Using Ultrasound Elastography to Predict Development of Hepatic Sinusoidal Obstruction Syndrome
Using Ultrasound Elastography to Predict Development of Hepatic Sinusoidal Obstruction Syndrome
To perform an receiver operating characteristic (ROC) analysis, define a threshold and
 quantify the sensitivity and specificity of US SWE for risk stratification of patients into
 three categories as defined by the European Bone Marrow Transplant (EBMT) adult and pediatric
 criteria: no sinusoidal obstruction syndrome (SOS), mild to moderate SOS, and severe to very
 severe SOS. Secondarily, the investigators would also like to quantify the temporal
 relationship between US SWE changes and SOS diagnosis according to various clinical criteria
 (Modified Seattle, Baltimore, EBMT consortium).
Hepatic sinusoidal obstructive syndrome (SOS), also known as veno-occlusive disease, is a
 complication of hematopoietic stem cell transplant (HCT) that is associated with high
 morbidity and mortality. 57,000 patients in the United States and Europe undergo HCT 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 HCT. 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 not
 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.

 SOS is most commonly defined by two clinical criteria: the modified Seattle criteria and the
 Baltimore criteria. The modified Seattle criteria state that at least two of the following
 criteria must be present within 20 days of HCT: bilirubin > 2mg/dL; hepatomegaly and/or
 ascites; and/or weight gain > 5% above baseline weight (6). Pediatric SOS incidence in HCT 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 HCT.
 However, the European Society for Blood and Marrow Transplantation has proposed new
 prospective SOS diagnosis and grading schemes that could become standard of care since it can
 be performed prospectively and thus can guide treatment.

 Defibrotide 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 (14). 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 difficult due to high drug costs
 ($155,000 for 21-day course). 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.

 The investigators of this study recently conducted a single site prospective cohort study
 involving 25 patients undergoing myeloblative HCT patients from December 2015 through June
 2017. The investigators found increased velocities in all patients who developed SOS. US SWE
 velocity values showed no difference between pre-conditioning median US SWE velocity in the
 SOS group (1.24 + 0.09 m/s) and non-SOS group (1.41 + 0.18 m/s) (p=0.06). By day +5, patients
 with SOS had US SWE velocities that significantly increased by 0.25 + 0.21 m/s from baseline
 compared to 0.02 + 0.18 m/s in patients without SOS from baseline (p=0.02). By day +14,
 patients with SOS had US SWE velocities that significantly increased by 0.91 + 1.14 m/s from
 baseline compared to 0.03 + 0.23 m/s in patients without SOS from baseline (0.01). These
 values are both clinically and statistically significant, demonstrating that patients with
 SOS have significantly increased liver stiffness as measured by US SWE compared to patients
 without SOS. Additionally, SWE changes happened on average 9 to 11 days before clinical
 diagnostic criteria became positive. The sensitivity and specificity of this test were 60-80%
 and 67-93% in our small cohort of 25 patients depending on the threshold used and the test
 timing.

 Data Collection Procedures: Candidates for the study will be identified by a HCT 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.

 Consented subjects will have an US SWE within two weeks prior to starting their conditioning
 regimen and at the following time points based on disease course:

 1. All Patients: patients will undergo ultrasound elastography within two-weeks prior to
 admission for conditioning AND twice per week through Day +30 or discharge, whichever
 comes first.

 Patients whom are still an inpatient after Day +30, and are not clinically suspicious
 for SOS/VOD, will undergo ultrasound elastography every 30 days (Day +60 and Day +90)
 until discharge.

 2. Late Onset SOS/VOD as INPATIENT (AFTER DAY +30): patients will undergo ultrasound
 elastography twice a week during course of SOS/VOD treatment. If patient is still
 admitted at end of treatment, patient will undergo ultrasound elastography once every 30
 days through day +100 or discharge, whichever comes first.

 3. Late Onset SOS/VOD as OUTPATIENT (DAY +30 - DAY + 100): patients will undergo ultrasound
 elastography once a week during course of SOS/VOD treatment
Inclusion Criteria:

 -  Any patient undergoing a myeloablative conditioning regimen for HCT between 4/1/2019
 and 12/31/2120 defined as one of the following:

 -  TBI >= 1200 cGy (fractionated)

 -  Cyclophosphamide + TBI (> 500 cGy (single) or > 800cGy (fractionated))

 -  Cyclophosphamide + Etoposide + TBI (> 500 cGy (single) or > 800 cGy
 (fractionated))

 -  Cyclophosphamide + Thiotepa + TBI (> 500 cGy (single) or > 800 cGy
 (fractionated))

 -  Busulfan (Total dose > 7.2 mg/kg IV or >9.0mg/kg orally) + Cyclophosphamide

 -  Busulfan (Total dose >7.2 mg/kg IV or >9.0 mg/kg orally) + Melphalan

 -  Busulfan (Total dose >7.2 mg/kg IV or >9.0 mg/kg orally) + Thiotepa

 -  NOTE: Busulfan cumulative plasma AUC of >75 mg/L per hour or >18270 microMolar
 per minute could be used in the preceding criteria in lieu of the mg/kg doses.

 OR

 2. Any patient who has a myeloablative conditioning regimen (as defined by the local HSCT
 team) that includes sirolimus and tacrolimus for GVHD prophylaxis.

 OR

 3. Any patient who is high risk for SOS irrespective of conditioning regimen:
 Neuroblastoma, HLH, Osteopetrosis, Thalassemia, treatment with inotuzumab or gemtuzumab
 within 3 months prior to HSCT admission, 2nd HSCT if it is myeloablative and within 6
 months of prior, iron overload, steatohepatitis, active inflammatory or infection hepatitis
 or any other condition which puts the patient at a higher risk of developing SOS.

 Exclusion Criteria:

 -  Any patient who has contraindication to US SWE (e.g. unable to hold still)