Incidence and Management of Hepatic Severe Veno-Occlusive Disease in 273 Patients in a Single Centre with Deﬁbrotide

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LETTER TO THE EDITOR Incidence and management of hepatic severe veno-occlusive disease in 273 patients in a single centre with deﬁbrotide

Bone Marrow Transplantation (2016) 51, 1262–1264; doi:10.1038/ The median age of the 13 patients with VOD was 60.5 years bmt.2016.99; published online 25 April 2016 (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 Veno-occlusive disease (VOD)/sinusoidal obstruction syndrome the Baltimore criteria for diagnosing VOD, the remainder of the (SOS) is a clinical syndrome comprising of hyperbilirubinaemia, patients had severe disease as defined by either multiorgan failure painful enlargement of the liver, ascites and weight gain. The (MOF) (including acute kidney injury and pleural effusions) or diagnosis of VOD/SOS is in the range of 14% (range 0–60%) rapidly escalating bilirubin levels and marked weight gain 45%, depending upon the risk factors present.1 The diagnosis of VOD is consistent with higher risk as originally defined by the Bearman based primarily on established clinical criteria (modified Seattle or model. All the patients in our series had severe VOD and after Baltimore criteria).2 It is recommended that patients are assessed early diagnosis, were promptly started on defibrotide therapy for risk factors for VOD before HSCT.2 The condition causes given the evidence that prompt intervention with defibrotide considerable morbidity and mortality, and severe VOD is therapy is associated with better outcome.12 The mean time to associated with a mortality of over 90% by day +100 following develop VOD was 8.3 days post BMT (range 3–21 days). Flamsa- 3,4 HSCT. The incidence of VOD is lower after autologous SCT and Bu-conditioned patients developed VOD by day 3 post BMT. All reduced intensity conditioning transplantation compared with patients had a serum bilirubin 456 umol/L with a median of 1,5 myeloablative allogeneic HSCT. A 6-month prospective 105 mmol/L (56–1166). Five of the patients had moderately European Group for Blood and Marrow Transplantation study elevated transaminases. Acute kidney injury was classified as per reported an incidence of VOD post autologous and allogeneic 4 the international Kidney Disease: Improving Global Outcomes bone marrow transplantation at 3.1 and 8.9%, respectively. (KDIGO) criteria.13 Tweleve out of 13 patients had acute kidney However the incidence of non-myeloablative allogeneic transplant injury (AKI), mostly moderate to severe in nature (acute kidney VOD was 8.8% in a recent study in a single centre using the injury stage 2 and stage 3) evolving into hepatorenal syndrome. reduced intensity regimen (fludarabine, BU and antithymocyte fl 6 fi This required meticulous management with uids and diuretics to globulin). De brotide, a single-stranded polydeoxyribonucleotide maintain adequate intravascular volume and renal perfusion. has anti-thrombotic, anti-inflammatory and anti-ischaemic Seven out of 13 patients also had pleural effusions. All received properties and is recommended as the definitive treatment – defibrotide therapy (25 mg/kg per day) within 24 h of diagnosis of for VOD.7 10 VOD and aggressive supportive management with respect to fluid We report a single-centre experience based on case note review fi from over a 45-months period (January 2011 till September 2014) balance. The median duration of de brotide therapy was 14 days – (Table 1). A total of 273 allogeneic transplants were performed (6 21). Four patients out of 13 died before day 100. One patient and VOD was diagnosed in 13. The indications for stem cell died due to sepsis at day 100 and one patient died due to drug- transplantation in these cases included AML (n = 7), myelofibrosis induced liver failure at day 60, both after resolution of VOD. There (n = 2), difuse large B cell lymphoma (DLBCL) (n = 1), CML (n = 1), was only 1 VOD-related death by day 100 and another patient myelodysplastic syndrome (MDS) (n = 1) and chronic myelomo- nocytic leukaemia (CMML) (n = 1). Ten patients were in CR at the time of transplant. Of the 13 patients diagnosed with VOD, none VOD had prior liver disease but 2 patients had mildly raised 100 transaminases prior to HSCT. Four patients received myeloablative No VOD 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 50 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 survival Percent 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/ 0 m2 for 4 days, then rest for next 4 days, followed by busulfan 015050 100 3.2 mg/kg once daily, IV on days − 5 and − 4, that is, 6.4 mg/kg Days elapsed over 2 days and cyclophosphamide 40 mg/kg for siblings and 60 mg/kg for unrelated donor transplants and using ATG 2.5 mg/ P value 0.8221 by log-rank (Mantel-Cox) test 11 kg for 2 days) for refractory AML and 2 patients received – fl Figure 1. Shows Kaplan Meier survival curves at day 100. There was udarabine, melphalan and alemtuzumab (FMC) conditioning. no difference in day 100 overall survival among patients who had Twelve of 13 patients had an unrelated donor and 12 out of 13 VOD compared with patients who did not have VOD. A full color patients had in vivo T-cell depletion with alemtuzumab (n = 4) or version of this figure is available at the Bone Marrow Transplantation ATG (n = 8) with 1 patient having had prior allogeneic transplant. journal online. 06McilnPbihr iie,pr fSrne aue oeMro rnpatto 21)1262 (2016) Transplantation Marrow Bone Nature. Springer of part Limited, Publishers Macmillan 2016 ©

Table 1. Patient characteristics

Age/sex Conditioning Transplant Diagnosis Bilirubin Time Duration of Liver AKI VOD Lungs AKI MOF VOD USG/CT scan Cause of maximum to VOD deﬁbrotide failure criteria involvement severity death at day (days) (CT/CXR) 100

61/Male FluBuATG (RIC) MUD IMF 810 14 21 Y Y Baltimore Nil AKI Y-kidneys Severe Hepatomegaly, Alive stage 1 gallbladder thick walled 25/Male CYTBI (MA) MUD AML 61 10 16 Y Y Modified Right sided AKI Y-lungs Severe No hepatomegaly, Alive Seattle effusion stage 2 and spleen enlarge kidney 14 cm 60/Male FluBuATG (RIC) MUD Fibrotic MDS 174 7 12 N N Modified Nil Normal None Severe No hepatomegaly, Alive Seattle spleen enlarged 16.3 cm 66/Male FlamsaBu (RIC) MUD rAML 136 3 15 N Y Baltimore Bilateral AKI Y-lungs Severe Normal liver, Death due effusions stage 3 and galbladder to sepsis kidneys oedamatous 70/Male FluBuATG (RIC) MUD IMF 56 8 9 N Y Modified Nil AKI Y-kidneys Severe Liver and spleen Alive Seattle stage 1 normal 68/Male FamsaBu (RIC) MUD AML 70 3 12 N Y Modified Nil AKI Y-kidneys Severe No hepatomegaly, Alive Seattle stage 1 enlarged spleen 17 cm 45/Male CYTBI (MA) MUD CML 1111 21 14 Y Y Modified Nil AKI Y-kidneys Severe Gallbladder Death due Seattle stage 3 collapsed, normal to severe liver and spleen VOD 64/Male FluBuATG (RIC) MUD CMML2 56 11 12 Y Y Baltimore Bilateral AKI Y-lungs Severe Slightly coarse Alive Editor the to Letter effusions stage 2 and liver mild kidneys hepatomegaly, spleen enlarged 14 cm 43/Male CYTBI (MA) MUD 2AML 1166 9 14 N Y Baltimore Large AKI Y-lungs Severe No ascites, Death due bilateral stage 3 and hepatolmegaly to drug- effusions kidneys induced liver failure 69/Male FMC (RIC) MUD DLBL 69 7 6 N Y Baltimore Effusions AKI Y-lungs Severe Normal liver, Death due stage 3 and unremarkable to sepsis kidneys spleen, ascites 27/ FlamsaBu (RIC) MUD AML 182 3 15 N Y Baltimore Bilateral AKI Y-lungs Severe Normal liver, Alive Female effusions stage 2 and spleen, small kidneys amount ascites 40/Male CYTBI (MA) SIB AML 105 8 14 N Y Modified Nil AKI Y-kidneys Severe Liver Alive Seattle stage 1 unremarkable, spleen slightly enlarged 12.5 cm 61/Male FMC (RIC) RIC AML 60 6 11 N Y Modified Bilateral AKI Y-lungs Severe Normal liver and Alive Seattle effusions stage 2 and spleen kidneys Abbreviations: CT ¼ computed tomography; CXR ¼ chest X-ray; CYTBI ¼ cyclophosphamide-TBI; DLBL ¼ diffuse large B cell lymphoma; FMC ¼ fludarabine, cyclophosphamide, alemtuzumab; IMF ¼ idiopathic myelofibrosis; MA ¼ myeloablative; MOF ¼ multiorgan failure; MUD ¼ matched unrelated donor; SIB ¼ sibling; USG ¼ ultrasonography; VOD ¼ veno-occlusive disease. – 1264 1263 Letter to the Editor 1264 died of septic shock at day 6. VOD gradually resolved after a REFERENCES median of 14 days in 11 out of 12 evaluable patients. 1 Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A et al. Hepatic In terms of risk factors for VOD, 7/20 patients (35%) who received veno-occlusive disease following stem cell transplantation: incidence, clinical busulphan as part of their conditioning during the time period course, and outcome. Biol Blood Marrow Transplant 2010; 16:157–168. studied had VOD compared 4/42 patients (9.5%) with a myeloa- 2 Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A et al. On behalf of blative transplant (Cy-TBI) and 2/101 (1.9%) patients conditioned with the Haemato-oncology Task Force of the British Committee for Standards in the FMC regimen. 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