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CASE REPORT
Year : 2009  |  Volume : 5  |  Issue : 4  |  Page : 312-314

Late-onset hepatic veno-occlusive disease post autologous peripheral stem cell transplantation successfully treated with oral defibrotide


BMT Unit, Department of Medical Oncology, Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Center, Kharghar, Navi Mumbai - 410 208, Maharashtra, India

Date of Web Publication11-Feb-2010

Correspondence Address:
Navin Khattry
BMT Unit, Department of Medical Oncology, Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Center, Kharghar, Navi Mumbai - 410 208, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.59910

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 > Abstract 

Hepatic veno-occlusive disease (VOD) remains one of the commonest and most serious complications after myeloablative hematopoietic stem cell transplantation (HSCT). Clinical diagnosis of hepatic VOD is based on the finding of the triad of painful hepatomegaly, hyperbilirubinemia, and unexplained fluid retention occurring within 21 days of the transplant. However, the uncommon clinical entity of late-onset VOD can occur even beyond 20 days and should be considered in the differential diagnosis of any liver disease of more than 3 weeks' duration.
While mild cases usually resolve spontaneously, severe VOD is associated with a grim prognosis. Defibrotide, a polydisperse mixture of single-stranded oligonucleotide with antithrombotic and fibrinolytic effects on microvascular endothelium, has emerged as an effective and safe therapy for patients with severe VOD. We describe a patient who presented 55 days post transplant with clinical features suggestive of VOD. Upon treatment with oral defibrotide, he showed complete resolution of the VOD.

Keywords: Hematopoietic stem cell transplantation, hepatic veno-occlusive disease, oral defibrotide


How to cite this article:
Shah MS, Jeevangi NS, Joshi A, Khattry N. Late-onset hepatic veno-occlusive disease post autologous peripheral stem cell transplantation successfully treated with oral defibrotide. J Can Res Ther 2009;5:312-4

How to cite this URL:
Shah MS, Jeevangi NS, Joshi A, Khattry N. Late-onset hepatic veno-occlusive disease post autologous peripheral stem cell transplantation successfully treated with oral defibrotide. J Can Res Ther [serial online] 2009 [cited 2019 Nov 23];5:312-4. Available from: http://www.cancerjournal.net/text.asp?2009/5/4/312/59910


 > Introduction Top


Hepatic veno-occlusive disease (VOD) is one among a spectrum of organ injury syndromes that occurs after the high-dose chemotherapy employed with hematopoietic stem cell transplantation. [1],[2] VOD generally occurs in about 10% of patients after allogeneic stem cell transplantation employing myeloablative-conditioning regimens, [3] but the incidence is lower after autologous stem cell transplantation and reduced-intensity allogeneic transplantation. [4]

Defibrotide, a polydisperse oligonucleotide mixture with protective effects on vascular endothelium has demonstrated encouraging responses and little toxicity in multicenter phase I/II trials. [5] We describe here a case of late-onset VOD post autologous stem cell transplantation in a case of metastatic Ewing sarcoma; this patient was successfully treated with oral defibrotide.


 > Case Report Top


An 18-year-old male was diagnosed with Ewing sarcoma of the left iliac bone in November 2007; he had bone marrow involvement and pulmonary metastasis. He was treated with four cycles of vincristine, ifosfamide, and etoposide (VIE) and two cycles of vincristine, adriamycin, and cyclophosphamide (VAC). In view of the very good response to chemotherapy, the patient was taken up for autologous transplant after peripheral stem cell collection, with busulfan-melphalan (Bu-Mel) as conditioning regimen. He received acyclovir, itraconazole, and ursodeoxycholic acid as prophylaxis from day -7. Busulfan (1 mg/kg) was given from day -6 to day -3 and melphalan (140 mg/m 2 ) on day -1.

The CD34 and mononuclear count (MNC) of stem cells infused were 9.2 × 10 6 /kg and 3.7 × 10 8 /kg, respectively. The patient achieved neutrophil engraftment (absolute neutrophil count >500/mm 3 ) on day +10 and platelet engraftment (platelet count >20,000/mm 3 , unsupported) on day +9. His immediate post transplant period was uneventful. After discharge, he was planned for lung bath (12.6 Gy/7#) and definitive radiotherapy to the hemipelvis (55.8 Gy/31#).

One week after starting radiotherapy (day + 55), he presented again with abdominal distension and pain referred to his right shoulder. On examination, he was found to have right hypochondriac pain, ascites, and weight gain. He had grade 4 thrombocytopenia (platelet count <20,000/mm 3 ) and the liver function tests showed total bilirubin of 2.4 mg/dl, SGOT 353 U/l, and SGPT 721 U/l. Ultrasonography showed normal liver parenchyma with diffuse gall bladder wall edema and ascites. Contrast-enhanced CT scan of the thorax, abdomen, and pelvis revealed bilateral pleural effusion, moderate ascites, and hepatomegaly; the distal hepatic veins were not visualized. His clinical and radiological features were suggestive of VOD.

He was treated with fluid restriction, diuretics, and ursodeoxycholic acid. Oral defibrotide was started at a dose of 400 mg (5 mg/kg) four times a day. The patient responded to the above treatment, with complete resolution of VOD by day +75. The liver function profile during this period is shown in [Table 1]. He completed his definitive radiotherapy to the local site after recovery from VOD.


 > Discussion Top


VOD is usually diagnosed within the first 30 days of bone marrow transplant as per the Baltimore [6] and Seattle [3] criteria. The Seattle criteria for diagnosis of VOD require the presence of two of the following three criteria to be present within 20 days: bilirubin > 2mg/dl, hepatomegaly or right upper quadrant pain of hepatic origin, and > 2% weight gain due to fluid accumulation. The Baltimore criteria require the presence of hyperbilirubinemia within 21 days of bone marrow transplant as well as the presence of two of the following three criteria: painful hepatomegaly, ascites, and > 5% weight gain. However, this requirement may be inappropriate because with some regimens VOD can develop even later than 20 days post transplant..

Recognized pretransplant risk factors for the development of VOD include older age, poor performance status, female gender, donor-recipient HLA disparity, advanced malignancy, prior abdominal radiation, second myeloablative transplant, reduced pulmonary diffusion capacity, and prior liver disease (including elevated liver enzymes or cirrhosis). The type and intensity of conditioning chemotherapy also determines the risk of VOD. VOD risk increases with higher total body irradiation and higher busulfan doses. [2],[4] The prognosis of VOD depends on the extent of hepatic injury and liver dysfunction and the presence of multi-organ failure (MOF). [2] Severe VOD, which is characterized by MOF, is associated with over 90% mortality by day +100.

The treatment of VOD is largely supportive. The use of thrombolytic agents or systemic anticoagulants has been associated with excessive bleeding and has not improved survival. Of the numerous drugs used for the prophylaxis of VOD, ursodeoxycholic acid was reported to reduce the severity of VOD in two randomized trials. [7],[8] Recently, defibrotide has been demonstrated to be an effective agent for theprophylaxis and treatment of VOD.

Defibrotide has antithrombotic, anti-inflammatory, and anti-ischemic properties in human vascular disorders, without demonstrating any significant systemic anticoagulant effects. It has affinity for adenosine receptors A1 and A2 and causes thrombin antagonism in vitro. The drug is usually administered by intravenous (IV) infusion in doses ranging from 5 to 60 mg/kg per day, with dose escalation as per response. [9] In the dose range of 10-40 mg/kg/day, complete response (CR) rates of 55% was seen in a study by Chopra et al. [5] Richardson et al. [10] randomized 150 patients of severe VOD to 25 mg/kg/day vs 40 mg/kg/day doses. No difference in CR rates was seen although, in pediatric patients, those receiving 25 mg/kg per day showed higher CR rates and superior day +100 survival. Since IV defibrotide was not available, we used the oral form in our patient in a dose of 5 mg/kg 6 hourly.

Thus, late-onset VOD must be kept as a diagnostic consideration in patients developing clinical or biochemical liver dysfunction and/or weight gain 3-4 weeks post stem cell transplantation. In our patient, the cause of late-onset VOD may have been the previous chemotherapy that he had received, conditioning with busulfan, and probably some scattered radiation to the liver received during lung bath. Even the oral formulation of defibrotide has proven to be an effective and safe treatment option for patients who develop moderate to severe VOD.

 
 > References Top

1.Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988;6:1562-8.   Back to cited text no. 1
[PUBMED]  [FULLTEXT]  
2.Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995;85:3005-20.   Back to cited text no. 2
[PUBMED]  [FULLTEXT]  
3.McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: A cohort study of 355 patients. Ann Intern Med 1993;118:255-67.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.Carreras E, Bertz H, Arcese W, Vernant JP, Tomas JF, Hagglund H, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: A prospective cohort study of the European Group for Blood and Marrow Transplantation: European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood 1998;92:3599-604.  Back to cited text no. 4
    
5.Chopra R, Eaton JD, Grassi A, Potter M, Shaw B, Salat C, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: Results of the European compassionate-use study. Br J Haematol 2000;111:1122-9.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987;44:778-83.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Ohashi K, Tanabe J, Watanabe R, Tanaka T, Sakamaki H, Maruta A, et al. The Japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation. Am J Hematol 2000;64:32-8.   Back to cited text no. 7
[PUBMED]  [FULLTEXT]  
8.Essell JH, Schroeder MT, Harman GS, Halvorson R, Lew V, Callander N, et al. Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:975-81.   Back to cited text no. 8
[PUBMED]  [FULLTEXT]  
9.Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D, et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002;100:4337-43.  Back to cited text no. 9
[PUBMED]  [FULLTEXT]  
10.Richardson P, Soiffer R, Antin J, Jin Z, Kurtzberg J, Martin P, et al. Defibrotide (DF) for the treatment of severe veno-occlusive disease (sVOD) and multi-organ failure (MOF) post SCT: Final results of a multi-center, randomized, dose-finding trial. Blood 2006;108:178.  Back to cited text no. 10
    



 
 
    Tables

  [Table 1]


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