Using Ultrasound Elastography to Predict Development of Hepatic Sinusoidal Obstruction Syndrome

Using Ultrasound Elastography to Predict Development of Hepatic Sinusoidal Obstruction Syndrome

Sponsors

Lead sponsor: Children's Mercy Hospital Kansas City

Collaborator: Jazz Pharmaceuticals
Nationwide Children's Hospital
Dana-Farber Cancer Institute
University of California, San Francisco
M.D. Anderson Cancer Center
University Hospitals Cleveland Medical Center
St. Jude Children's Research Hospital

Source Children's Mercy Hospital Kansas City
Brief Summary

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).

Detailed Description

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

Overall Status Recruiting
Start Date April 1, 2019
Completion Date June 30, 2021
Primary Completion Date December 31, 2020
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
Define Sensitivity and Specificity Threshold for US SWE Risk 100 days post transplant
Secondary Outcome
Measure Time Frame
Quantify Temporal Relationship between SWE and SOS and Modified Seattle Criteria 100 days post transplant
Quantify Temporal Relationship between SWE and SOS and Baltimore Criteria 100 days post transplant
Quantify Temporal Relationship between SWE and SOS and EBMT Consortium 100 days post transplant
Enrollment 250
Condition
Intervention

Intervention type: Diagnostic Test

Intervention name: Ultrasound Elastography

Description: Ultrasound shear wave elastography

Arm group label: Patients Undergoing HCT

Eligibility

Criteria:

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)

Gender: All

Minimum age: 1 Month

Maximum age: 99 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Sherwin S Chan, MD, PhD Principal Investigator Children's Mercy Hospital Kansas City
Overall Contact

Last name: Amie Robinson, BSRT,CCRP

Phone: 8163028311

Email: [email protected]

Location
facility status contact contact_backup investigator
Amie Robinson Recruiting Amie Robinson 816-302-8311 [email protected] Sherwin S Chan, MD, PhD Principal Investigator
Location Countries

United States

Verification Date

January 2020

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Arm group label: Patients Undergoing HCT

Arm group type: Experimental

Description: All patients enrolled will undergo US SWE at specific time points as outlined in the protocol based on disease course.

Patient Data No
Study Design Info

Allocation: N/A

Intervention model: Single Group Assignment

Intervention model description: All patients undergoing myeloblative conditioning regimen as part of h ematopoietic cell transplant will be consecutively studied

Primary purpose: Diagnostic

Masking: None (Open Label)

Source: ClinicalTrials.gov