Sinusoidal obstruction syndrome/veno-occlusive disease after high-dose intravenous busulfan/melphalan conditioning therapy in high-risk Ewing Sarcoma

Abstract

This mono-institutional observational study was conducted to determine incidence, severity, risk factors, and outcome of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) in high-risk Ewing sarcoma (ES) patients treated with intravenous busulfan and melphalan (BU-MEL) followed by autologous stem cell transplantation (ASCT). During the past 10 years, 75 consecutive ES patients resulted evaluable for the analysis. After diagnosis of SOS/VOD, defibrotide therapy was started as soon as the medication was available. The variables analyzed as potential risk factors were: gender, patient's age at diagnosis, primary tumor site, disease stage, and prior radiation therapy (RT) given, focusing on RT liver exposure. The median age at diagnosis was 18.8 years. Five patients developed moderate to severe SOS/VOD (cumulative incidence, 6.67%). None of 32 pediatric patients (≤17 years) developed SOS/VOD (p = 0.0674). In univariate analysis, prior RT liver exposure resulted statistically significant (p = 0.0496). There was one death due to severe SOS/VOD. This study reports the largest series of high-risk ES patients treated with intravenous BU-MEL before ASCT. The incidence of SOS/VOD was lower when compared with other studies that used oral busulfan. Any prior RT liver exposure should be avoided. Earlier defibrotide treatment confirms to be effective.

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

“…Pharmacokinetics of plasma busulfan were monitored in all patients. 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].…”

“…The recently reported data demonstrate that although certain risk factors are established for VOD/SOS, independent risk factors may vary across populations and may include risks not previously noted in the literature. In addition, although review data indicate that VOD/SOS occurs most commonly after allogeneic HSCT [4], 3 recent studies (adult and pediatric) in autologous HSCT reported VOD/SOS incidence of approximately 7%, 8%, and 31% (Table 5) [5,36,40]. Other studies have also reported the incidence of VOD/SOS in patients receiving haploidentical HSCT [45,46], including delayed cases (e.g., median onset 44.5 days post-HSCT) [46].…”

Sinusoidal Obstruction Syndrome of the Liver Associated With 6-Mercaptopurine During Maintenance in a Child With T-cell Acute Lymphoblastic Leukemia

“…For patients with solid tumors, previous evidence suggests that various regimens, such as actinomycin D, high-dose cyclophosphamide, busulfan and melphalan followed by autologous stem cell rescue, and other highintensity chemotherapy regimens, with or without radiation therapy, may pose a risk to develop SOS, although the cumulative incidence is still rare. 2,[9][10][11][12][13][14] For patients with acute lymphoblastic leukemia/lymphoma, the incidence of SOS in the absence of HSCT is also unknown, but the most well-known risk factor for this patient population is the use of 6-TG. 3,4 6-TG is thought to be a more potent thiopurine than its analog 6-MP; however, increased toxicities associated with 6-TG have historically limited its utilization.…”

“…SOS may affect up to 27% of pediatric patients undergoing allogeneic HSCT:1 the incidence in oncology patients, in the absence of allogeneic HSCT, is more difficult to quantify. For patients with solid tumors, previous evidence suggests that various regimens, such as actinomycin D, high-dose cyclophosphamide, busulfan and melphalan followed by autologous stem cell rescue, and other high-intensity chemotherapy regimens, with or without radiation therapy, may pose a risk to develop SOS, although the cumulative incidence is still rare 2,9–14…”

High-dose chemotherapy with autologous hematopoietic stem cell transplantation in high-risk neuroblastoma patients: Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg experience

“…Это может объясняться различиями в индукционной терапии, возрастом и более поздними сроками приживления в исследованной когорте. Полученные данные близки к частоте веноокклюзионной болезни печени в близкой по возрастным характеристикам когорте пациентов с опухолями семейства саркомы Юинга, получивших тот же режим кондиционирования [25]. Только 1 смерть непосредственно связана с токсичностью процедуры и еще в 1 случае смерть больного связана с последствиями геморрагического инсульта, произошедшего после восстановления показателей гемопоэза при значениях тромбоцитов более 20 × 10 9 .…”