Late-Onset Hepatic Veno-Occlusive Disease after Allografting: Report of Two Cases with Atypical Clinical Features Successfully Treated with Defibrotide
Alessia Castellino1, Stefano Guidi2, Chiara Maria Dellacasa3, Antonella Gozzini2, Irene Donnini2, Chiara Nozzoli2, Sara Manetta3, Semra Aydin1, Luisa Giaccone3, Moreno Festuccia3, Lucia Brunello3, Enrico Maffini3, Benedetto Bruno3, Ezio David4 and Alessandro Busca3.
1 A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, Ematologia, Torino, Italy.
2 SODc Terapie Cellulari e Medicina Trasfusionale, AOU Careggi, Firenze.
3 A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.
4 S.C. Anatomia Patologica 1, A.O.U. Città della Salute e della Scienza di Torino.
Received: August 2, 2017
Accepted: November 5, 2017
Mediterr J Hematol Infect Dis 2018, 10(1): e2018001 DOI 10.4084/MJHID.2018.001
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Veno-Occlusive Disease (VOD) is a potentially severe complication of
hematopoietic stem cell transplantation (HSCT). Here we report two
patients receiving an allogeneic HSCT who developed late onset VOD with
atypical clinical features. The two patients presented with only few
risk factors, namely, advanced acute leukemia, a myeloablative
busulphan-containing regimen and received grafts from an unrelated
donor. The first patient did not experience painful hepatomegaly and
weight gain and both patients showed only a mild elevation in total
serum bilirubin level. Most importantly, the two patients developed
clinical signs beyond day 21 post-HSCT. Hepatic transjugular biopsy
confirmed the diagnosis of VOD. Intravenous defibrotide was promptly
started leading to a marked clinical improvement. Based on our
experience, liver biopsy may represent a useful diagnostic tool when
the clinical features of VOD are ambiguous. Early therapeutic
intervention with defibrotide represents a crucial issue for the
successful outcome of patients with VOD.
Here we describe two HSCT recipients who developed late-onset VOD with atypical clinical features.
|Table 1. Criteria for definition of Late-Onset VOD (according to “The new classification from the European Society for Blood and Marrow Transplantation”, BMT 2016).|
Given that clinical symptoms and laboratory tests did not allow to discriminate between VOD, acute GVHD, toxicity or infective causes, a hepatic transjugular biopsy was performed. Histology studies showed the expansion of the hepatic sinusoid spaces, with gaps in the sinusoidal barrier which were highly suggestive of hepatic VOD in the light of the involvement of zone 3, zone 2 and partially zone 1 of the hepatic acinus (Figure 1).
|Figure 1. Images of hepatic transjugular biopsy: in the middle, the red arrows showed the expansion of hepatic sinusoid spaces, on the right the figure showed a centrilobular vein|
Intravenous defibrotide was started at the dose of 6.25 mg/kg QID on day +37 for 21 days, along with ancillary therapy including albumin replacement and low dose diuretics; nonsteroids have been administered. Two-three days after the beginning of defibrotide, the patient showed a marked clinical improvement with gradual improvement and normalization of liver and renal function tests (Figure 2). One week after the beginning of defibrotide, the patient developed hemorrhagic cystitis, treated with 2 bladder instillations of hyaluronic acid which led to progressive improvement and complete resolution upon regular discontinuation of defibrotide after 21 days of treatment. Hemorrhagic cystitis did not require an earlier discontinuation of defibrotide. During the treatment course, platelet count remained low between 10.000 to 20.000/mmc even with transfusion support. The patient was discharged on day +76 in complete remission of his underlying disease on low doses of cyclosporine.
|Figure 2. Diagnostic interventions with liver function profile from clinical onset of VOD until resolution, and treatment of VOD in case 1.|
The patient was readmitted because of severe anemia and thrombocytopenia (Hb 5,8 gr/dl; platelet 5000/ul) and complaints of right abdominal pain with melena on day +89. Significant weight gain (+7 kg) along with abdominal distension and anasarca were observed on day +91. Laboratory exams showed total bilirubin 3,30 mg/dl, AST/ALT 140/164 UI, GGT 725 Ul, INR 1,7; aPTT 41,3”, serum creatinine 2,0 mg/dl; platelet count was 20.000/mmc. An abdominal CT scan revealed ascites and hepatic veins compression. Transjugular measurement of the hepatic venous pressure gradient showed severe sinusoidal portal hypertension with a significant transhepatic/caval gradient diagnostic for severe VOD. Transjugular liver biopsy showed sinusoidal dilation and bleeding with erythrocytes in the Disse space, and significant iron overload. Histology studies were consistent with severe VOD.
Intravenous defibrotide was promptly started at the dose of 6.25 mg/kg QID for 22 days.
Ancillary therapy included plasma and red blood cells transfusions, no steroid have been administered. A complete and sustained response was achieved. The patient was discharged on day +121. The patient is currently alive, 188 days after transplant, with normal liver function, no evidence of GvHD, or any other relevant clinical complication. A bone marrow aspirate showed complete remission of his underlying disease.
|Figure 3. Diagnostic interventions with liver function profile from clinical onset of VOD until resolution, and treatment of VOD in case 2.|
Both the British guidelines and the EBMT recommendations indicate that liver biopsy should be reserved for those patients in whom the diagnosis of VOD is unclear, and there is an urgent need to rule out other possible causes of liver dysfunction. In our experience, a transjugular liver biopsy was safe despite severe thrombocytopenia and, most importantly, was conclusive for the diagnosis of VOD ruling out drug toxicities, viral infections, sepsis or GVHD.[11-13] In keeping with our findings, Kis et al. reported only 1.8% of major complications during 166 transjugular liver biopsies.
Defibrotide is the only agent approved for the treatment of VOD in Europe. Defibrotide has been shown to have antithrombotic and anti-inflammatory properties and may promote revascularization inducing endothelial cell proliferation and angiogenesis. In our patients, the combination of clinical features and histology studies prompted us to start defibrotide only a few days after the onset of symptoms. Our experience strengthens the observation reported by Richardson et al., that the timely administration of defibrotide may represent a crucial issue for the successful outcome of patients with VOD. Sixty % of patients were alive when defibrotide was started within 2 days from the onset of symptoms as compared with 14% when treatment was delayed and started after 7 days. Similar results were reported by Corbacioglu et al. Our patients began defibrotide treatment within 7 days from the onset of symptoms but within 1 day from the histological diagnosis. They did not fall exactly in the early treatment category. Nevertheless, defibrotide has been initiated within 7 days, representing the crucial threshold to achieve a good outcome. Phase 2 and 3 studies[18-22] demonstrated that defibrotide was generally well tolerated with manageable toxicity. Hemorrhagic complications were reported as the most frequent adverse event. Hemorrhagic cystitis, which occurred in one of our patients, is a common complication in HSCT recipients. Though other causes may have been involved, we could not rule out that it may have been related to defibrotide treatment given its prompt resolution upon drug discontinuation.
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