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Incidence of Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease and Treatment with Defibrotide in Allogeneic Transplantation: A Multicenter Australasian Registry Study
Coutsouvelis, J., Kirkpatrick, C. M., Dooley, M., Spencer, A., Kennedy, G., Chau, M., Huang, G., Doocey, R., Copeland, T. S., Do, L., et al
Transplantation and cellular therapy. 2023;29(6):383.e1-383.e10
Abstract
Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is an established complication in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT). Defibrotide is an effective and safe pharmacologic option for treating diagnosed SOS/VOD. By exploring data provided to the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) by centers in Australia and New Zealand, this study aimed to describe the incidence of SOS/VOD and patterns of defibrotide use from 2016 to 2020. Patients who underwent allogeneic hemopoietic stem cell transplantation between 2016 and 2020 were identified from the ABMTRR. Data were extracted for a total of 3346 patients, 2692 from adult centers and 654 from pediatric centers, with a median follow-up of 21.5 months and 33.3 months, respectively. Descriptive statistics were used to describe the patient population, including the incidence of SOS/VOD and defibrotide use. Comparisons were made between patients without SOS/VOD and those with SOS/VOD, divided into defibrotide and no defibrotide cohorts. Associations with overall survival (OS) and day 100 survival with such variables as sex, age, disease at transplantation, stem cell source, conditioning agents, SOS/VOD diagnosis, and use of defibrotide, were determined. The reported incidence of SOS/VOD was 4.1% in adult centers and 11.5% in pediatric centers. Defibrotide was administered to 74.8% of adult patients and 97.3% of pediatric patients with SOS/VOD. Significant variability in the use, dosage, and duration of defibrotide was seen across the adult centers. The day 100 survival rate and median OS for patients managed with defibrotide was 51.8% and 103 days, respectively, for adult patients and 90.4% and not reached, respectively, for pediatric patients. In adults, older age at transplantation, an HLA-matched nonsibling relative donor, and a diagnosis of SOS/VOD treated with defibrotide were associated with reduced OS. In pediatric patients, the patient and transplantation characteristics associated with reduced OS were a diagnosis of SOS/VOD and a ≥2 HLA-mismatched related donor. A collaborative approach across Australasia to diagnosing and managing SOS/VOD, particularly with respect to consistent defibrotide use, is recommended.
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Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study
Mohty, M., Blaise, D., Peffault de Latour, R., Labopin, M., Bourhis, J. H., Bruno, B., Ceballos, P., Detrait, M., Gandemer, V., Huynh, A., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.
PICO Summary
Population
Adults and children receiving defibrotide for treatment or prophylaxis of veno-occlusive disease / sinusoidal obstruction syndrome (VOD/SOS) between July 2014 to March 2020 at 53 French HCT centres (n=798)
Intervention
Defibrotide for severe/very severe VOD/SOS (n=251); Defibrotide for mild/moderate VOD/SOS (n=81)
Comparison
Defibrotide for VOD/SOS prophylaxis (n=381)
Outcome
In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated complete remission (CR) at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%.
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Defibrotide-treated patients with anicteric or icteric veno-occlusive disease/sinusoidal obstruction syndrome after hematopoietic cell transplantation: an EBMT study
Mohty, M., Cluzeau, T., Jubert, C., Lawson, S., Ryan, R. J., Hanvesakul, R., Perruccio, K.
Bone marrow transplantation. 2022
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A multicentre, multinational, prospective, observational registry study of defibrotide in patients diagnosed with veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation: an EBMT study
Mohty, M., Battista, M. L., Blaise, D., Calore, E., Cesaro, S., Maximova, N., Perruccio, K., Renard, C., Wynn, R., Zecca, M., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan-Meier-estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.
PICO Summary
Population
Patients with veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) treated with defibrotide (n=104)
Intervention
Patients with severe VOD/SOS (n=62)
Comparison
None
Outcome
SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan-Meier-estimated Day 100 survival rate was 73% with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. Multi-organ dysfunction/failure (MOD/MOF) resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis.
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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.
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Prior Gemtuzumab Ozogamicin Exposure in Adults With Acute Myeloid Leukemia Does Not Increase Hepatic Veno-occlusive Disease Risk After Allogeneic Hematopoietic Cell Transplantation: A CIBMTR Analysis
Ho, V. T., Martin, A. S., Perez, W. S., Steinert, P., Zhang, M. J., Chirnomas, D., Hoang, C. J., Loberiza, F. R., Jr., Saber, W.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
Gemtuzumab ozogamicin (GO) therapy prior to allogeneic hematopoietic cell transplantation (alloHCT) has been historically associated with an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with acute myeloid leukemia (AML). The current analysis examined VOD/SOS risk and outcomes in a cohort of patients who in recent years reported to the Center for International Blood & Marrow Transplant Research. Adults with AML who had GO exposure prior to myeloablative alloHCT were matched 1:4 by age and disease status at transplant to recipients without GO exposure (controls). A total of 137 patients with GO exposure and 548 matched controls who underwent alloHCT between 2008 and 2011 were included in this analysis. With a median approximately 8-year follow-up of survivors, the 5-year overall survival probability was similar in the 2 cohorts: 38% and 38% in the GO-exposed versus control (P=.97) group. Incidence of VOD/SOS and severe VOD/SOS, respectively, at 100 days was 4% (95% confidence interval [CI]: 1-7) and 3% (95% CI: 1-6) in GO-exposed patients and 3% (95% CI: 2-5) and 1% (95% CI: 0-2) in controls. Correspondingly, among patients who developed VOD/SOS, 1-year survival probability after VOD/SOS diagnosis was 33% (95% CI: 5-72) and 27% (95% CI: 11-47) (P=.78). In multivariate analyses, GO exposure prior to alloHCT was not associated with an increased risk of VOD/SOS (odds ratio 1.10; P=.85) or death (hazard ratio 1.08; P=.57). Three (3%) deaths in the GO group and 3 (<1%) deaths in the control group were attributed to VOD/SOS. Our results suggest that GO treatment prior to myeloablative alloHCT in the recent era is not associated with an increased risk of post-transplant VOD/SOS or death.
PICO Summary
Population
Adults with acute myeloid leukaemia (n=685)
Intervention
Gemtuzumab ozogamicin (GO) therapy prior to myeloablative allogeneic transplant (n=137)
Comparison
Age- and disease-matched controls without GO exposure (n=548)
Outcome
The 5-year overall survival probability was similar in the 2 cohorts: 38% and 38% in the GO-exposed versus control group. Incidence of VOD/SOS and severe VOD/SOS, respectively, at 100 days was 4% and 3% in GO-exposed patients and 3% and 1% in controls. Correspondingly, among patients who developed VOD/SOS, 1-year survival probability after VOD/SOS diagnosis was 33% and 27%. In multivariate analyses, GO exposure prior to alloHCT was not associated with an increased risk of VOD/SOS or death. Three (3%) deaths in the GO group and 3 (<1%) deaths in the control group were attributed to VOD/SOS.
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The incidence and risk factors of hepatic veno-occlusive disease after hematopoietic stem cell transplantation in Taiwan
Lee, C. C., Chang, H. H., Lu, M. Y., Yang, Y. L., Chou, S. W., Lin, D. T., Jou, S. T., Yao, M., Li, C. C., Yeh, S. P., et al
Annals of hematology. 2019
Abstract
Hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). We conducted this study to investigate the incidence and risk factors of hepatic VOD for patients receiving HSCT in Taiwan. We retrospectively analyzed the data from a nationwide registry for patients receiving HSCT, which was collected by the Taiwan Society of Blood and Marrow Transplantation. The data collection period was from 2009 to 2014. A total 2345 patients were reviewed and 39 patients among them were diagnosed as having hepatic VOD. The cumulative incidence of hepatic VOD in the whole cohort of 2345 patients was 1.66%. In multivariate analysis, disease diagnosis of myelodysplastic syndrome, chronic HCV infection, condition regimens of bulsulfan intravenously administered, and antithymocyte immunoglobulin were independent factors to predict higher risk of hepatic VOD. The overall mortality rate for patients with hepatic VOD was 79%. Patients with hepatic VOD had significant worse survival outcomes when compared with those without hepatic VOD (P = 0.00063). In conclusion, although the incidence is low, hepatic VOD remains a serious complication after HSCT in Taiwan. The findings of this study could be the basis for developing prophylactic or early treatment strategies for hepatic VOD.
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"Risk Score for Development of Veno-Occlusive Disease After Allogeneic Hematopoietic Cell Transplant"
Strouse, C., Zhang, Y., Zhang, M. J., DiGilio, A., Pasquini, M., Horowitz, M. M., Lee, S., Ho, V., Ramanathan, M., Chinratanalab, W., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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Editor's Choice
Abstract
BACKGROUND A risk score identifying patients at high risk for veno-occlusive disease (VOD) may aid efforts to study preventive strategies for this uncommon complication of hematopoietic cell transplantation (HCT). METHODS Patients receiving a first allogeneic HCT between 2008-2013 as reported to the Center for International Blood & Marrow Transplant Research (N=13,097) were randomly divided into training and validation sets. Independent prognostic factors for development of VOD by day+100 post HCT were identified with a multivariate logistic regression model. A risk score was constructed in the training set using the significant factors and confirmed in the validation set. RESULTS Baseline characteristics of the training and validation sets were balanced. In total, 637 patients (4.9%) developed VOD by day+100. Younger age, positive hepatitis B/C serology (HBV, HCV), lower Karnofsky performance score (KPS), use of sirolimus, disease, disease status at transplant, and conditioning regimen were independent prognostic factors. Myeloablative (MAC) regimens were associated with higher risk of VOD. Busulfan-based MAC regimens guided by pharmacokinetic monitoring (PK) were associated with higher risk than those without PK. The patients were stratified into 4 distinct, statistically significantly different groups by their risk score percentile. CONCLUSION This pre-transplant risk score successfully stratified allogeneic HCT patients by risk of developing VOD, was validated in an independent set, and demonstrated strong discriminatory ability to identify a high-risk cohort.
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Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research
Strouse, C., Richardson, P., Prentice, G., Korman, S., Hume, R., Nejadnik, B., Horowitz, M. M., Saber, W.
Biology of Blood & Marrow Transplantation. 2016;22(7):1306-12
Abstract
Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.