Stem Cell Transplant Complications Clinical Trial
Official title:
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.
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