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Low Dose Defibrotide for Management of Hepatic Veno-Occlusive Disease
Hepatic veno-occlusive disease (VOD) is recognized as one of the common and serious regimen-related toxicity seen after hematopoietic stem cell transplantation (HSCT). VOD develops in 10% to 60% of patients after HSCT, and ranges in severity from mild to a severe syndrome associated with multiorgan failure and death. Defibrotide (DF) is the only drug found to be effective in the management of VOD. A randomised study showed that 25 mg/kg/d was equally effective with lesser toxicity compared to 40mg/kg/d. DF is prohibitively expensive and availability is scarce in our country.
Methods:
Two hundred and ninety nine patients (166 autologous and 133 allogeneic; 210 male and 89 female) who underwent HSCT between November 2007 and June 2013 were included in this study. All patients received ursodeoxycolic acid as prophylaxis. The diagnosis and severity of VOD was defined according to Seattle criterion. Risk of development of severe VOD was estimated by Bearman model. Patients who developed VOD were initially treated with frusemide and analgesia. Patients not responding to above measures in 36-48 hours were given DF.
Results:
Seven patients (2.3%) were diagnosed with VOD at a median of days +14 post transplant (range 11 to 16 days). All 7 patients were classified as having moderate VOD. All patients received DF in doses ranging from 5 mg /kg/d to 10 mg/kg/d in two divided doses for median of 8 days (range 6 to12 days). Six patients received intravenous DF while 1 patient received oral DF. All patients had complete resolution of VOD by day +22 post transplant (range day + 17 to day +28). No dose response relationship was observed between DF dose and time to resolution of VOD. None developed any side effects of DF.
Conclusion:
A lower dose of DF is effective and safe in treatment of moderate VOD. This is especially relevant in a limited resource setting, however needs prospective evaluation.
Patient and disease characteristics:
Case No |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
|
Age |
21 |
45 |
4 |
42 |
46 |
12 |
29 |
|
Diagnosis |
CML-CP |
AML |
JMML |
AML |
CML -BC |
AML |
SAA |
|
Conditioning regimen |
FLU-MEL |
Flu-Busulfan |
Flu-Bu-Mel |
FLA+Ara-C+Ida+Mel |
Flu-Mel |
Flu-Mel-Ara-c-ATG |
Flu-CY |
|
Risk factor |
|
High Ferritin |
|
Haplo-HSCT |
|
High Ferritin,MUD HSCT |
High Ferritin |
|
VOD on day |
11 |
11 |
12 |
14 |
14 |
14 |
16 |
|
Maximal Bilirubin |
3.8 |
5 |
1.2 |
1.4 |
3.2 |
1.34 |
3.1 |
|
Weight gain (%) |
5 |
22 |
10 |
7.5 |
5 |
3 |
13 |
|
Bearman score |
10 |
10 |
20 |
16 |
12 |
11 |
16 |
|
DF Dose mg/kg/d |
5 |
7 |
7 |
5 |
10 |
10 |
10 |
|
Duration |
6 |
12 |
10 |
6 |
8 |
8 |
12 |
|
Resolution by |
D+17 |
D+28 |
D+21 |
D+20 |
D+22 |
D+10 |
D+24 |
|
Organ dysfunctioon |
|
hepatic encephalopathy |
Oxygen desaturation |
|
renal failure, hepatic encephalopathy, Oxygen desaturation |
Oxygen desaturation |
renal dysfunction, hepatic encephalopathy, oxygen desaturation |
|