Defibrotide: real-world management of veno-occlusive disease/sinusoidal obstructive syndrome after stem cell transplant

Abstract

Hepatic veno-occlusive disease or sinusoidal obstructive syndrome (VOD/SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Defibrotide is the only medication approved by the US Food and Drug Administration for the management of severe VOD/SOS after HSCT. We report our center’s experience with commercially available defibrotide as treatment of patients with VOD/SOS. We retrospectively identified 28 cases of VOD/SOS, based on the European Society for Blood and Marrow Transplantation criteria, from March 2016 through June 2019. The median day of VOD/SOS onset was 25 days (range, 8-69 days), and defibrotide was initiated on day of diagnosis in 71% of patients. Complete resolution of VOD/SOS occurred in 75% of patients. Day 100 survival was 64% for all HSCT patients and 53% for those with very severe VOD/SOS. Response rates and survival were similar in patients with VOD/SOS after myeloablative or reduced-intensity chemotherapy HSCT. Therapy-related adverse events were mild and included hematuria (43%), epistaxis (18%), and hypotension (11%). Severe hemorrhagic adverse events occurred in 2 patients (pulmonary hemorrhage and upper gastrointestinal hemorrhage; 7%) and both in the setting of progressive VOD/SOS. Early diagnosis, prompt initiation of defibrotide, and minimization of dosing interruptions may be key to successful treatment of VOD/SOS.

Prospective assessment of risk biomarkers of sinusoidal obstruction syndrome after hematopoietic cell transplantation

“…Six out of the ten patients diagnosed with SOS received defibrotide while the other patients were not able to receive the treatment due to contraindications, particularly bleeding. This highlights the importance of early diagnosis based on revised criteria and early intervention (15,16,34).…”

The evolving role of liver sinusoidal endothelial cells in liver health and disease

“…In mouse models, genetic deletion of neutrophils elastase impairs thrombosis, fibrosis, and ameliorates portal hypertention [9] The anticoagulant rivaroxaban improves NO bioavailability and endothelial dysfunction [10] Alcohol-associated liver disease Chronic induction of LSEC CYP2E1 and Hsp90 acetylation decreases HSP90 its interaction with eNOS and reduces NO production Overexpression of histone deacetylase 6 (HDAC6) rescue HSP90 acetylation in LSECs and NO production and endothelial dysfunction [11] Increased LSEC chemokine production and neutrophils recruitment to the liver CXCL1 neutralizing antobody [12] DILI Acetaminophen-induced injury: vWF accumulation enhances hepatic platelet retention and impairs liver repair Blocking vWF or the platelet integrin α IIb β 3 reduces hepatic platelet aggregation and accelerates liver repair [13] Acetaminophen-induced injury: Podaplanin released by macrophage binds to the platelet cognate receptor CLEC-2, enhance platelets sequestration and worsens liver injury Blocking platelet CLEC-2 signaling enhances liver recovery by increasing TNF-α production and reparative hepatic neutrophil recruitment [14] Chemotherapeutic agents and herbal medicines-induced toxic injury: sloughing of the sinusoidal endothelium, infiltration of blood components into the space of Disse, and procoagulant changes all lead to the sinusoidal obstruction syndrome Prophylaxis: low-dose unfractionated heparin and ursodiol [15,16] Treatement: defibrotide [17] Nonalcoholic fatty liver disease…”

“…[15,16] The key role of LSECs in the pathogenesis of sinusoidal obstruction syndrome is also highlighted by the fact that defibrotide, the only Food and Drog administrationapproved therapy, functions by reducing EC activation and promoting fibrinolysis through increased expression of tissue plasminogen activator and thrombomodulin. [17] NAFLD NAFLD, defined by hepatic steatosis in the absence of alcohol consumption, is the most common chronic liver disease worldwide. [161] A subset of patients with NAFLD develop NASH, characterized by excess circulating toxic lipids, along with liver inflammation, and progressive liver fibrosis.…”

“…Although ursodeoxycholic acid is currently the preferred agent for the prevention of sinusoidal obstruction syndrome, recent studies have further implicated thrombosis in this condition by noting that low-dose heparin may be an effective prophylactic strategy by interfering with the procoagulant effects of damaged LSECs that exacerbate sinusoidal obstruction 15,16 . The key role of LSECs in the pathogenesis of sinusoidal obstruction syndrome is also highlighted by the fact that defibrotide, the only Food and Drog administration–approved therapy, functions by reducing EC activation and promoting fibrinolysis through increased expression of tissue plasminogen activator and thrombomodulin 17 …”

Introductory Chapter: RNA Drugs Development and Commercialization

“…siRNA drugs has become invaluable in the field of transplantology, where life-saving hematopoietic stem cell transplantation is accompanied by numerous pre-and posttransplant complications [18,19]. One of the complications is hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS), which has been successfully treated by the drug Defibrotide, which was formulated as a mixture of single-and double-stranded oligonucleotides [20]. Patients who undergo transplantation procedures are often at high risk for GVHD and acute kidney injury, which now can be mitigated by siRNA against p53 mRNA (Teprasiran, Quark-Pharmaceuticals) [21].…”