Validating Ultrasound Biomarkers for Hepatic Sinusoidal Obstruction Syndrome in Pediatric Hematopoietic Cell Transplant Patients

Validating Ultrasound Biomarkers for Hepatic Sinusoidal Obstruction Syndrome in Pediatric Hematopoietic Cell Transplant Patients

Validating Ultrasound Biomarkers for Hepatic Sinusoidal Obstruction Syndrome in Pediatric Hematopoietic Cell Transplant Patients

Hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is a potentially fatal complication of hematopoietic cell transplant (HCT). Historically VOD/SOS has been clinically diagnosed using the modified Seattle criteria or the Baltimore criteria. The modified Seattle Criteria define VOD/SOS diagnosis is made when two of the following three criteria are present in a patient within 21 days of transplantation: hyperbilirubinemia (total serum bilirubin > 2 mg/dL), hepatomegaly or right upper quadrant liver pain, and weight gain (> 2% of baseline) or ascites. Other conditions like graft versus host disease, sepsis syndrome (fever and hypotension), cardiac failure, or tumor infiltration) have to be excluded. This definition was from a well-designed retrospective cohort study on 255 adult and pediatric HCT patients in which the VOD/SOS incidence was 21%. McDonald et al followed up this work with a prospective cohort study of 355 patients noting an incidence of VOD/SOS of 54%. These seminal studies have had a major impact on the field by defining clinical diagnostic criteria. An alternative diagnostic criteria (Baltimore criteria) was proposed by Jones et al as a part of a well-designed retrospective review of 235 HCT patients finding a VOD/SOS incidence of 22%. Jones defined VOD/SOS as the presence of hyperbilirubinemia (total serum bilirubin > 2 mg/dL) along with at least 2 of 3 other findings: hepatomegaly, ascites, and weight gain (> 5% of baseline).

Hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is a potentially fatal complication of hematopoietic cell transplant (HCT). Historically VOD/SOS has been clinically diagnosed using the modified Seattle criteria or the Baltimore criteria. The modified Seattle Criteria define VOD/SOS diagnosis is made when two of the following three criteria are present in a patient within 21 days of transplantation: hyperbilirubinemia (total serum bilirubin > 2 mg/dL), hepatomegaly or right upper quadrant liver pain, and weight gain (> 2% of baseline) or ascites. Other conditions like graft versus host disease, sepsis syndrome (fever and hypotension), cardiac failure, or tumor infiltration) have to be excluded. This definition was from a well-designed retrospective cohort study on 255 adult and pediatric HCT patients in which the VOD/SOS incidence was 21%. McDonald et al followed up this work with a prospective cohort study of 355 patients noting an incidence of VOD/SOS of 54%. These seminal studies have had a major impact on the field by defining clinical diagnostic criteria. An alternative diagnostic criteria (Baltimore criteria) was proposed by Jones et al (1987) as a part of a well-designed retrospective review of 235 HCT patients finding a VOD/SOS incidence of 22%. Jones defined VOD/SOS as the presence of hyperbilirubinemia (total serum bilirubin > 2 mg/dL) along with at least 2 of 3 other findings: hepatomegaly, ascites, and weight gain (> 5% of baseline). A large well-executed meta-analysis on 24,920 adults and pediatric patients confirms the fact that applying the more stringent Baltimore criteria results in a lower incidence rate for VOD/SOS of 9.6% as compared to 17.3% with the modified Seattle criteria. A major weakness of this large meta-analysis is that it did not perform a separate pediatric incidence. A small retrospective cohort study of 142 pediatric patients (Barker et al, BMT 2003) reported an incidence of 18% using the modified Seattle criteria corroborating the findings from the meta-analysis. VOD/SOS is important to study because the survival rates in severe disease with multi-organ failure are very low. Day 100 (post HCT) survival rate for severe VOD/SOS in the meta-analysis was only 16%; most patients died of multi-organ failure. Fortunately, defibrotide seems to be effective in increasing survival rates. Richardson et al (2016) demonstrated in a well-designed and executed phase 3 clinical trial that defibrotide increased day 100 survival in severe VOD/SOS (defined by the Baltimore criteria) with multi-organ failure from 25% to 38%. Weaknesses of this study were that it only included 44 pediatric patients and a historical cohort was used as the control population. A well-designed small, multi-institution, retrospective cohort study in 45 pediatric patients diagnosed with VOD/SOS showed that the complete response rate was 83% in the cohort who started defibrotide treatment within two days of diagnosis and the complete response rate decreased to 10% in patients who started treatment three or more days after clinical diagnosis. A large, well conducted and executed trial of defibrotide involving 101 centers in the USA was also able to confirm this survival benefit. In the 570 pediatric (< 16 years old) patients in this study, the estimated day 100 survival rate was 67.9%. In 512 pediatric and adult patients with VOD/SOS with multi-organ failure, the estimated survival rate was 49.5%. This large study also showed that earlier initiation of defibrotide was associated with increased survival, especially if treatment could be initiated within day 2 after diagnosis. This study lacked a control arm for comparison but historical data showing a survival rate of 16% can again serve as a control here. In 2017 the European society for Blood and Marrow Transplantation (EBMT) consortium proposed VOD/SOS diagnostic and severity grading criteria specifically for children, which are not distinguished as separate in the Baltimore or Seattle criteria (Corbacioglu et al, 2017). These criteria highlight how VOD/SOS in children differs from adults. Unlike the Baltimore or modified Seattle criteria, EBMT criteria have no time limitation for the diagnosis. The EBMT criteria reinforces the fact that hyperbilirubinemia in children is a late finding. The EBMT proposed grading of severity into four categories: mild, moderate, severe and very severe VOD/SOS. Defibrotide has been investigated and has shown benefit primarily as treatment for VOD/SOS with multi-organ failure, which corresponds to severe and very severe disease by the EBMT severity grading. The weakness of these criteria is that they are not yet tested, but this is something we also aim to do with the proposed research. One of the greatest clinical challenges is determining which patients will progress to severe disease, so that specific therapy can be initiated early. Currently, no clinical, laboratory or imaging biomarkers can reliably differentiate VOD/SOS from other HCT complications. Additionally, there is no biomarker that can reliably differentiate VOD/SOS patients who will go on to develop severe or very severe disease versus VOD/SOS patients who never progress to those severe disease states. Therefore, this research is timely because the investigator's preliminary data reviewed below show that promising imaging biomarkers may be available that can diagnose VOD/SOS earlier than current clinical criteria. These biomarkers could help refine the clinical criteria to allow earlier diagnosis of VOD/SOS, thereby allowing earlier initiation of specific therapy which can help decrease the high mortality from severe VOD/SOS. Additionally, if these biomarkers could identify the VOD/SOS patients at risk of progression to severe or very severe VOD/SOS, this therapy could even be more targeted. 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 grayscale US, Doppler US, US SWE and CEUS within 30 days prior to starting their conditioning regimen. US Schedule (All exams can be performed +/- 2 days compared to the prescribed date): Baseline exam: one time within 30 days before start of conditioning (~Day -9). Inpatient exams: Day -3, day +3, day +7, day + 10, day +17, day +24, day +31, day +60 and day +90 after HCT. If the patient is discharged earlier than day +100 from the HCT admission, then all exams after the discharge day will be canceled. Concern for VOD/SOS: If the HCT team is suspecting VOD/SOS a patient admitted for HCT, then US will be performed twice a week during the time of concern for VOD/SOS.

Sinusoidal Obstruction Syndrome, Veno Occlusive Disease, Hepatic, Bone Marrow Transplant Complications, Stem Cell Transplant Complications

All patients undergoing myeloblative conditioning regimen as part of hematopoietic cell transplant or prior liver damage or other high risk factor will be consecutively studied

All patients enrolled will undergo grayscale US, Doppler US, US SWE and CEUS at specific time points as outlined in the protocol based on disease course.

Define Sensitivity and Specificity of US (grayscale, Doppler and SWE) for Diagnosis and Severity Grading for SOS/VOD

Determine the sensitivity and specificity of US for diagnosis and severity grading of VOD/SOS in a cohort of 250 pediatric HCT patients.

Determine the sensitivity and specificity of contrast enhanced ultrasound (CEUS) variables for diagnosis and severity grading of VOD/SOS as compared to the pediatric EBMT criteria.

Determine the optimal timing for ultrasound measurements to help predict early diagnosis and risk stratification of VOD/SOS.

Inclusion Criteria: HCT patient under 25 years of age with myeloablative conditioning, prior liver damage or other high risk factor: Neuroblastoma, HLH, Osteopetrosis, Thalassemia, Treatment with inotuzumab or gemtuzumab within 3 months prior to HCT admission, Hepatic iron overload, Steatohepatitis, Active inflammatory or infection hepatitis or Any other condition which puts the patient at a higher risk of developing VOD). Exclusion Criteria: Any patient who has contraindication to any of the ultrasound procedures (e.g. unable to hold still).

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