Anatomic and Clinical Pathology Characterization of Drug-Induced Sinusoidal Obstruction Syndrome (Veno-Occlusive Disease) in Cynomolgus Macaques

Abstract

Sinusoidal obstruction syndrome (SOS) is a unique form of liver injury that occurs after exposure to chemotherapeutic drugs and toxins. The diagnosis of SOS in humans remains a challenge as the clinical criteria have low specificity and there are no reliable noninvasive biomarkers. The mechanism of injury is believed to be damage to liver endothelial cells, primarily sinusoidal endothelial cells (SECs), which leads to sinusoidal dilation, central venous fibrosis, and/or nodular regeneration. Nonclinical data suggest that this uncommon liver toxicity can be recapitulated in cynomolgus monkeys, and it is critical that pathologists are familiar with its characteristic clinicopathologic features. Elevations in liver enzymes, in particular aspartate aminotransferase, associated with isolated thrombocytopenia, should raise the suspicion of SEC injury for specific drug classes. Characterization of liver microscopic findings in monkeys benefits from the use of appropriate stains, such as reticulin stain, and VEGFR2 and CD34 immunohistochemical (IHC) stains. CD41 IHC demonstrates platelet accumulation in injured sinusoids, the likely cause of thrombocytopenia commonly reported in SOS. In conclusion, this report provides a comprehensive characterization of the pathology findings of drug-induced SOS in monkeys with the objectives of ensuring appropriate nonclinical recognition of the liability and informing clinical development strategy and monitoring.

The Influence of Geographical Origin, Age, Sex, and Animal Husbandry on the Spontaneous Histopathology of Laboratory Cynomolgus Macaques (Macaca Fascicularis): A Contemporary Global and Multisite Review of Historical Control Data

“…31,32 In general, cytokine release stimulates the activation of vascular endothelial cells, which results in a recruitment of leukocytes into the affected tissue in which inflammation and inflammatory infiltrates can occur. 33 In the liver, in particular, sinusoidal leukocytosis and Kupffer cell activation, with or without sinusoid dilatation, platelets or erythrocyte sequestration, or hemosiderin pigment in Kupffer cells may be observed as a nonspecific innate liver response to general cytokine release, 34 in addition to immune complex disease associated with monoclonal antibody therapeutic agents, 35 certain antibody drug conjugates, 36,37 or bispecific T-cell engagers. 38 Many aspects of these liver lesions (sinusoidal leukocytosis, sinusoidal dilation, Kupffer cell activation, and congestion with hemosiderosis) frequently occur spontaneously in macaques with some opportunistic infections, particularly in the GIT (Figures 3 and 4); and diarrhea and soft feces are generally the most common clinical observation observed in these animals.…”

Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery

“…The relevant details of the IHC assay are provided in the Table 3 . The slides were counterstained with hematoxylin, dehydrated in graded alcohol, cleared with xylene, and cover slipped [ 20 ].…”

Select Toxicologic Pathology Case Studies of the Hepatobiliary System

“…Rebecca Kohnken (senior principal pathologist at AbbVie) described a case of sinusoidal obstruction syndrome (SOS) in monkeys resulting from administration of a cytotoxin-bearing antibody-drug conjugate (ADC). 3 The title of her presentation was, “ADC-Associated Liver Sinusoidal Injury in Monkeys.” Histologic features of this toxicity in monkeys include multifocal sinusoidal dilation, midzonal hepatocellular atrophy (Figure 4A), and occasional nodular regenerative hyperplasia (Figure 4B). The proposed pathogenesis of SOS involves initial injury to liver sinusoidal endothelial cells (LSECs), and in this case, it was due to non-target-mediated uptake of the ADC by endocytosis.…”