-
1.
Defibrotide plus best standard of care compared with best standard of care alone for the prevention of sinusoidal obstruction syndrome (HARMONY): a randomised, multicentre, phase 3 trial
Grupp, S. A., Corbacioglu, S., Kang, H. J., Teshima, T., Khaw, S. L., Locatelli, F., Maertens, J., Stelljes, M., Stepensky, P., Lopez, P., et al
The Lancet. Haematology. 2023
-
-
-
Full text
-
Editor's Choice
Abstract
BACKGROUND Sinusoidal obstruction syndrome, also known as veno-occlusive disease, is a potentially life-threatening complication of haematopoietic stem-cell transplantation (HSCT). We aimed to compare defibrotide prophylaxis plus best supportive care versus best supportive care alone for sinusoidal obstruction syndrome prevention after HSCT. METHODS This open-label, randomised, multicentre, phase 3 trial was done in 104 centres in 14 countries. Patients who were at least 1 month old, were scheduled to receive allogeneic HSCT (adult [aged >16 years] or paediatric [aged >1 month to ≤16 years] patients) or autologous HSCT (paediatric patients only), and were at high risk or very high risk of developing sinusoidal obstruction syndrome were eligible for inclusion. Patients were randomly assigned (1:1) by an interactive web response system to receive intravenous defibrotide 25 mg/kg per day (four equal doses [6·25 mg/kg per dose]) and best supportive care (determined by individual institutional guidelines; defibrotide prophylaxis group) or best supportive care only (best supportive care group). Randomisation was stratified by sinusoidal obstruction syndrome risk, age, and country. The primary endpoint, sinusoidal obstruction syndrome-free survival at day 30 after HSCT, was assessed by an independent Endpoint Adjudication Committee in the intention-to-treat (ITT) population. Safety was assessed in all patients who received protocol treatment. The trial is registered with ClinicalTrials.gov, NCT02851407. FINDINGS Between Jan 11, 2017, and Oct 20, 2020, 372 patients (172 [46%] women and 200 [54%] men; median age 14·0 years [IQR 4·0-41·0] were randomly assigned to the defibrotide prophylaxis group (n=190) or best supportive care group (n=182; ITT population). On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurely stopped for presumed futility. At the final analysis, sinusoidal obstruction syndrome-free survival by day 30 after HSCT was 67% (95% CI 58-74) in the defibrotide prophylaxis group and 73% (62-80) in the best supportive care group (HR 1·27 [95% CI 0·84-1·93]; p=0·85). Treatment-emergent adverse events were similar between groups during the randomised prophylaxis phase; most treatment-emergent adverse events were related to the transplantation rather than to study drug. The most common grade 3 or 4 treatment-emergent adverse events were stomatitis (grade 3, 52 [29%] of 181 patients in the defibrotide prophylaxis group and 56 [32%] of 174 patients in the best supportive care group; grade 4, two [1%] in the defibrotide prophylaxis group and two [1%] in the best supportive care group) and febrile neutropaenia (grade 3, 51 [28%] in the defibrotide prophylaxis group and 52 [30%] in the best supportive care group; grade 4, no patients in the defibrotide prophylaxis group and three [2%] in the best supportive care group). Serious treatment-emergent adverse events occurred in 74 (41%) of 181 patients in the defibrotide prophylaxis group and 61 (35%) of 174 patients in the best supportive care group. In the rescue phase, when patients in both treatment groups received defibrotide as rescue treatment, fatal treatment-related adverse events occurred in one (4%) of 25 patients in the defibrotide prophylaxis group (intracranial haemorrhage) and one (3%) of 31 patients in the best supportive care group (sinusoidal obstruction syndrome). INTERPRETATION Defibrotide did not show a benefit in the prophylaxis of sinusoidal obstruction syndrome. Additional studies of carefully selected patients at high risk of sinusoidal obstruction syndrome after HSCT are warranted. FUNDING Jazz Pharmaceuticals.
PICO Summary
Population
Adults and children at least one month old who were scheduled to receive allogeneic transplant or children 1 month – 16 years scheduled to receive autologous transplant, and at high or very high risk of developing sinusoidal obstruction syndrome (n=372)
Intervention
Defibrotide prophylaxis plus best supportive care (n=190)
Comparison
Best supportive care alone (n=182)
Outcome
On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurely stopped for presumed futility. At the final analysis, sinusoidal obstruction syndrome-free survival by day 30 after HSCT was 67% (95% CI 58-74) in the defibrotide prophylaxis group and 73% (62-80) in the best supportive care group (HR 1·27 [95% CI 0·84-1·93]; p=0·85). Treatment-emergent adverse events were similar between groups during the randomised prophylaxis phase; most treatment-emergent adverse events were related to the transplantation rather than to study drug. Serious treatment-emergent adverse events occurred in 74 (41%) of 181 patients in the defibrotide prophylaxis group and 61 (35%) of 174 patients in the best supportive care group. In the rescue phase, when patients in both treatment groups received defibrotide as rescue treatment, fatal treatment-related adverse events occurred in one (4%) of 25 patients in the defibrotide prophylaxis group (intracranial haemorrhage) and one (3%) of 31 patients in the best supportive care group (sinusoidal obstruction syndrome).
-
2.
Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study
Svec, P., Elfeky, R., Galimard, J. E., Higham, C. S., Dalissier, A., Quigg, T. C., Bueno Sanchez, D., Han Lum, S., Faraci, M., Cole, T., et al
Bone marrow transplantation. 2022
Abstract
Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study.
-
3.
A Systematic Review and Meta-Analysis of Studies of Defibrotide Prophylaxis for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome
Corbacioglu, S., Topaloglu, O., Aggarwal, S.
Clinical drug investigation. 2022
Abstract
BACKGROUND AND OBJECTIVES Defibrotide is approved to treat severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after haematopoietic cell transplantation in patients aged > 1 month in the European Union and for VOD/SOS with renal/pulmonary dysfunction post-haematopoietic cell transplantation in the United States. This meta-analysis estimated the incidence and risk of VOD/SOS after intravenous defibrotide prophylaxis using the published literature. METHODS PubMed, Embase and Web of Science were searched through 30 November 2021 for defibrotide studies in VOD/SOS "prevention" or "prophylaxis," excluding phase I studies, case reports, studies with fewer than ten patients and reviews. RESULTS The search identified 733 records; 24 met inclusion criteria, of which 20 (N = 3005) evaluated intravenous defibrotide for VOD/SOS prophylaxis. Overall VOD/SOS incidence with intravenous defibrotide was 5%, with incidences of 5% in adults and 8% in paediatric patients. In eight studies with data on intravenous defibrotide prophylaxis vs controls (e.g. heparin, no prophylaxis), VOD/SOS incidence in controls was 16%. The risk ratio for developing VOD/SOS with defibrotide prophylaxis vs controls was 0.30 (95% confidence interval 0.12-0.71; p = 0.006). CONCLUSIONS This analysis suggests a low incidence of VOD/SOS following intravenous defibrotide prophylaxis, regardless of age group, and a lower relative risk for VOD/SOS with defibrotide prophylaxis vs controls in patient populations at high risk of VOD/SOS.
-
4.
Extracorporeal membrane oxygenation in children receiving haematopoietic cell transplantation and immune effector cell therapy: an international and multidisciplinary consensus statement
Di Nardo, M., Ahmad, A. H., Merli, P., Zinter, M. S., Lehman, L. E., Rowan, C. M., Steiner, M. E., Hingorani, S., Angelo, J. R., Abdel-Azim, H., et al
The Lancet. Child & adolescent health. 2021
Abstract
Use of extracorporeal membrane oxygenation (ECMO) in children receiving haematopoietic cell transplantation (HCT) and immune effector cell therapy is controversial and evidence-based guidelines have not been established. Remarkable advancements in HCT and immune effector cell therapies have changed expectations around reversibility of organ dysfunction and survival for affected patients. Herein, members of the Extracorporeal Life Support Organization (ELSO), Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network (HCT and cancer immunotherapy subgroup), the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT), the supportive care committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC), and the Pediatric Intensive Care Oncology Kids in Europe Research (POKER) group of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) provide consensus recommendations on the use of ECMO in children receiving HCT and immune effector cell therapy. These are the first international, multidisciplinary consensus-based recommendations on the use of ECMO in this patient population. This Review provides a clinical decision support tool for paediatric haematologists, oncologists, and critical care physicians during the difficult decision-making process of ECMO candidacy and management. These recommendations can represent a base for future research studies focused on ECMO selection criteria and bedside management.
-
5.
Heparanase wildtype is associated with a reduced incidence of transplant-associated systemic vasculopathies
Mueckenhausen, R., Föll, J., Kleinschmidt, K., Tröger, A., Malaisé, M., Wolff, D., Holler, E., Matthes, M., Heise, T., Sommer, G., et al
Hematology/oncology and stem cell therapy. 2021
Abstract
Some of the early complications of hematopoietic stem cell transplantation (HSCT) concerning the small vessels can be summarized as transplant-associated systemic vasculopathies (TASV). One enzyme known to play a major role in inflammation, tissue remodeling, and repair processes as well as tumor metastasis is heparanase (HPSE). HPSE genetic variants have recently been associated with significant influence on the risk of developing certain TASV such as a sinusoidal obstruction syndrome. This study aimed to validate the two known HPSE single nucleotide polymorphisms (SNPs)-rs4693608 and rs4364254-as a genetic predictor of TASV in a cohort of 494 patients and were correlated retrospectively with the clinical course post-HSCT. Significant association was revealed for rs4364254, showing that the incidence of TASV (38.0% vs. 57.8%, p?=?.009) and in particular of acute graft-versus-host disease (aGvHD) (36.3% vs. 54.0%, p?=?.0138) was lower in wildtype CC carriers than in TC/TT carriers. Moreover, compared with all other genotypes, the allelic combination GG-CC had the lowest incidence of TASV (34.9% vs. 57.4%, p?=?.0109) and aGvHD in particular (34.9% vs. 53.5%, p?=?.0315). A competing risk regression analysis confirmed a significantly reduced risk for a TASV in patients with GG (subhazard ratio [SHR]?=?0.670, p?=?.043) and CC (SHR?=?0.598, p?=?.041) compared with the corresponding homozygote SNP as well as for allelic combinations correlated with low HPSE gene expression (SHR?=?0.630, p?=?.016) and in correlation with clinical risk factors. In summary, our study emphasizes an association of HPSE gene SNPs with TASV, in particular with aGvHD, which could be implementable as pre-transplant risk stratification if validated prospectively.
-
6.
Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party
Bazarbachi, A. H., Al Hamed, R., Labopin, M., Halaburda, K., Labussiere, H., Bernasconi, P., Schroyens, W., Gandemer, V., Schaap, N. P. M., Loschi, M., et al
Bone marrow transplantation. 2020
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is a complex, potentially fatal therapy featuring a myriad of complications. Triggering event(s) of such complications vary significantly, but often a so-called "multi-organ failure" (MOF) is reported as the leading cause of death. The identification of the exact trigger of MOF is critical towards early and disease-specific intervention to improve outcome. We examined data from 202 alloHCT patients reported to have died of MOF from the EBMT registry aiming to determine their exact cause of death focusing on veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) due to its life-threatening, often difficult to capture yet preventable nature. We identified a total of 70 patients (35%) for whom VOD/SOS could be considered as trigger for MOF and leading cause of death, among which 48 (69%) were previously undiagnosed. Multivariate analysis highlighted history of hepatic comorbidity or gentuzumab use and disease status beyond CR1 as the only significant factors predictive of VOD/SOS incidence (OR?=?6.6; p?=?0.001 and OR?=?3.3; p?=?0.004 respectively). VOD/SOS-related MOF was widely under-reported, accounting for 27% of deaths attributed to MOF of unknown origin without a previous VOD/SOS diagnosis. Our results suggest most missed cases developed late VOD/SOS beyond 21 days post-alloHCT, highlighting the importance of the newly revised EBMT criteria.
-
7.
Incidence of Anicteric Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome and Outcomes With Defibrotide Following Hematopoietic Cell Transplantation in Adult and Pediatric Patients
Corbacioglu, S., Kernan, N. A., Pagliuca, A., Ryan, R. J., Tappe, W., Richardson, P. G.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) that is traditionally diagnosed using Baltimore or modified Seattle criteria. While Baltimore criteria require the presence of hyperbilirubinemia (bilirubin ≥2 mg/dL) for diagnosis of VOD/SOS, modified Seattle criteria do not. Prior to approval by the US Food and Drug Administration, defibrotide was available in the US through an expanded-access study (T-IND). The T-IND protocol initially required post-HCT diagnosis of VOD/SOS by Baltimore criteria or biopsy but was later amended to include patients diagnosed using modified Seattle criteria. This post-hoc analysis examined the incidence of VOD/SOS with bilirubin levels <2 mg/dL, before and after Day 21 post-HCT in T-IND patients enrolled following the amendment allowing for diagnosis by modified Seattle criteria. Survival of adult and pediatric patients with or without hyperbilirubinemia and with or without multi-organ dysfunction (MOD) was also evaluated. Of 803 post-HCT patients with VOD/SOS enrolled following the protocol amendment, 181 (23%) had bilirubin <2 mg/dL and would not have been diagnosed if hyperbilirubinemia was required. The bilirubin level at diagnosis was <2 mg/dL in 165/331 (50%) patients diagnosed by modified Seattle criteria and 16/23 (70%) patients diagnosed by biopsy. VOD/SOS with bilirubin <2 mg/dL was more common in pediatric patients (29%), although it also occurred in adult patients (15%). Patients with hyperbilirubinemia had lower Day 100 survival (54% vs 87% in patients with bilirubin <2 mg/dL) and a higher incidence of MOD (41% vs 26% in patients with bilirubin <2 mg/dL). The incidence of treatment-emergent adverse events and serious adverse events was lower in patients with bilirubin <2 mg/dL. These results indicate that anicteric VOD/SOS occurs in both adult and pediatric patients post-HCT and can be diagnosed before and after Day 21 in both groups. The worse survival in patients with bilirubin ≥2 mg/dL suggests requiring hyperbilirubinemia may result in a progressed disease stage associated with worse outcomes. Together these results highlight the importance of awareness and the possibility of VOD/SOS in the absence of elevated bilirubin levels.
-
8.
Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syndrome: an international expert position statement
Mahadeo, K. M., Bajwa, R., Abdel-Azim, H., Lehmann, L. E., Duncan, C., Zantek, N., Vittorio, J., Angelo, J., McArthur, J., Schadler, K., et al
The Lancet. Haematology. 2019
-
-
-
Full text
-
Editor's Choice
Abstract
Sinusoidal obstructive syndrome, also known as hepatic veno-occlusive disease, is a potentially life-threatening complication that occurs in children undergoing haemopoietic stem-cell transplantation (HSCT). Differences in the incidence of genetic predisposition and clinical presentation of sinusoidal obstructive syndrome between children and adults have rendered the historical Baltimore and Seattle diagnostic criteria insufficient for children. In 2017, the European Society for Blood and Marrow Transplantation (EBMT) proposed the first paediatric diagnostic and severity grading guidelines for sinusoidal obstructive syndrome, intended for implementation across European centres. However, universally accepted paediatric criteria are needed to ensure prompt diagnosis, definitive treatment, and improved outcomes for children, adolescents, and young adults with sinusoidal obstructive syndrome, and to facilitate international clinical research collaboration. We convened an international panel of multidisciplinary experts including physicians with expertise in HSCT, paediatric intensive care, nephrology, hepatology, radiology, pathology, and transfusion medicine; HSCT advanced-practice providers and medical trainees; pharmacists; and translational and basic science researchers from the Pediatric Acute Lung Injury and Sepsis Investigators Network, the EBMT, the Pediatric Blood and Marrow Transplant Consortia, and several other institutions with extensive experience in sinusoidal obstructive syndrome. Panellists convened at The University of Texas, MD Anderson Cancer Center (Houston, TX, USA) in February, 2019, to evaluate the available evidence. In this expert position statement paper, we provide consensus recommendations for the international implementation of guidelines for the diagnosis, severity grading, and treatment of sinusoidal obstructive syndrome among children, adolescents, and young adults. We endorse universal adoption of paediatric diagnostic guidelines for sinusoidal obstruction syndrome as proposed by the EBMT, and provide implementation guidance for standardisation across centres; we have further proposed adjunctive use of age-appropriate organ-specific toxicity criteria for severity grading and provided prophylaxis and treatment considerations among children and adolescent and young adult patients. Key recommendations include: (1) liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of sinusoidal obstructive syndrome in children, adolescents, and young adults; (2) platelet refractoriness can be defined as a corrected count increment of less than 5000-7500 following at least two sequential ABO-compatible fresh platelet transfusions; (3) hepatomegaly is best defined as an absolute increase of at least 1 cm in liver length at the midclavicular line; and if a baseline measurement is not available, hepatomegaly can be defined as greater than 2 SDs above normal for age; and (4) the presence and volume of ascites can be categorised as mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all three regions with >1 cm fluid in at least two regions).
PICO Summary
Population
Paediatric patients with sinusoidal obstruction syndrome / hepatic veno-occlusive disease
Intervention
Guidelines produced by an international panel of multidisciplinary experts from the Pediatric Acute Lung Injury and Sepsis Investigators Network, the EBMT, the Pediatric Blood and Marrow Transplant Consortia, and several other institutions with extensive experience in sinusoidal obstructive syndrome.
Comparison
None
Outcome
Key recommendations include: (1) liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of sinusoidal obstructive syndrome in children, adolescents, and young adults; (2) platelet refractoriness can be defined as a corrected count increment of less than 5000-7500 following at least two sequential ABO-compatible fresh platelet transfusions; (3) hepatomegaly is best defined as an absolute increase of at least 1 cm in liver length at the midclavicular line; and if a baseline measurement is not available, hepatomegaly can be defined as greater than 2 SDs above normal for age; and (4) the presence and volume of ascites can be categorised as mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all three regions with >1 cm fluid in at least two regions).
-
9.
Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)
Richardson, P., Aggarwal, S., Topaloglu, O., Villa, K. F., Corbacioglu, S.
Bone marrow transplantation. 2019
-
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) conditioning or high-dose nontransplant chemotherapy. VOD/SOS with multi-organ dysfunction (MOD) is associated with a mortality rate of > 80%. Defibrotide (25 mg/kg/day) is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post HSCT in the United States and to treat severe hepatic VOD/SOS in patients > 1 month of age in the European Union. A random effects model was used for pooling data from 17 systematically chosen defibrotide studies. For patients in these reports (n = 2598), and those in the subset of 10 reports of patients treated with ~ 25 mg/kg/day (n = 1691), estimated Day + 100 survival rates were 54% and 56%, respectively. Among those patients treated with ~ 25 mg/kg/day, estimated Day + 100 survival was 44% among patients with MOD and 71% in patients without MOD; survival was 41% and 70%, respectively, for the population of patients receiving any dose of defibrotide. Safety results were not pooled owing to differences in reporting methodology but were generally consistent with the known tolerability profile of defibrotide. This analysis provides the largest assessment of survival in patients treated with defibrotide for VOD/SOS with or without MOD.
PICO Summary
Population
Patients with veno-occlusive disease / sinusoidal obstruction syndrome in 17 defibrotide studies (n=2598)
Intervention
Defibrotide ~ 25 mg/kg/day (n = 1691)
Comparison
Any defibrotide dose
Outcome
Day + 100 survival rates were 56% and 54%, respectively. Among those patients treated with ~ 25 mg/kg/day, estimated Day + 100 survival was 44% among patients with MOD and 71% in patients without MOD; survival was 41% and 70%, respectively, for the population of patients receiving any dose of defibrotide. Safety results were not pooled owing to differences in reporting methodology but were generally consistent with the known tolerability profile of defibrotide.
-
10.
Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: Final Results From the International Compassionate-Use Program
Corbacioglu, S., Carreras, E., Mohty, M., Pagliuca, A., Boelens, J. J., Damaj, G., Iacobelli, M., Niederwieser, D., Olavarria, E., Suarez, F., et al
Biology of Blood & Marrow Transplantation. 2016;22(10):1874-82
Abstract
Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable and potentially fatal complication of hematopoietic cell transplantation (HCT) or nontransplantation-associated chemotherapy/radiotherapy. In cases of severe hepatic VOD/SOS, typically defined by associated multiorgan failure (MOF, also known as multiorgan dysfunction), mortality exceeds 80%. Preclinical and early clinical data have provided a rationale for defibrotide treatment in hepatic VOD/SOS. Based on this evidence and in recognition of the dismal prognosis for these patients, defibrotide was made available through an international multicenter compassionate-use program conducted from December 1998 to March 2009. Physicians participating in the program voluntarily provided demographic and outcome data for patients given defibrotide. Efficacy and safety analyses were performed using the data received for 710 treated patients. Defibrotide was given at 10, 25, 40, 60, or 80mg/kg/day for a median of 15 days (range, 1 to 119 days). By Kaplan-Meier analysis, the estimated overall day +100 survival was 54% (58% in the 25mg/kg/day dose group). Adverse events (AEs) were reported in 53% of patients. The most common AEs were MOF, progression of hepatic VOD/SOS, sepsis, and graft-versus-host disease, which were consistent with the AEs expected for this patient population. No clinically meaningful trends in AEs were identified by gender, age, or dose group. Safety and efficacy resultswere consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25mg/kg/day dose. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.