Risk Factors for Development of and Progression of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

Abstract

A B S T R A C T Veno-occlusive disease, also known as sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of allogeneic or autologous hematopoietic stem cell transplantation (HSCT) most commonly associated with high-intensity chemotherapies. The development of VOD/SOS may be rapid and unpredictable, and the importance of identifying risk factors to facilitate prompt diagnosis and timely treatment has become increasingly recognized. The reporting of new retrospective study data for adults and children and the emergence of novel anticancer therapies that may increase the risk of VOD/SOD also necessitate updates on risk factors, as provided in this review. The latest studies reporting VOD/SOS risk factors support previously published data, although the importance of patient-related factors, such as acute kidney injury, increased international normalized ratio, female sex (in children), and platelet refractoriness, is given greater emphasis in the recent data. Nontransplantation-related chemotherapies associated with increased risk for VOD/SOS include oxaliplatin and 5-fluorouracil chemotherapies. The novel antibody drug conjugates gemtuzumab ozogamicin and inotuzumab ozogamicin are now reported in product labeling to pose risks for VOD/SOS based on clinical trial data; an expert consensus panel has issued recommendations for risk reduction measures with inotuzumab ozogamicin treatment, including VOD/SOS prophylaxis and limitation to 2 inotuzumab ozogamicin treatment cycles. A wide range of biomarkers, including genetic, hematologic, hepatic, and inflammatory factors, as well as novel diagnostic techniques such as thromboelastography and measures of liver stiffness, may further enhance future risk calculation for VOD/SOS, although none has been widely adopted. Continual monitoring for and recognition of VOD/SOS risk factors are essential for optimal management of this complication.

Aberrant von Willebrand factor expression of sinusoidal endothelial cells and quiescence of hepatic stellate cells in nodular regenerative hyperplasia and obliterative portal venopathy

“…Further studies also showed that increased vWF levels can be used as a non‐invasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis 19,33 . It has been known that the pathogenesis of sinusoidal obstructive syndrome, also termed veno‐occlusive disease, involves direct toxic injury to the sinusoidal endothelial cell that triggers endothelial activation and damage in the setting of bone marrow transplantation, especially haematopoietic stem cell transplantation, and the use of oxaliplatin‐based adjuvant or neoadjuvant regimens to treat patients with liver metastatic colorectal cancer 34–36 . The increase of biomarkers of endothelial injury such as vWF can be used to predict sinusoidal obstructive syndrome in bone marrow transplant patients 37,38 .…”

Diagnosis and Treatment of VOD/SOS After Allogeneic Hematopoietic Stem Cell Transplantation

“…Several biomarkers (70) have been proposed for VOD/SOS diagnosis and/or prevention; they are markers of hemostasis and coagulation such as plasminogen activator inhibitor 1 (PAI-1) or other markers of endothelial injury, such as elevated levels of von Willebrand factor, thrombomodulin, soluble intercellular adhesion molecule 1, suppressor of tumorigenicity 2, angiopoietin 2, hyaluronic acid (HA), or markers of inflammation [interleukin 6 (IL-6), IL-10, CD97].…”

“…The authors did not include pretransplant therapies impacting on VOD/SOS, so the applicability of this model to patient receiving either gemtuzumab ozogamicin or inotuzumab ozogamicin is still unknown. Prospective validation of risk factors is yet to be completed and needs further assessment to provide a more precise estimation of the magnitude of each risk factor (70).…”

Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatic SOS/VOD after haematopoietic cell transplantation

“…Reports examining such features often utilise odds ratio data to characterise the degree of risk for each factor associated with this multi‐organ syndrome (Table I). Most importantly, prior and/or current liver dysfunction, prior intense chemo and/or radiotherapy and abnormal busulfan pharmacokinetics have been major factors in the past for increasing the risk of VOD post‐HCT (Dalle & Giralt, 2016; Hwang et al , 2016; Yakushijin et al , 2016; Corbacioglu et al , 2019; Faraci et al , 2019). Importantly, administering high‐dose busulfan prior to high‐dose cyclophosphamide prior to HCT significantly increases the levels of cyclophosphamide metabolites, including hydroxycyclophosphamide and carboxyethylphosphoramide, which is significantly associated with an increased risk of SOS/VOD.…”