. Blinatumomab pharmacokinetics (continuous intravenous infusion) from a phase 2 study (n = 189; NCT01466179) were assessed noncompartmentally. Associations between steady-state concentration (C ) and efficacy (complete remission [CR] or CR with partial hematologic recovery [CRh]) or safety (cytokine release syndrome [CRS] and neurologic events [NEs]) were evaluated with statistical models. Blinatumomab mean ± SD C was 621 ± 502 pg/mL (28 μg/day dose). Cytokines were transiently elevated in >50% of patients; B-cell levels decreased in most patients. Lower B-cell and bone marrow (BM) blast percentages and higher T-cell percentages were associated with higher CR/CRh (P < .001) in univariate analysis. Higher C (OR, 1.90; 95%CI, 1.12-3.21), higher peak IL-10 level (1.59; 1.13-2.22), and lower BM blast percentage (0.78; 0.69-0.89) were associated with higher CR/CRh in multivariate analysis. Higher C (HR, 1.40; 1.01-1.94) and lower B-cell level (0.90; 0.84-0.97) were associated with shorter time to NEs. Cytokine peaks were not associated with NEs or CRS. In conclusion, blinatumomab led to T cell-mediated depletion of target B cells in blood and blasts in the bone marrow. Immune system effectiveness was important for treatment responses.

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

“…Previous studies have shown that blinatumomab infusion resulted in rapid, robust and sustained depletion of B cells, and redistribution of T cells . Consistent with those data, most patients in the current study had depletion of CD19+ B cells and transient reduction in T‐cell subsets after infusion of blinatumomab.…”

“…Our analysis of associations between cytokines/cell subsets and response to blinatumomab was likely impacted by the small sample size. A previous analysis of a much larger patient population (N = 189) showed that response to blinatumomab was associated with higher peak levels of IL‐10, higher proportions of CD3+ T cells, lower proportions of CD19+ B cells and higher proportions of granulocytes at baseline …”

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

“…Using the established concentration-response relationships from Nalm-6, Karpas-422, MEC-1 and Raji cells (Tables 1 and 2), the TBE model was used to predict blinatumomab-mediated B cell depletion in human blood and bone marrow by replacing system-specific parameters, such as concentrations of the drug, effector cells, and target cells, with values obtained from patients with leukemia. Baseline T cell and B cell concentrations in the blood were assigned at 500 and 300 cells per µL, respectively, based on the most recently reported data in relapsed/refractory acute lymphoblastic leukemia (ALL) patients who received blinatumomab treatment; 34 baseline T cell and B cell concentrations in bone marrow were assigned at 2,000 and 20,000 cells per µL, respectively, based on multiple reported assessments of bone marrow lymphocyte subsets, which include patients with advanced ALL who received blinatumomab treatment. 35–37 Other blinatumomab binding-associated parameters (e.g., KD CD3, KD receptor_CD19 ) and compound and reaction system-associated parameters (e.g., EC 50 , γ, τ reference , k τ1, k τ2 ) were assumed to be the same for in vitro and in vivo conditions.…”

Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors

“…In a recent publication, higher C ss with blinatumomab at a dose of 9 μg/day was associated with a greater incidence of NE events in the univariate analysis but not in the multivariate analysis [13]. Other disease- or treatment-related factors, such as more than two prior salvage therapies, may have affected the occurrence of NEs.…”