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Journal of Cancer Research and Therapeutics, Vol. 5, No. 4, October-December, 2009, pp. 312-314 Case Report Late-onset hepatic veno-occlusive disease post autologous peripheral stem cell transplantation successfully treated with oral defibrotide Shah MithunS, Jeevangi Nandish KumarS, Joshi Amit, Khattry Navin 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 Code Number: cr09075 PMID: 20160371 DOI: 10.4103/0973-1482.59910 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 Introduction 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 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 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
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