Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Diagnostic Patterns Among United States and European Union Hematologists and Oncologists Managing Patients Receiving Stem Cell Transplantation
Authors: Corn Tim , Ogram Peter , Doede Tina 
Published: October 2019

Abstract
Introduction
Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially fatal complication of hematopoietic stem cell transplantation (HSCT) and high-dose chemotherapy. The VOD/SOS pathologic cascade is initiated by endothelial and hepatocyte damage. VOD/SOS is usually diagnosed using Baltimore criteria (≤21 days post transplant: bilirubin >2 mg/dL, plus 2 or more of hepatomegaly, ascites, and weight gain ≥5%) or modified Seattle criteria (≤20 days post transplant: 2 or more of bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain >2%). Severe VOD/SOS, usually characterized by multi-organ dysfunction (ie, pulmonary and/or renal dysfunction), may develop in a substantial number of high-risk patients and may be associated with >80% mortality.
To understand the diagnostic patterns for VOD/SOS in the United States (US) and European Union (EU), a quantitative online survey was conducted among HSCT specialists.
Methods
Participating hematology-oncology specialists for pediatric and adult patients had ≥2 years direct involvement in performing HSCT, spent ≥25% of their time in direct patient care, and managed ≥10 HSCT patients (≥10 allogeneic) in the past year. Their facilities were accredited and performed ≥80 adult HSCT procedures in the US (≥50 in the EU) or ≥20 pediatric HSCT procedures (US or EU). In this survey, VOD/SOS severity was rated as early (milder) or severe (with multi-organ dysfunction). On average, the online survey took 30 to 40 minutes to complete.
Results
Surveys were completed by 100 US physicians (70 adult, 30 pediatric) and 153 EU physicians (122 adult, 31 pediatric; from France, Germany, Italy, Spain, and the United Kingdom). Each physician directly managed an average of 179 (US) or 95 (EU) HSCT patients in the past year. In adult patients, the median percentages of patients treated for severe/early VOD/SOS were 7%/7% in the US and 3%/6% in the EU; in pediatric patients, the median percentages were 9%/12% in the US and 5%/10% in the EU.
The most commonly used VOD/SOS diagnostic signs and symptoms (Table) were weight gain and bilirubin level. The median level of weight gain to trigger follow-up action (action not specified but could include further diagnostic testing) was 10% in the US and 5% in the EU, for both adult and pediatric patients; the Baltimore and Seattle criteria specify a weight gain of 5% and 2%, respectively. US physicians were less likely than EU physicians to take action at weight gain of ≤5% (Figure): about half as likely for adults (29% vs 56%) and about a fifth as likely for pediatric patients (14% vs 67%). In addition, at ≤5% weight gain, US physicians of pediatric patients were about twice as likely to take action as US physicians of adult patients. The median bilirubin levels at which US physicians initiated action were 3 mg/dL in adults and 4 mg/dL in pediatric patients, compared with 2 mg/dL for EU physicians in both adult and pediatric patients (Figure); the Baltimore and modified Seattle criteria specify a bilirubin level of 2 mg/dL.
Conclusions
The survey results show that a substantial proportion of US HSCT physicians take follow-up action at weight gain or bilirubin thresholds higher than those in the Baltimore or modified Seattle criteria. Treatment patterns in the EU, particularly among pediatric physicians, appear to be more closely aligned with the diagnostic criteria. The established criteria have limitations; neither set takes into account late onset of VOD/SOS or presentation of edema and weight gain in the absence of other signs and symptoms. As discussed in a recent publication (Mohty M et al. BMT. 2015;50[6]:781-789), elevated bilirubin may be absent in VOD/SOS developing late after HSCT and in children, which prompted the authors to suggest the need for a criteria update.
Support: Jazz Pharmaceuticals. Participants received financial remuneration for their survey participation.
Table. VOD/SOS Assessment Measures Used by Physicians Baltimore/Seattle Item US(n=95), % EU(n=152), % Weight increase Y 50 78* Bilirubin increase Y 46 62* Hepatomegaly Y 36 57* Ascites Y 36 49* Ultrasound 27 47* Liver Doppler 23 29 Pain Y 16 29* Jaundice Y 25 28 Liver function Y 25 26 Distention/Swelling Y 22 18 *P <.05 vs US.
Figure 1. Figure 1.

Disclosures
Corn: Jazz Pharmaceuticals: Employment, Equity Ownership. Ogram:Jazz Pharmaceuticals: Employment, Equity Ownership. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership.