Blinatumomab Pharmacodynamics and Exposure-Response Relationships in Relapsed/Refractory Acute Lymphoblastic Leukemia.
J Clin Pharmacol
; 58(2): 168-179, 2018 02.
Article
em En
| MEDLINE
| ID: mdl-28922466
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 (Css ) 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 Css 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 Css (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 Css (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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Anticorpos Biespecíficos
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Antineoplásicos
Tipo de estudo:
Clinical_trials
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Risk_factors_studies
Limite:
Adolescent
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Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article