Ultrasound Elastography to Predict Development of SOS

Hepatic sinusoidal obstructive syndrome (SOS) is a complication of blood and marrow
transplant (BMT) that is associated with high morbidity and mortality. 57,000 patients in the
United States and Europe undergo BMT annually, and SOS affects up to 15% of these patients.
SOS pathogenesis is thought to be caused by damage to the hepatic venous endothelium due to
the preparative regimen used before BMT. This damage results in obstruction of blood flow
through the liver. Pathology shows collagen deposition in the sinusoids and fibrosis of
venous lumens. The severity of the disease is correlated to the number and severity of the
histological changes. Mild and moderate SOS can resolve with supportive treatment. Severe SOS
(30% of SOS) is commonly associated with multi-organ failure and has a mortality rate of 80%
despite available prophylaxis and treatment (Table 1).

SOS is most commonly defined by two clinical criteria: the modified Seattle criteria and the
Baltimore criteria (Table 2). The modified Seattle criteria state that at least two of the
following criteria must be present within 20 days of BMT: bilirubin > 2mg/dL; hepatomegaly
and/or ascites; and/or weight gain > 5% above baseline weight. Pediatric SOS incidence in BMT
is 20% and is higher compared to adults. Death or multi-organ dysfunction affects 30-60%
children who develop SOS. The most common definition of severe SOS is retrospective, namely
death from SOS-related causes or persistent multi-organ dysfunction at 100 days post BMT.
However, the European Society for Blood and Marrow Transplantation has proposed a new
prospective SOS grading scheme that will likely become standard of care since it is pediatric
patient specific and it is can be performed prospectively and thus can guide treatment.

Recently, a promising drug for SOS treatment has been discovered, defibrotide, which is a DNA
derivative from porcine intestine that protects and repairs endothelial cells. Prior trials
showed that defibrotide decreased the incidence of multi-organ failure and death from SOS.
The main caveat is that treatment must be initiated very close to the time of clinical
diagnosis using the Baltimore criteria to be effective. A study showed that 31/33 (94%)
patients had complete remission of their SOS when treated with defibrotide <3 days after
diagnosis, whereas only 3/12 (25%) patients had complete remission when treated >3 days of
diagnosis. However, universal prophylaxis is infeasible due to high drug costs ($155,000 for
patient) (2016). There is a critical need for an early and effective SOS diagnostic test that
can identify patients who would benefit from defibrotide treatment.

Several adult and pediatric prospective studies have evaluated the efficacy of grayscale and
Doppler ultrasound (US) in diagnosing SOS and have concluded that the clinical criteria are
superior to US criteria for SOS diagnosis. The main reason for this conclusion is that
conventional US is able to diagnose SOS only after the clinical diagnosis. This research has
resulted in multiple recent guidelines recommending US only for confirming clinical diagnoses
or following disease progression and not for primary diagnosis. Ultrasound shear wave
elastography (SWE) has been shown to effectively diagnose passive hepatic congestion. Fontan
physiology is the best studied example. SWE values markedly increased after the Fontan
operation. This surgery connects the hepatic venous circulation to the pulmonary arteries
exposing the liver to increased resistance from the pulmonary circulation thereby increasing
hepatic venous congestion. Additionally, the effect sizes in the Fontan studies are large
compared with the effect sizes in hepatic fibrosis studies. The common thread of hepatic
venous congestion between Fontan physiology and SOS physiology led us to hypothesize that SWE
could be useful in SOS diagnosis. Additionally, preliminary SWE studies in adults showed that
it might be useful in the setting of SOS.

Data Collection Procedures Candidates for the study will be identified by a BMT physician
taking care of the patient and will be identified as a potential candidate for the study.
Subjects will be approached for consent by a member of the research team prior to start of
conditioning regimen. Consented subjects will have demographic, laboratory and clinical data
collected from the chart at each ultrasound time point.

Ultrasound Examinations and Timeline After enrollment and within two weeks prior to starting
their conditioning regimen, a limited abdominal US with Doppler measurements of the hepatic
arteries, hepatic and portal veins, as well as SWE will be performed.

Subjects will be undergo US examinations based on disease course as outlined below:

1. All Patients: Patients will undergo limited abdominal US with Doppler and SWE once a
week upon admission for conditioning until the patient day +30 BMT or discharge,
whichever comes first.

2. Inpatient SOS: patients will undergo limited abdominal US with doppler and SWE once a
week upon admission for conditioning until resolution of SOS.

3. Late Onset SOS: patients will undergo limited abdominal US with Doppler and SWE once a
week upon admission for conditioning until resolution of SOS.

Clinically indicated US and SWE exams for suspicion for SOS will be included in our analysis.
All imaging will be performed using General Electric Logiq E9 US machines by dedicated
pediatric sonographers and interpreted by board-certified pediatric radiologists. Twelve
shear wave velocity measurements will be taken 2-3 cm below the liver capsule at the
mid-clavicular line in the right hepatic lobe and another 12 will be taken in the left
hepatic lobe near midline avoiding areas of vasculature. By necessity, the sonographer and
interpreting radiologist will not be blinded to the clinical status of the patient. US and
clinical data will be collected weekly and managed using REDCap electronic data capture tools
hosted at Children's Mercy Hospital.

Inclusion Criteria:

- Children and adults, ages 1 month through 21 years who are undergoing allogenic or
autologous myeloablative stem cell transplant.

Exclusion Criteria:

- Any other medical or social condition that in the opinion of the investigator would
make them unsuitable to participate.

- Inability to properly image patient by ultrasound (e.g. uncooperative)