Clinicopathologic features of late-onset veno-occlusive disease/sinusoidal obstruction syndrome after high dose intravenous busulfan and hematopoietic cell transplant

Abstract

Most cases of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) occur <21 days after allogeneic hematopoetic stem cell transplantation (HCT). Rarely, however, VOD/SOS can occur later, and can be confused with other causes. We report the clinicopathologic features of 8 patients with advanced hematologic malignancies developing VOD/SOS >30 days after dose-escalated busulfan/fludarabine/alemtuzumab and HCT. Median time to diagnosis=52 days (range: 33–77). For 7 patients, VOD/SOS was confirmed by liver biopsies showing classical features including reticulin deposition within sinusoids, central vein occlusions, hepatocyte atrophy/necrosis, sinusoidal/perivenular hemorrhage, and sparing of portal tracts. VOD/SOS risk was directly related to higher busulfan plasma exposures. Two patients died from VOD/SOS, and in another two patients VOD/SOS was contributory to death. Late-onset VOD/SOS may be underrecognized and should be considered in the differential diagnosis of patients undergoing HCT, particularly after high dose busulfan. Liver biopsy should be entertained even late in the course if appropriate signs/symptoms exist.

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

“…SOS has also been referred to as VOD in transplantation. Autopsy reports have shown that the pathology of human VOD includes reticulin deposition within sinusoids, central vein occlusion, hepatocyte atrophy/necrosis, sinusoidal hemorrhage, and sparing of portal tracts (34). Earlier histopathological findings of VOD can be detected by examining liver biopsy specimens.…”

Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia

“…In previous studies, it was found that not only GO can contribute to this side effect. Also, the combination of GO with thioguanine, busulfan or stem cell transplantation can account for the occurrence of VOD [40].…”

Allogeneic hematopoietic SCT for adults AML using i.v. BU in the conditioning regimen: outcomes and risk factors for the occurrence of hepatic sinusoidal obstructive syndrome

“…BU. 25 Hasegawa et al 26 reviewed 140 children with hematologic malignancies that underwent allogeneic BMT to clarify the incidence, onset time and risk factors for VOD of the liver. Multivariate analysis showed that low serum albumin levels (p3.7 g/dL) before the start of pretransplant conditioning and donor mismatch (other than HLA-matched relatives) were most significantly associated with the development of SOS.…”

“…15,[19][20][21][22][23] The pathogenesis of SOS is thought to involve chemotherapy and radiation-induced damage to the sinusoidal endothelium, resulting in endothelial injury, microthrombosis, subendothelial damage and cytokine activation. 24,25 Severe SOS is typically associated with multi-organ failure and high mortality. 25 Some well-established risk factors are younger age, hepatic inflammation, previous abdominal irradiation, hepatic fibrosis or cirrhosis, myeloablation, use of gemtuzumab ozogamicin, alternative donor transplantation and advanced status of the disease at the time of transplant.…”

“…24,25 Severe SOS is typically associated with multi-organ failure and high mortality. 25 Some well-established risk factors are younger age, hepatic inflammation, previous abdominal irradiation, hepatic fibrosis or cirrhosis, myeloablation, use of gemtuzumab ozogamicin, alternative donor transplantation and advanced status of the disease at the time of transplant. 19,26 However those factors were mainly observed in series of HSCT recipients after using TBI or oral BU in the conditioning regimen.…”