1.
Current incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients: an EBMT Transplant Complications Working Party study
Ruutu, T., Peczynski, C., Houhou, M., Polge, E., Mohty, M., Kröger, N., Moiseev, I., Penack, O., Salooja, N., Schoemans, H., et al
Bone marrow transplantation. 2023
Abstract
The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (>day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade (p < 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS (p = 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome.
2.
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
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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).