Abstract
BackgroundBlinatumomab has shown a remission rate of 69% in an exploratory single-arm, phase II dose-escalation study in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We evaluated changes in laboratory parameters and immunopharmacodynamic markers in patients who received blinatumomab in the exploratory phase II study.MethodsData from 36 adults with relapsed/refractory ALL receiving blinatumomab as 4-week continuous IV infusions in various dose cohorts were analyzed for changes in liver enzymes, first-dose parameters, peripheral blood cell subpopulations, and cytokine/granzyme B release. Associations with clinical response were evaluated.ResultsLiver enzymes and inflammatory parameters transiently increased primarily during the first treatment week without clinical symptoms and reversed to baseline levels thereafter. B and T cells showed expected depletion and redistribution kinetics, respectively. Similarly, thrombocytes and T cells displayed an initial decline in cell counts, whereas neutrophils peaked during the first days after infusion start. T-cell redistribution coincided with upregulation of LFA-1 and CD69. Patients who responded to blinatumomab had more pronounced T-cell expansion, which was associated with proliferation of CD4+ and CD8+ T cells and memory subsets. Release of cytokines and granzyme B primarily occurred during the first week of cycle 1, except for IL-10, which was released in subsequent cycles. Blinatumomab step-dosing was associated with lower cytokine release and lower body temperature.ConclusionsIn this study of relapsed/refractory ALL, blinatumomab-induced changes in laboratory parameters were transient and reversible. The evaluated PD markers demonstrated blinatumomab activity, and the analysis of cytokines supported the rationale for stepwise dosing.(ClinicalTrials.gov Identifier NCT01209286.)
Highlights
Blinatumomab has shown a remission rate of 69% in an exploratory single-arm, phase II dose-escalation study in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL)
The first comprehensive pharmacokinetic (PK) and pharmacodynamic (PD) analysis in response to blinatumomab treatment was conducted in patients who were in complete hematologic remission after receiving treatment for ALL but maintained minimal residual disease (MRD)-positive disease, an indicator of chemotherapy resistance [10]
Pharmacokinetics and anti‐blinatumomab antibodies In this exploratory phase II study, 36 patients with relapsed/refractory ALL received blinatumomab via continuous IV infusion
Summary
Blinatumomab has shown a remission rate of 69% in an exploratory single-arm, phase II dose-escalation study in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). In an exploratory phase II dose-finding study in relapsed/ refractory ALL, 69% of patients achieved complete remission (CR) or CR with partial hematologic recovery (CRh) within two treatment cycles. The first comprehensive pharmacokinetic (PK) and pharmacodynamic (PD) analysis in response to blinatumomab treatment was conducted in patients who were in complete hematologic remission after receiving treatment for ALL but maintained MRD-positive disease, an indicator of chemotherapy resistance [10]. Treatment-induced cytokine release may cause rare events of cytokine release syndrome (CRS), and blinatumomab treatment has been associated with changes in liver enzyme parameters [6, 7]. Detailed serum chemistry, including liver enzymes such as alkaline phosphatase (AP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and gamma-glutamyl transferase (GGT), provides important information on a patient’s liver function in response to drug treatment and may reveal druginduced hepatocellular, cholestatic or mixed liver injury [17,18,19]
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