Bone Marrow Transplantation (2008) 41, 287–291

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ORIGINAL ARTICLE

Successful treatment of hepatic veno-occlusive disease after myeloablative

allogeneic hematopoietic stem cell transplantation by early administration
of a short course of methylprednisolone

A Al Beihany1, H Al Omar1, E Sahovic1, N Chaudhri1, F Al Mohareb1, F Al Sharif1, H Al Zahrani1,

A Al Shanqeeti1, P Seth1, S Zaidi1, M Morshed1, K Al Anazi1, G Mohamed2, M Gyger1 and M Aljurf1
1
King Faisal Cancer Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia and 2Department of
Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Hepatic veno-occlusive disease (VOD) is one of the
most common and important regimen-related toxicities
observed after hematopoietic stem cell transplantation
(HSCT). There are no universally accepted preventative
or therapeutic approaches for VOD. We prospectively
evaluated the safety and efficacy of a short course of
methylprednisolone (MP) in 48 patients undergoing
allogeneic HSCT who were diagnosed with hepatic
VOD. MP was administered at a dose of 0.5 mg/kg i.v.
every 12 h for a total of 14 doses, and then discontinued
without taper. Thirty (63%) patients responded with a
reduction in total serum bilirubin of 50% or more after 10
days of treatment. In univariate analysis, non-responders
had a higher total bilirubin at the start of MP therapy,
more weight gain, evidence of fungal infection and platelet
refractoriness. High SGPT and early engraftment were
significant factors among responders. Twenty-five of the
30 responders survived up to day þ 100, whereas all but
three non-responders died within 100 days post-HSCT,
for a probability of survival of 58% among responders and
10% for non-responders. Prospective comparative studies
are needed to confirm the observed encouraging outcome
of MP therapy for VOD.
Bone Marrow Transplantation (2008) 41, 287–291;
doi:10.1038/sj.bmt.1705896; published online 5 November 2007
Keywords: stem cell transplantation; veno-occlusive dis-
ease; methylprednisolone
unexplained weight gain.1–4 VOD is an important regi-
men-related toxicity observed after hematopoietic stem cell
transplant (HSCT).1–9 VOD is usually diagnosed based on
clinical findings.3,10,11 Patients who meet all the criteria for
VOD but have confounding causes of liver dysfunction, or
meet only one of the criteria for VOD (jaundice or fluid
retention), are considered to have liver dysfunction of
uncertain etiology.3,10,11 The course of VOD ranges from a
mild reversible one to a severe syndrome associated with
multiorgan failure.1–4 Treatment is usually supportive, as
approximately half of the patients with uncomplicated
VOD ultimately recover spontaneously.12
The precise sequence of events leading to the develop-
ment of VOD is unknown. Cytokines such as TNF-a and
IL-1, which are produced by macrophages and other
reticuloendothelial cells in response to cytotoxic therapy,
infection, ionizing radiation and hypoxia have cellular
effects, which suggest that they play a major role in the
development of VOD.1,13–18 Corticosteroids are potent
inhibitors of cytokines and, therefore, could potentially
have a role in the treatment of VOD.1,2,13 In this study we
have tested the safety and efficacy of the administration of
a short course of methylprednisolone (MP) for the
treatment of VOD.
Materials and methods

Introduction
Hepatic veno-occlusive disease (VOD) is a clinical
syndrome characterized by painful hepatomegaly, jaundice,
ascites and fluid retention manifested by otherwise
Correspondence: Dr M Aljurf, King Faisal Cancer Center, King Faisal
Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211,
Saudi Arabia.
E-mail: maljurf@kfshrc.edu.sa
Received 7 December 2006; revised 8 May 2007; accepted 5 June 2007;
published online 5 November 2007
Study population
From January 1997 to December 2002, a total of 325
allogeneic HSCT procedures were performed at our center.
Forty-eight (15%) patients were diagnosed as having
hepatic VOD. The diagnosis of VOD was established
based on the Seattle criteria that require the presence of two
of the following before day 30 post transplantation:
jaundice, hepatomegaly and/or right upper quadrant pain,
ascites and/or unexplained weight gain.3 Other causes of
liver dysfunction were excluded by careful clinical and
laboratory evaluation, including physical examination,
hepatitis serology, routine cultures, fungal culture and liver
sonography. At the same time, hepatic drug toxicity
was always entertained as a possible differential diagnosis.
 Steroid therapy for VOD following stem cell transplantation
A Al Beihany et al
288
A liver biopsy and hepatic venous pressure gradient
measurement were not routinely performed for all patients.
The Bearman model was used to assess the severity of
VOD.19
Evaluation of therapy-related complications
Known early toxicities of high-dose MP including hyper-
glycemia, hypertension, psychosis, sepsis, fungal infection
and episode of severe bleeding were evaluated in all patients
from the day MP started to day þ 100 or until death.

Treatment design Statistical methods

Once the patient was diagnosed with VOD, MP was
administered at a dose of 0.5 mg/kg. i.v. every 12 h for a
total of 14 doses, then discontinued without taper. Other
concurrent therapies for VOD such as heparin, tPA,
warfarin or non-steroidal anti-inflammatory drugs were
not permitted. All patients received supportive care,
including diuretics for fluid mobilization and narcotics for
pain control as needed. Complications such as encephalo-
pathy and/or single or multiorgan failure were managed
according to standard medical practice.
Categorical variables were summarized as frequencies and
percentages whereas continuous variables were presented as
mean (s.d.) or median and range. Treatment duration and
factors that may influence response to therapy were further
compared in responders and non-responders using Fisher’s
exact test and the Mann–Whitney U-test for categorical
and continuous variables, respectively. The Kaplan–Meier
method was used to construct survival plots of time to
death from VOD and survival curves were compared by the
log-rank test. A P-value o0.05 was considered significant.

Patient monitoring
In addition to history and physical examination, each Results
patient was followed with serial laboratory studies includ-
ing complete blood count, total serum bilirubin, alkaline Patient characteristics
phosphatase, serum glutamic oxaloacetic transaminase, Table 1 summarizes demographic characteristics, under-
serum glutamic pyruvic transaminase (SGPT), serum lying diagnoses and transplantation information for the 48
creatinine, blood urea nitrogen (BUN) and electrolytes, patients who received MP for the treatment of VOD.
prothrombin time, activated partial thromboplastin time, GVHD prophylaxis consisted of CYA and short course of
fibrinogen, fibrinogen degradation product (FDP) and MTX (15 mg/m2 on day 1, 10 mg/m2 on days 3 and 6) for
appropriate blood cultures. Blood glucose was monitored all patients. Acute GVHD was observed in 25% of patients
for the evidence of hyperglycemia, which was treated with at a median of 26 days (range 20–65) and was not
insulin as necessary. Time of onset of VOD was defined as significantly different between responders and non-respon-
the first day the patient fulfilled the diagnostic criteria ders (P ¼ 0.73) (Table 2). Antimicrobial prophylaxis con-
outlined above. sisted of i.v. acyclovir in addition to oral fluconazole, which
was routinely discontinued with the earliest sign of liver
function abnormality. One patient was seropositive for
Evaluation of multiorgan failure (MOF) and major hepatitis B virus and another patient was positive
bleeding for hepatitis C virus. Seventy nine percent of all patients
Patients were considered to have MOF if there was
documentation of dysfunction of one other system in
addition to the liver. Renal dysfunction was defined as a Table 1 Patient characteristics and risk factors
doubling of admission baseline creatinine or dialysis Number 48
dependence; pulmonary dysfunction was defined by the Male 50%
need for supplemental oxygen and/or documentation of
hypoxemia by arterial blood gas determination or the need Diagnosis
ALL 11
for mechanical ventilation; and central nervous system AML 13
dysfunction was defined by the attending physician CML 17
documentation of confusion, lethargy, delirium and/or MDS 6
coma. Major bleeding was defined as any bleeding in the Lymphoma 1
CNS or lung or requirement of X2 units of RBCs per day Preparative regimen
for two consecutive days. BuCy2 36 (75%)
Cy-TBI 12 (25%)

Definition of response Source of stem cells

Marrow 42 (88%)
Response to high-dose MP was defined as a reduction in Blood 6 (13%)
total serum bilirubin by 50% or more within 10 days of the
initiation of treatment as described by Bearman et al.20 HLA match
Clinical improvement with fluid mobilization, weight Matched sibling 47
Mismatched sibling 1
reduction, improved coagulopathy and/or reduction of
other organ dysfunction was not used to confirm response Abbreviations: Bu ¼ oral busulfan 1 mg/kg q6h  16 doses; Cy ¼ cyclopho-
as traditional supportive therapies such as diuretics, dialysis sphamide 60 mg/kg IV daily  2 days; TBI ¼ total body irradiation
and respiratory support may influence these parameters. 1200 rads given in 6 fractions over 3 days.

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 Steroid therapy for VOD following stem cell transplantation
A Al Beihany et al
289
Table 2 Characteristics of responders and non-responders
Parameters All patients Responders Non-responders P-value
N ¼ 48 N ¼ 30 N ¼ 18

Days post-transplant to VOD diagnosis (median, range) 13 (3–34) 14 (7–22) 13 (3–34) 1

Days post-transplant to start of MP (median, range) 13.5 (3–34) 14 (7–23) 13 (3–34) 0.814
% weight gain at start of MP (median, range) 2.5 (0–7.5) 2.5 (0–7.5) 7.5 (2.5–7.5) 0.023
Evidence of ascites at start of MP 24 (50%) 12 (40%) 12 (67%) 0.068
Total bilirubin at start of MP (ı̀mol/L) (median, range) 164 (38–1169) 124 (38–432) 303.5 (111–1169) 0.0001
Elevated SGPT at start of MP 17 (35%) 14 (47%) 3 (17%) 0.034
Elevated alkaline phosphatase at start of MP 18 (38%) 13 (43%) 5 (28%) 0.22
Elevated SGOT at start of MP 15 (31%) 11 (37%) 4 (22%) 0.23
Acute GVHD 12 (25%) 8 (27%) 4 (22%) 0.731
Abnormal serum creatinine at start of MP 22 (46%) 11 (37%) 11 (61%) 0.089
Fungal infection at start of MP 15 (31%) 4 (13%) 11 (61%) 0.001
Sepsis at start of MP 22 (45%) 9 (30%) 13 (72%) 0.004
Platelet refractoriness at start of MP 28 (58%) 13 (43%) 15 (83%) 0.007
Patients continued on MP as GVHD prophylaxis 9 (19%) 3 (10%) 6 (33%) 0.11
Use of cytokines (G-CSF/GM-CSF) 30 (63%) 16 (53%) 14 (78 %) 0.17
Myeloid engraftment 41 (85%) 29 (97%) 12 (67%) 0.008

were ABO compatible, while 21% had a major or minor Table 3 Causes of death
ABO mismatch, with a similar distribution between
Cause Responders Non responders
responders vs non-responders. n ¼ 30 n ¼ 18

MOF with VOD 0 14a

Characteristics of VOD Infection 1a 0
These are shown in Table 2. RUQ pain was documented in Respiratory failure 2a 1a
Relapse 9 1
32 (67%) patients. Ascites was documented radiologically Interstitial pneumonitis 1 0
in 24 (50%) patients and hepatomegaly in 43 (90%) Bleeding 1a 0
patients. MOF was documented in 15 (31%) patients, with Not evaluable 1a 0
nine patients having organ dysfunction in four systems and Total deaths 15 (50%) 16 (89%)
Death within 100 days 5 (17%) 15 (83%)
six in three systems. Another 17 patients had single organ
failure in addition to the hepatic VOD, including nine a
Death within 100 days.
patients with renal failure, six with respiratory failure; one
had cardiac failure and one had CNS toxicity (Table 2).
refractoriness. High SGPT and earlier engraftment were
Treatment with methylprednisolone observed among responders.
Methylprednisolone was started at a median of 13.5 days
(range 3–34 days) post transplantation. The median Therapy-related complications
interval from clinical diagnosis of VOD to the initiation Hyperglycemia (blood glucose 4200 mg/dl) was the main
of MP was 4 days (range 0–15). Nine patients were complication and was observed in 29 (60%) patients.
continued on MP at 1 mg/kg/day as GVHD prophylaxis Fourteen (29%) patients developed hypertension, which
as their CYA was put on hold due to increased serum required pharmacologic intervention and one patient
creatinine or other side effects thought to be secondary to developed psychosis thought to be steroid-related. Addi-
CYA. tionally, MP could have been a contributing factor for
sepsis, CMV reactivation and fungal infection observed in 8
(17%), 16 (34%), and 5 (10%) patients, respectively.
Response However, the overall frequency of these infections was
When assessed 10 days from the start of MP therapy, 30 similar to their frequency in other allogeneic HSCT patients
(63%) patients responded. The total serum bilirubin in not receiving MP in our unit.
responding patients decreased from a median of 124 mmol/l
(range 38–432) at the start of treatment to a median of
51 (range 21–288) 10 days after the start of therapy Survival
(P ¼ 0.018). Twenty-five of the 30 responders survived to day þ 100;
and of these, 15 were alive as of June 2004. All but three
non-responding patients died within 100 days post-HSCT
Predictors of response and one of those three died of relapse at 298 days. The
Fifteen variables were examined by the Fisher’s exact test other two are still alive at the time of this analysis; causes of
for association with response (Table 2). When compared to death are shown in Table 3. No mortality from VOD or
the responding patients, non-responders had a higher other regimen-related toxicity was seen beyond day þ 100
total bilirubin at the start of MP therapy, higher weight with disease recurrence being the most common cause of
gain, greater likelihood of fungal infection and platelet late death. The probability of survival obtained using

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 Steroid therapy for VOD following stem cell transplantation
A Al Beihany et al
290
Kaplan–Meier method was 58% for the 30 MP responders
and 10% for the 18 non-responders and this was
statistically significant (P ¼ 0.0001).
Discussion
Our study shows 63% response to MP in patients with
VOD within 10 days as measured by decline in bilirubin
with 58% survival to day þ 100 without the evidence of
VOD. This is encouraging given the compromised condi-
tion of this cohort of patients; 67% of whom had at least
one other organ failure in addition to the liver.
Independent of VOD, patients undergoing HSCT with
the evidence of organ dysfunction in more than one system
have been reported to have a much higher procedure-
related mortality.21 The mortality of patients with VOD
correlates with the severity of the syndrome and can be less
than 10% in patients with mild VOD to greater than 90%
in severe VOD.10 In our study all except two patients
with VOD and MOF died within 100 days of trans-
plantation with progressive VOD and were among the
non-responders.
We used a reduction in bilirubin of 50% or more as a
surrogate marker for response to therapeutic intervention
as has been used in other studies.20 In our study patients,
the bilirubin level peaked approximately 5 days after the
initial rise; and among those who responded, it declined
significantly within an average of 3 days from the initiation
of therapy (mean 8 days, median 3 days). Among VOD
patients treated only with supportive care, the peak
bilirubin level was usually observed at an average of 10
days; and among responders, the bilirubin level returned
close to baseline in approximately 10 days.1 Based on the
above, the rapid response observed in our study is less
likely to represent spontaneous recovery and more likely to
be the result of an effective intervention.
In univariate analysis, high serum bilirubin, percentage
of weight gain, presence of fungal infection and platelet
refractoriness were predictors of poor response. On the
other hand, early engraftment and elevated serum SGPT
were predictors of good response. Although it is possible
that early engraftment helps in recovery and response of
VOD to treatment, it is much more likely that patients
responding to VOD treatment will have enhanced engraft-
ment. The significantly higher incidence of fungal infection
at the start of therapy among non-responders suggests that
perhaps those with active fungal infections should not be
considered for this treatment.
Treatment with this regimen was very well-tolerated with
minimal side effects, and no serious sequel was documen-
ted. Transient steroid-induced hyperglycemia was the most
frequently observed side effect seen in 34 (70%) of the
patients and was well controlled with insulin. Hypertension
was the next most frequent side effect and was observed in
14 (29%) of the patients; however, many other factors
could have contributed to this side effect.
Khoury et al.22 have used high-dose MP at a dose of
500 mg/m2 every 12 h for six doses to treat hepatic regimen-
related toxicity in 28 patients, including 20 patients with
VOD and eight patients with liver dysfunction of uncertain
Bone Marrow Transplantation
etiology. Overall, 17 patients (61%) responded to this
treatment, including 12 patients with VOD, and five
patients with liver disease of unknown etiology. At 100
days post-transplantation, hepatic regimen-related toxicity
resolved in all 13 survivors who responded to high-dose MP
and one non-responding patient. The result of the above
study is consistent with the responses observed in our
study, however our treatment regimen involved adminis-
tration of MP at a much lower dose but for a longer
duration. In a subsequent report from the same group,23
regimen-related toxicity (RRT) was noted, and it was
suggested that this treatment modality should be evaluated
only in non-GVHD hepatic RRT.
The reported incidence of VOD in the literature ranges
from 0 to 70% and the fatality rate can be as low as 3% in
mild cases and approaching 100% by day þ 100 in the
established severe VOD cases with multiorgan failure.1,4
The incidence observed at our center was 15%. The
disparity in the reported incidence and severity of VOD is
related to the inherent toxicity of different conditioning
regimens, patient selection and definition of what consti-
tutes VOD1 as well as the lack of histologic confirmation of
clinically defined cases as it also applies to our study.
Despite the progress that has been made toward under-
standing the pathophysiology of hepatic VOD, there is still
a lack of a well-established prevention and therapeutic
approach for this disease. The available approaches are
limited both in number and efficacy, and some are
associated with significant toxicity.
To date, the majority of the clinical trials that have
evaluated a therapeutic intervention for the management of
established VOD, including our study, have been uncon-
trolled. Thus, it is difficult to determine the independent
effect of these interventions. Many variables besides
therapeutic intervention may have contributed to the
observed outcomes, including the fact that many studies,
including ours, lack histologic confirmation of clinically
defined cases to exclude the possibility of alternate
diagnoses. These variables represent a significant challenge
in the design of future prospective controlled trials to
determine the potential efficacy of an agent or intervention
used for the treatment of this disease.
Acknowledgements
We thank Mr Ibrahim El Hassan, MPH, for his help in the
statistical analysis and Mr Edgardo Colcol for his help in the
data management of this study.
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