Pathogenesis-Based Development of Potential Mitigation Strategies for Blinatumomab-Associated Neurologic Events (NEs)

Introduction: Blinatumomab (blin), a CD19/CD3 bispecific T-cell engager (BiTE^®) antibody construct, has shown clinical efficacy in patients with both B-precursor acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma (NHL). NEs are known blin-associated adverse drug reactions; most NEs occur early during the first treatment cycle and are transient and fully reversible. While NEs are manageable in ALL (favorable risk/benefit profile at a maximum target dose of 28 µg/day), NEs increase in frequency and were dose-limiting in low-grade NHL. The maximum tolerated dose in NHL was 112 µg/day. Here we present translational and single-patient data for potential mitigation strategies for blin-associated NEs.

Methods: Pharmacokinetic and pharmacodynamic data from blin clinical studies in NHL and ALL were combined to develop a pathogenetic model for blin-associated NEs. The mitigation potential of substances with antiadhesive properties was studied in vitro in a flow chamber system mimicking blin-induced T-cell redistribution. Three patients with low-grade NHL who had a higher risk of developing NEs due to their low peripheral blood B/T-cell ratios received concomitant pentosan polysulfate (PPS) at infusion start and dose step. ClinicalTrials.gov NCT00274742, NCT00560794, NCT01209286, NCT01471782.

Results: T-cell redistribution occurred at infusion start and dose step of blin irrespective of circulating B cells. Concurrently, T cells upregulated the activation marker CD69 and the T-cell adhesion molecule LFA-1 switched from its low to intermediate affinity isoform as shown by binding of soluble ICAM-1. Blood vessel endothelial cells were activated as indicated by release of angiopoietin-2 and clinical signs of peripheral edema. Monocyte and thrombocyte redistribution were also observed. Both B and T cells were detected in cerebrospinal fluid (CSF) of some patients with NEs, and quantifiable blin concentrations were measured in CSF of some patients independent of blood-CSF barrier integrity. A low B/T-cell ratio in peripheral blood (NHL) and/or bone marrow (ALL) has been identified as a potential risk factor for developing NEs. In flow chamber experiments, addition of blin mimicked T-cell redistribution as indicated by reduced T-cell rolling velocity and increased T-cell adhesion to brain microvascular endothelial cells and by upregulation of P-selectin and ICAM-1 adhesion molecules on endothelial cells. Substances potentially interfering with interactions between T cells and endothelial cells (eg, PPS, minocycline) reversed the above-described effects to levels seen without the addition of blin. T-cell kinetics of three patients receiving concomitant PPS at infusion start and dose step showed delayed T-cell redistribution (without circulating B cells) compared with patients without PPS coadministration. These altered T-cell kinetics correlated with less severe NEs; no treatment interruptions or discontinuations were necessary. Finite PPS coadministration had no apparent negative impact on clinical response as two patients achieved an objective response, including one patient who has been in ongoing remission for more than six years.

Conclusion: We propose an evidence-based model for the development of blin-associated NEs: 1) First exposure to blin or dose steps increase endothelial adhesiveness of circulating T cells. 2) Adhering T cells activate the endothelium and start extravasating; activated endothelium attracts other circulating leukocytes. 3) At low B/T-cell ratios, extravasated T cells first encountering (rare) B cells in the brain are activated by blin in the perivascular space to locally secret cytokines and chemokines that induce transient neuroinflammation including transmigration of monocytes. 4) Attracted non-T cells and other released factors enhance transient neurotoxicity. Based on this model, T-cell adhesion to blood vessel endothelial cells is the first necessary (but not sufficient) step in the pathogenesis of blin-associated NEs. Coadministration of substances with antiadhesive properties at infusion start and dose steps may offer opportunities to mitigate blin-associated NEs to further improve the safety and efficacy of blin therapy.