Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Autologous or Allogeneic Hematopoietic Stem Cell Transplantation in Children: a retrospective study of the Italian Hematology-Oncology Association–Hematopoietic Stem Cell Transplantation Group

Abstract

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy by applying the new European Society for Blood and Marrow Transplantation (EBMT) criteria and to analyze the risk factors underlying this complication. We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica)-affiliated centers between January 2000 and April 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. Among 5072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD, and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range, 1 to 104). Sixty-nine patients (67%) were treated with defibrotide for a median time of 16 days (range, 4 to 104). In multivariable analysis age < 2 years, use of busulfan during the conditioning regimen, female gender, and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival at 1 year was worse in patients with SOS/VOD (P = .0033), and this difference disappeared 5 years after HSCT. Nonrelapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (P < .001). Based on the application of new EBMT criteria, the overall incidence of SOS/ VOD recorded in this large Italian pediatric retrospective study was 2%. Nonrelapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood.

Risk Factors for Development of and Progression of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

“…Risk factors for VOD/SOS identified in these studies following univariate, but not multivariate, analysis included cyclophosphamide in an adult study [37] and previous radiation therapy in adults (but not in children in the same study) with high-risk Ewing sarcoma [40]. Transplantation-related factors that reduced the risk of VOD/SOS were reported in 2 pediatric studies [30,39]. These included the use of tacrolimus instead of cyclosporine as a prophylaxis for graft-versus-host disease [39] and the use of cord blood cells as a stem cell source, although this source was used in only 6% of patients in the study [30].…”

“…serum level-adjusted administration of busulfan (adults and adolescents) [38], myeloablative conditioning regimens (total body irradiation-based and busulfan-based) and 2 or more HSCTs [26], use of busulfan-thiotepa conditioning in adults with VOD/SOS requiring pharmacologic treatment with at least analgesics or diuretics [36], and increased trough serum tacrolimus level (above the target range of 5 to 10 ng/mL) [21]. In children, the use of busulfan in conditioning regimens versus nonuse of busulfan was an independent risk factor for VOD/ SOS, diagnosed with the EBMT pediatric criteria in a large study (n = 5072), associated with a cumulative incidence of 5.1% (95% CI, 4.1% to 6.3%; P < .001) [30]. The 90 patients given busulfan who developed VOD/SOS included 5 of the 35 (14.2%) who received oral busulfan and 10 of the 55 (18.1%) who received i.v.…”

“…A retrospective study in children undergoing HSCT (n = 87) in Denmark found that the updated EBMT criteria, which do not require hyperbilirubinemia within 21 days post-HSCT (Table 1), demonstrated higher sensitivity for identifying VOD/SOS than either the modified Seattle or Baltimore criteria [28]. A large Italian study in 5072 children undergoing HSCT at 13 centers found that retrospective use of the EBMT criteria was superior to the Seattle and Baltimore criteria in identifying patients in need of treatment for severe VOD/SOS, although the EBMT identified a relatively low overall cumulative VOD/SOS incidence of 2% [30], compared with previous study data showing a VOD/SOS incidence of 20% to 30% in the pediatric HSCT population [4,15,19,30]. The study authors suggested that use of the EBMT criteria may have omitted mild and moderate cases of VOD/SOS, accounting for the low incidence of VOD/SOS in this population, or that lower-risk conditioning regimens, better supportive treatments, and use of defibrotide as prophylaxis may explain the lower rate [30].…”

“…A large Italian study in 5072 children undergoing HSCT at 13 centers found that retrospective use of the EBMT criteria was superior to the Seattle and Baltimore criteria in identifying patients in need of treatment for severe VOD/SOS, although the EBMT identified a relatively low overall cumulative VOD/SOS incidence of 2% [30], compared with previous study data showing a VOD/SOS incidence of 20% to 30% in the pediatric HSCT population [4,15,19,30]. The study authors suggested that use of the EBMT criteria may have omitted mild and moderate cases of VOD/SOS, accounting for the low incidence of VOD/SOS in this population, or that lower-risk conditioning regimens, better supportive treatments, and use of defibrotide as prophylaxis may explain the lower rate [30]. Earlier rather than delayed defibrotide treatment for VOD/ SOS is also associated with improved outcomes, which further emphasizes the importance of risk assessment and early detection.…”

“…Transplantation-related factors that reduced the risk of VOD/SOS were reported in 2 pediatric studies [30,39]. These included the use of tacrolimus instead of cyclosporine as a prophylaxis for graft-versus-host disease [39] and the use of cord blood cells as a stem cell source, although this source was used in only 6% of patients in the study [30].…”