VOD - SOS in HSCT

VOD/SOS in
HSCT
DIAGNOSIS AND
TREATMENT
Kakada, MD.
Le Tan Dat, MD, Ph.D.
Introduction
1920: VOD first described in South African people, who use
Senecio tea, contaning pyrrolizidine alkaloids. The
terminal venules of the liver in these individuals are
occluded the term veno-occlusive disease
Recently, new term VOD/SOS due to the fact that the
sinusoidal changes are primary events in the pathology of
the disease.
1979: VOD developing after allogeneic SCT was first

described
VOD also has been described in association with
chemotherapeutic agents (actinomycin D, mithramycin,
dacarbazine, cytosine arabinoside, and 6thioguanine), azathioprine, radiotherapy, or liver
Mayo Clin Proc. 2003;78:589-59
transplantation.
Introduction
Nowadays, most VOD is a complication of HSC transplantation
(both allogeneic and autologous), and is considered a
conditioning-related toxicity.
Incidence: 5% - 70%, depending on: the diagnostic criteria, the
population studied (eg, pediatric vs adult), and the differences
in conditioning therapy used.
VOD lead to increase considerably the morbidity and mortality
in patients undergoing SCT.
Pathophysiology
Figure 1. Schematic representation of the hepatic acinus.

In sinusoidal obstruction syndrome, obstruction of the
hepatic sinusoids occurs in
Bone Marrow Transplantation (2015) 50, 781
Figure 2. Sinusoidal obstruction syndrome pathogenesis.
(a) Normal hepatic sinusoid;
(b) sinusoidal endothelial

cells damaged during
conditioning round up
favoring the appearance of
gaps in the sinusoidal
barrier;
Figure 2. Sinusoidal obstruction syndrome pathogenesis

(contd)
(c) RBCs, leucocytes and

cellular debris penetrate into
the space of Disse detaching
the endothelial lining;
(d) the sloughed sinusoidal

lining cells embolize
downstream and obstruct the
sinusoidal flow
(sinusoidal obstruction
syndrome).
https://progressivevod.com
VOD is an unpredictable disease with the potential

to rapidly progress to multiorgan failure (MOF) or
8
even death
Time of onset of VOD and multiorgan failure is based on 190 patients from a prospective cohort evaluation
of 355 consecutive patients. A diagnosis of VOD was made based on the occurrence of 2 of the following
events within 20 days of transplantation: bilirubin >2mg/dL, hepatomegaly or right upper quadrant pain of
hepatic origin, and sudden weight gain (>2% of baseline weight). No other explanation for these signs and
symptoms could be present at the time of diagnosis.
https://progressivevod.com
Diagnosis
Clinical Features
10
The onset of veno-occlusive disease usually occurs prior to

20 days after HSCT, with a peak 12 days posttransplantation.
The clinical symptoms of veno-occlusive disease(VOD):
weight gain ( 2%)
An increase in abdominal circumference (hepatomegaly, right

upper quadrant pain, ascites)
Elevated T and D bilirubin levels
Thrombocytopenia with no detectable cause(transfusionrefractory)
Typical early symptoms include weight gain and hepatomegaly,

followed by edema and ascites,
Establish diagnosis
criteria for VOD
11
Seattle or Baltimore criteria:
modified Seattle criteria
Baltimore criteria
-At least two of the following,

occurring within 20d of
transplantation:
Serum bilirubin > 34 umol/L (>
2mg/dL)
Hepatomegaly with right upper
quadrant pain
> 2% weight gain from baseline
due to fluid retention
Serum bilirubin > 34 umol/L (>

2mg/dL) within 21d of
transplantation AND at least two of
the following:Hepatomegaly
> 5% weight gain from baseline
Ascites
Determine severity
(Seattle criteria)
12
13
Diagnostic techniques
Ultrasonography usually fails to show any parenchymal abnormality

in VOD, but it is more useful in excluding other disorders that can
mimic VOD.
Other findings on ultrasonography include ascites, hepatomegaly,

attenuated hepatic flow, and hepatic vein dilatation.
MRI of liver, , which may complement ultrasonography findings.
Liver biopsy is the definitive method of diagnosis. But take high risk
of bleeding complications.
A decrease in PAI-1(plasminogen activator inhibitor 1) levels has

also been shown correlate with treatment outcome.
Risk Factors for Veno-occlusive

Disease
14
Pretransplantation factors
Transplantation-related factors
-Preexisting liver dysfunction

(elevated transaminases, fibrosis or
cirrhosis, low albumin level)
-Presence of hepatic C viral infection
-Advanced age
-Prior radiation treatment of the
liver1
-Use of vancomycin or acyclovir in
the pretransplantation period
-Previous stem cell transplantation
-Prior therapy with gemtuzumab
ozogamicin (Mylotarg)
-High-dose conditioning regimens

(Busulfan for conditioning, especially
when area under the curve is
>1500 mol min1 L1 and
combined with cyclophosphamide
-TBI associate with
cyclophosphamide
(depends on total dose and
fractionation)
-Grafts from unrelated donors or
related HLA mismatched transplants
-Methotrexate as part of graft-vshost disease prophylaxis
Differential Diagnosis of Venoocclusive Disease
Acute GVHD
Cyclosporine-induced hepatotoxicity
Fungal infiltration
Viral hepatitis, including cytomegalovirus
Sepsis-related cholestasis (cholangitis lenta)
Drug-induced cholestatic hepatitis (fluconazole,
itraconazole,trimethoprim)
Total parenteral nutritionrelated cholestasis
Persistent tumor infiltration into the liver
Congestive heart failure
Neutropenic colitis
15
16
Prophylaxis
Prophylaxis: Ursodiol :
Ursodeoxycholic acid is suggested for use in the prophylaxis of

VOD/ SOS (2C) (British Journal of Haematology, 2013, 163, 444
457)
The randomized controlled trial of ursodiol for prophylaxis were
reported by Essell and al. 67 recipients of allogeneic BMT(Busu
+CyC) received ursodiol 300mg twice daily or placebo until day
+ 80. The incidence of SOS was 40% in placebo compared to
15% in ursodiol recipient(P=0,2). The authors concluded that
ursodiol prophylaxis seemed to decrease hepatic complication
after transplant.
Prostaglandin E1, Pentoxifylline, Heparin (unfractionated and

low molecular weight), antithrombin: all NOT suggested for
use in the prophylaxis of VOD/SOS
Treatment:
17
BCSH/BSBMT guideline
Defibrotide is recommended in the treatment of VOD/SOS in
adults and children (1B).
Tissue plasminogen activator is not recommended for use in
the treatment of VOD/SOS due to the associated risk of
haemorrhage (1B).
N-acetylcysteine is not routinely recommended for use in the
treatment of veno-occlusive disease due to lack of efficacy
(1A).
Methylprednisolone may be considered for use in the
treatment of veno-occlusive disease with the appropriate
caveats of caution regarding infection (2C).
Judicious clinical care, particularly in the management of fluid
balance, is recommended in the management of VOD/SOS
(1C).
British Journal of Haematology, 2013, 163, 444457
Treatment:
Focus on Defibrotide
18
Defibrotide is a single-stranded
polydeoxyribonucleotide that has anti-inflammatory and
antithrobotic properties, has been suggested for
treatment in severe VOD.
This agent appears to have a protective effect against

endothelial cell injury and has not been associated with
an increased bleeding risk despite reducing
procoagulant activity, increasing fibrinolysis and
modulating platelet activity
Table 1: Main studies on defibrotide in SOS/VOD

19
Richard et al : Reported on the use of defibrotide in 20

88 patients with severe VOD and multisystem
organ failure after HSCT.
The patients with median age 35 y were diagnosis by the

Baltimore criteria. Dose administrated IV 5-60mg/kg/day, CR
of SOS reported in 32 patients(36%) with 35% survival at the
day +100. The toxicity reported in grade I/II include
hypotension, fever, abdominal cramping and hot flash.
Biol Blood Marrow Transplant 2010; 16: 10051017.
Results Of The Large Prospective Study On

The Use Of Defibrotide In The Treatment Of
VOD In HSCT: Early Intervention Improves
Outcome (Rechardson PG et al. Blood
(2013)122:700)
21
The current interim analysis is based on 470 VOD pts enrolled

between December 2007 and December 2012 at 75 centers, 45 of
which developed VOD following chemotherapy and 425 had
undergone HSCT(Cyc, bulsu, TBI).
In HSCT patients, median age was 15 yrs; 284 pts had severe disease
at study entry. Median onset of VOD was 15 d post-HSCT. 35%
(147/425) achieved CR and 55% (Kaplan-Meier estimate) survived to
D+100. In pts with sVOD, CR was 29% and D+100 survival was 48%.
For pts with non-severe VOD, CR and D+100 survival was 47% and
69%, respectively. In all HSCT pts, delay of >2 d (vs 2 d) in the start
of DF after VOD diagnosis resulted in reduced CR.
Results Of The Large Prospective Study On

The Use Of Defibrotide In The Treatment Of
VOD In HSCT: Early Intervention Improves
Outcome (Blood (2013)122:700)
22
In the 45 non-HSCT patients, median age was 8 yrs (range 0.163).

Median onset of VOD after chemotherapy was 14 d, and sVOD was
present in 53% of pts at study entry. Of non-HSCT pts, 40% achieved
CR and 62% were alive at D+100. Toxicity proved generally
manageable.
DF therapy in sVOD/MOF pts achieved significantly improved

outcome, early treatment with DF (i.e. within 2 d of VOD diagnosis) is
recommended, and consistently improved outcome was seen in pts
who have not yet progressed to sVOD
23
Conclusion (1)
In summary, our future perspectives in the setting of
VOD / SOS are:
More accurate identification of risk factors;
Definition of new criteria for diagnosis and grading;
Identification of potential biomarkers;
Prospective trials evaluating endothelial syndrome
prevention with defibrotide (DF).
24
Conclusion (2)
Its time to redefine how VOD is viewed
V = Vigilance
over patients at risk for VOD
O = Observation
for signs and symptoms of progressive VOD
D = Detection/Diagnosis
of progressive VOD as soon as possible
25
Thank you!

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VOD/SOS in

1979: VOD developing after allogeneic SCT was first

Figure 1. Schematic representation of the hepatic acinus.

Figure 2. Sinusoidal obstruction syndrome pathogenesis.

(a) Normal hepatic sinusoid;

(b) sinusoidal endothelial

Bone Marrow Transplantation (2015) 50, 781

Figure 2. Sinusoidal obstruction syndrome pathogenesis

(c) RBCs, leucocytes and

(d) the sloughed sinusoidal

VOD is an unpredictable disease with the potential

The onset of veno-occlusive disease usually occurs prior to

weight gain ( 2%)

An increase in abdominal circumference (hepatomegaly, right

Elevated T and D bilirubin levels

Thrombocytopenia with no detectable cause(transfusionrefractory)

Typical early symptoms include weight gain and hepatomegaly,

Seattle or Baltimore criteria:

modified Seattle criteria

-At least two of the following,

Serum bilirubin > 34 umol/L (>

Ultrasonography usually fails to show any parenchymal abnormality

Other findings on ultrasonography include ascites, hepatomegaly,

MRI of liver, , which may complement ultrasonography findings.

A decrease in PAI-1(plasminogen activator inhibitor 1) levels has

Risk Factors for Veno-occlusive

-Preexisting liver dysfunction

-High-dose conditioning regimens

Differential Diagnosis of Venoocclusive Disease

Ursodeoxycholic acid is suggested for use in the prophylaxis of

Prostaglandin E1, Pentoxifylline, Heparin (unfractionated and

British Journal of Haematology, 2013, 163, 444457

This agent appears to have a protective effect against

Table 1: Main studies on defibrotide in SOS/VOD

Bone Marrow Transplantation (2015) 50, 781

Richard et al : Reported on the use of defibrotide in 20

The patients with median age 35 y were diagnosis by the

Biol Blood Marrow Transplant 2010; 16: 10051017.

Results Of The Large Prospective Study On

The current interim analysis is based on 470 VOD pts enrolled

Results Of The Large Prospective Study On

In the 45 non-HSCT patients, median age was 8 yrs (range 0.163).

DF therapy in sVOD/MOF pts achieved significantly improved

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