Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced intensity conditioning (RIC) HCT is low compared to myeloablative transplantation, and the natural history, risk factors,
and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007-2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range 5, 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval 1.1%, 2.4%). Day 100 non-relapse mortality rate was 23% in the VOD/SOS cohort compared to 6.4% in patients without VOD/SOS (p=0.006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2+/-ATG (busulfan dose 6.4 mg/kg), compared to 0.15% after Flu/Bu1+/-ATG (busulfan dose 3.2 mg/kg) (p=0.0002); the incidence rate was 2.1% after RIC HCT with sirolimus containing GVHD prophylaxis, compared to 0.8% for RIC without sirolimus (p=0.06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio (HR) 5.1, 95% CI 1.8-14.2, p=0.002) and RIC regimen with Flu/Bu2+/-ATG (HR 34, 95% CI 4.5 - 252, p<0.001) or other (HR 32, 95% CI 3.9 - 257, p=0.001) compared to Flu/Bu1+/-ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared to a previously published cohort of 76 VOD/SOS pts who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT.