Using Ultrasound Elastography to Predict Development of Hepatic Sinusoidal Obstruction Syndrome

January 24, 2024 updated by: Sherwin Chan MD PhD, Children's Mercy Hospital Kansas City
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).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 myeloablative 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

Study Type

Interventional

Enrollment (Estimated)

250

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Maura Sien, MSML, CCRC
  • Phone Number: 8163028311
  • Email: mesien@cmh.edu

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94143
        • Recruiting
        • University of California, San Francisco
        • Principal Investigator:
          • Christine Higham, MD
        • Contact:
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Recruiting
        • Children's Mercy
        • Principal Investigator:
          • Sherwin S Chan, MD, PhD
        • Contact:
    • North Carolina
      • Durham, North Carolina, United States, 27705
        • Not yet recruiting
        • Duke University
        • Contact:
          • Mustafa Bashir, MD
    • Ohio
      • Cleveland, Ohio, United States, 44106
      • Columbus, Ohio, United States, 43205
    • Tennessee
      • Memphis, Tennessee, United States, 38105
        • Completed
        • St. Jude Children's Research Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 month to 99 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Any patient undergoing a myeloablative conditioning regimen for HCT between 3/1/2019 and 12/31/2025 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 HCT 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 HCT admission, 2nd HCT 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.

Subjects aged 1 month through 99 years will be eligible for the study. Patients who receive defibrotide and/or ursodiol for VOD/SOS prophylaxis will also be eligible for the study. At most 175 children (ages 1 month to 18 years) and 175 adults (>18 years old) can be enrolled into the study.

Inclusion dates: Patients seen between 1/1/2019 and 12/31/2025

Exclusion Criteria:

Any patient who has contraindication to ultrasound shear wave elastography (e.g. unable to hold still) Adults unable to consent Pregnant women Prisoners Wards of the state

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Patients Undergoing HCT
All patients enrolled will undergo US SWE at specific time points as outlined in the protocol based on disease course.
Diagnostic test: Ultrasound Elastography
Ultrasound shear wave elastography

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Define Sensitivity and Specificity Threshold for US SWE Risk
Time Frame: 100 days post transplant
To define a threshold and quantify the sensitivity and specificity of US SWE for risk stratification of patients into three categories as defined by the EBMTC adult and pediatric criteria: no SOS, mild to moderate SOS, and severe to very severe SOS
100 days post transplant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quantify Temporal Relationship between SWE and SOS and Modified Seattle Criteria
Time Frame: 100 days post transplant
Quantify the temporal relationship between US SWE changes and SOS diagnosis according to Modified Seattle Criteria
100 days post transplant
Quantify Temporal Relationship between SWE and SOS and Baltimore Criteria
Time Frame: 100 days post transplant
Quantify the temporal relationship between US SWE changes and SOS diagnosis according to various clinical criteria Baltimore Criteria
100 days post transplant
Quantify Temporal Relationship between SWE and SOS and EBMT Consortium
Time Frame: 100 days post transplant
Quantify the temporal relationship between US SWE changes and SOS diagnosis according to EBMT consortium.
100 days post transplant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's Mercy Hospital Kansas City

Collaborators

Dana-Farber Cancer Institute
Duke University
University of California, San Francisco
Nationwide Children's Hospital
University Hospitals Cleveland Medical Center
Jazz Pharmaceuticals

Investigators

  • Principal Investigator: Sherwin S Chan, MD, PhD, Children's Mercy Hospital Kansas City

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2019

Primary Completion (Estimated)

December 31, 2025

Study Completion (Estimated)

June 30, 2027

Study Registration Dates

First Submitted

March 1, 2019

First Submitted That Met QC Criteria

March 4, 2019

First Posted (Actual)

March 7, 2019

Study Record Updates

Last Update Posted (Actual)

January 25, 2024

Last Update Submitted That Met QC Criteria

January 24, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY0000548

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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