Veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) is a clinical syndrome comprising of hyperbilirubinaemia, painful enlargement of the liver, ascites and weight gain. The diagnosis of VOD/SOS is in the range of 14% (range 0–60%) depending upon the risk factors present.1 The diagnosis of VOD is based primarily on established clinical criteria (modified Seattle or Baltimore criteria).2 It is recommended that patients are assessed for risk factors for VOD before HSCT.2 The condition causes considerable morbidity and mortality, and severe VOD is associated with a mortality of over 90% by day +100 following HSCT.3, 4 The incidence of VOD is lower after autologous SCT and reduced intensity conditioning transplantation compared with myeloablative allogeneic HSCT.1, 5 A 6-month prospective European Group for Blood and Marrow Transplantation study reported an incidence of VOD post autologous and allogeneic bone marrow transplantation at 3.1 and 8.9%, respectively.4 However the incidence of non-myeloablative allogeneic transplant VOD was 8.8% in a recent study in a single centre using the reduced intensity regimen (fludarabine, BU and antithymocyte globulin).6 Defibrotide, a single-stranded polydeoxyribonucleotide has anti-thrombotic, anti-inflammatory and anti-ischaemic properties and is recommended as the definitive treatment for VOD.7, 8, 9, 10
We report a single-centre experience based on case note review from over a 45-months period (January 2011 till September 2014) (Table 1). A total of 273 allogeneic transplants were performed and VOD was diagnosed in 13. The indications for stem cell transplantation in these cases included AML (n=7), myelofibrosis (n=2), difuse large B cell lymphoma (DLBCL) (n=1), CML (n=1), myelodysplastic syndrome (MDS) (n=1) and chronic myelomonocytic leukaemia (CMML) (n=1). Ten patients were in CR at the time of transplant. Of the 13 patients diagnosed with VOD, none had prior liver disease but 2 patients had mildly raised transaminases prior to HSCT. Four patients received myeloablative conditioning with Cy-TBI (14.4 Gy), whereas nine patients had a reduced intensity transplant. Out of the reduced intensity regimes, 4 patients were conditioned with Fludarabine, Busulphan and anti-thymocyte globulin (ATG) (Busulphan dose: 3.2 mg/kg once daily, IV over 3 h on days −5 and −4 over 2 days and a further dose of 1.6 mg/kg IV on day −3, that is, 8 mg/kg in total), 3 patients were conditioned with Flamsa-Bu regimen (sequential therapy employing reduced intensity conditioning (RIC) with fludarabine 30 mg/m2, cytarabine 2 g/m2 and amsacrine 100 mg/m2 for 4 days, then rest for next 4 days, followed by busulfan 3.2 mg/kg once daily, IV on days −5 and −4, that is, 6.4 mg/kg over 2 days and cyclophosphamide 40 mg/kg for siblings and 60 mg/kg for unrelated donor transplants and using ATG 2.5 mg/kg for 2 days)11 for refractory AML and 2 patients received fludarabine, melphalan and alemtuzumab (FMC) conditioning. Twelve of 13 patients had an unrelated donor and 12 out of 13 patients had in vivo T-cell depletion with alemtuzumab (n=4) or ATG (n=8) with 1 patient having had prior allogeneic transplant.
The median age of the 13 patients with VOD was 60.5 years (range 25–70 years with 12 male and 1 female). All cases of VOD were diagnosed using the modified Seattle criteria but only 6/13 satisfied Baltimore criteria. Although 6 out of 13 patients satisfied the Baltimore criteria for diagnosing VOD, the remainder of the patients had severe disease as defined by either multiorgan failure (MOF) (including acute kidney injury and pleural effusions) or rapidly escalating bilirubin levels and marked weight gain >5%, consistent with higher risk as originally defined by the Bearman model. All the patients in our series had severe VOD and after early diagnosis, were promptly started on defibrotide therapy given the evidence that prompt intervention with defibrotide therapy is associated with better outcome.12 The mean time to develop VOD was 8.3 days post BMT (range 3–21 days). Flamsa-Bu-conditioned patients developed VOD by day 3 post BMT. All patients had a serum bilirubin >56 umol/L with a median of 105 mmol/L (56–1166). Five of the patients had moderately elevated transaminases. Acute kidney injury was classified as per the international Kidney Disease: Improving Global Outcomes (KDIGO) criteria.13 Tweleve out of 13 patients had acute kidney injury (AKI), mostly moderate to severe in nature (acute kidney injury stage 2 and stage 3) evolving into hepatorenal syndrome. This required meticulous management with fluids and diuretics to maintain adequate intravascular volume and renal perfusion. Seven out of 13 patients also had pleural effusions. All received defibrotide therapy (25 mg/kg per day) within 24 h of diagnosis of VOD and aggressive supportive management with respect to fluid balance. The median duration of defibrotide therapy was 14 days (6–21). Four patients out of 13 died before day 100. One patient died due to sepsis at day 100 and one patient died due to drug-induced liver failure at day 60, both after resolution of VOD. There was only 1 VOD-related death by day 100 and another patient died of septic shock at day 6. VOD gradually resolved after a median of 14 days in 11 out of 12 evaluable patients.
In terms of risk factors for VOD, 7/20 patients (35%) who received busulphan as part of their conditioning during the time period studied had VOD compared 4/42 patients (9.5%) with a myeloablative transplant (Cy-TBI) and 2/101 (1.9%) patients conditioned with the FMC regimen. Busulphan-based conditioning was statistically significant when compared with the other conditioning regimens as the risk factor for developing VOD (P value<0.0001 by exact Fischer's test). Furthermore, two out of six patients with myelofibrosis developed VOD with a trend towards being significant; P=0.065.
VOD occurred with a 4.7% incidence in our centre. Busulphan-based conditioning has previously been reported as the most important risk factor for VOD.14 Wong et al.15 also found a 36% incidence of VOD in their series of 53 patients with myelofibrosis. As the FluBuATG regime is commonly used as the conditioning of choice for patients with myelofibrosis,16 the risk of VOD in these patients is significantly increased. This makes the prophylactic use of defibrotide worthy of study in this specific cohort of patients. Patients 1 and 5 with myelofibrosis received busulphan as part of conditioning treatment. They satisfied modified Seattle criteria for diagnosing VOD. Patient 1 continued to deteriorate despite defibrotide at a standard dose of 25 mg/kg per day to a maximum of 810 mmoles/L. He had hepatic encephalopathy with hepatorenal syndrome and stage 1 acute kidney injury culminating in MOF. In an attempt to improve outcome, the dose of defibrotide was increased to 40 mg/kg per day and this together with rigorous supportive management resulted in the resolution of VOD. Patient 5 whilst satisfying the modified Seattle criteria had evidence of stage 1 acute kidney injury and escalating weight gain, and impending hepatorenal syndrome making the case of severe VOD thus justifying prompt definitive treatment with defibrotide. Defibrotide has been used for treatment and prophylaxis of hepatic VOD.17 Richardson et al.9 used defibrotide on a compassionate basis in 88 patients with hepatic VOD with CR of VOD observed in 36%, with an overall survival at day 100 of 35%. Most responses were seen at doses 20–40 mg/kg per day. In our study where patients were commenced on defibrotide within 24 h of diagnosis of VOD, the day 100 mortality due to VOD was only 8.3%; overall mortality at day 100 was 30% and the overall survival at day 100 was 70% (Figure 1). There is evidence that early treatment with defibrotide improves overall survival.10 The criteria for diagnosing VOD have been defined more than two decades ago when myeloablative regimens were used for HSCT. Since then many new changes have occurred in the practice of transplantation with respect to conditioning intensity, alternative donors, other organs affected by VOD together with thrombocytopenia with rapid platelet consumption and rapid progression of VOD. Moreover, these criteria are subjective and lack sensitivity and specificity. Hence new biomarkers are in need to objectively diagnose VOD alongside with clinical diagnosis and improve outcome.18 Early intervention with defibrotide along with supportive management was able to completely resolve VOD in 11 out of 12 evaluable patients. We conclude that early intervention with defibrotide is critical in optimising survival in VOD developing post HSCT.
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The authors declare no conflict of interest.
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Pol, R., Russell, N., Das-Gupta, E. et al. Incidence and management of hepatic severe veno-occlusive disease in 273 patients in a single centre with defibrotide. Bone Marrow Transplant 51, 1262–1264 (2016) doi:10.1038/bmt.2016.99
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