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Using Ultrasound Elastography to Predict Development of Hepatic Sinusoidal Obstruction Syndrome

Sponsor
Children's Mercy Hospital Kansas City (Other)
Overall Status
Recruiting
CT.gov ID
NCT03865589
Collaborator
Jazz Pharmaceuticals (Industry), Nationwide Children's Hospital (Other), Dana-Farber Cancer Institute (Other), University of California, San Francisco (Other), M.D. Anderson Cancer Center (Other), University Hospitals Cleveland Medical Center (Other), St. Jude Children's Research Hospital (Other), Boston Children's Hospital (Other)
250
Enrollment
1
Location
1
Arm
75
Anticipated Duration (Months)
3.3
Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease Intervention/Treatment Phase
  • Diagnostic Test: Ultrasound Elastography
 N/A

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.

  1. 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.

  2. 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 Design

Study Type:
Interventional
Anticipated Enrollment :
250 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
All patients undergoing myeloblative conditioning regimen as part of hematopoietic cell transplant will be consecutively studiedAll patients undergoing myeloblative conditioning regimen as part of hematopoietic cell transplant will be consecutively studied
Masking:
None (Open Label)
Primary Purpose:
Diagnostic
Official Title:
Using Ultrasound Elastography to Predict Development of Hepatic Sinusoidal Obstruction Syndrome
Actual Study Start Date :
Apr 1, 2019
Anticipated Primary Completion Date :
Dec 31, 2023
Anticipated Study Completion Date :
Jun 30, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

  1. Define Sensitivity and Specificity Threshold for US SWE Risk [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

Secondary Outcome Measures

  1. Quantify Temporal Relationship between SWE and SOS and Modified Seattle Criteria [100 days post transplant]

    Quantify the temporal relationship between US SWE changes and SOS diagnosis according to Modified Seattle Criteria

  2. Quantify Temporal Relationship between SWE and SOS and Baltimore Criteria [100 days post transplant]

    Quantify the temporal relationship between US SWE changes and SOS diagnosis according to various clinical criteria Baltimore Criteria

  3. Quantify Temporal Relationship between SWE and SOS and EBMT Consortium [100 days post transplant]

    Quantify the temporal relationship between US SWE changes and SOS diagnosis according to EBMT consortium.

Eligibility Criteria

Criteria

Ages Eligible for Study:
1 Month to 99 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

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

OR

  1. 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)

Contacts and Locations

Locations

Site City State Country Postal Code
1 Amie Robinson Kansas City Missouri United States 64108

Sponsors and Collaborators

  • Children's Mercy Hospital Kansas City
  • 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
  • Boston Children's Hospital

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
Children's Mercy Hospital Kansas City
ClinicalTrials.gov Identifier:
NCT03865589
Other Study ID Numbers:
  • STUDY0000548
First Posted:
Mar 7, 2019
Last Update Posted:
Oct 28, 2021
Last Verified:
Jun 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Keywords provided by Children's Mercy Hospital Kansas City
Ultrasound Elastography
Additional relevant MeSH terms:
Hepatic Veno-Occlusive Disease
Syndrome

Study Results

No Results Posted as of Oct 28, 2021