Early Clinical Predictors of Hepatic Veno-Occlusive Disease after Myeloablative Hematopoietic Stem Cell Transplantation: A Single-Center Report of 205 Cases

Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome (SOS), is a serious complication of stem cell transplantation (SCT) with mortality in its severe form exceeding 80%. Early intervention with defibrotide appears to improve outcomes, but prompt diagnosis can be difficult. We aimed to identify clinical features that could aid in early detection of VOD/SOS by reviewing renal function, platelet requirements, tacrolimus levels, and international normalized ratio (INR) preceding VOD/SOS development in a large, retrospective cohort study. From 1996 to 2015, 1823 patients (pts) underwent myeloablative SCT at our center. Of these, 205 (11.2%) developed VOD/SOS overall with median onset at day (d) +14 post SCT. VOD/SOS incidence declined at our institution from 12.5% in 1996-2011 to 5% in 2012-2015, but it remains an important challenge. Pts at greatest risk of VOD/SOS were those who received sirolimus (HR 2.44, 95% CI 1.81-3.29), cord blood SCT (HR 2.15, 95% CI 1.09-4.24), or mismatched related SCT (HR 2.11, 95% CI 1.08-4.12). Median survival time after VOD/SOS was 1.9 months. Pts surviving to d +100 had shorter OS (5y 48% vs 55%, P = .03) and higher NRM (2y 27% vs 15%, P = .004) compared to those without VOD/SOS. Acute kidney injury (AKI), defined as rise in creatinine by ≥.3 mg/dL or ≥50% over 48 hours, was observed in the 7 d preceding VOD/SOS onset in 61%. Platelet refractoriness, defined as requiring platelet transfusions on consecutive days for a set platelet goal without platelet count rising ≥10, was observed in 48%. Trough serum tacrolimus levels were outsideof target range (5-10 ng/mL) in 57% of pts at VOD/SOS onset, 52% 3 d, 42% 5 d, and 55% 7 d before onset respectively. The same clinical features were reviewed in 447 randomly selected controls on d +11 to +18 of SCT, a period chosen as a proxy for the week prior to VOD/SOS development as it spanned median time of VOD/SOS onset. Compared to controls, VOD/SOS cases had higher INR, greater platelet refractoriness, higher median tacrolimus levels, and were more likely to develop AKI (Table 1). The combination of these features should alert clinicians to the diagnosis of VOD/SOS earlier, thus expediting treatment to improve outcomes in this devastating complication of SCT.Table 1VOD/SOS CasesControlsP valueDevelopment of AKI61%33%<0.0001Creatinine, median [IQR]at VOD/SOS diagnosis1.1[0.7-1.7]0.7[0.6-1]<0.00017 d prior to VOD/SOS diagnosis (D-7)0.75[0.59-1]0.64[0.5-0.8]<0.0001Platelet refractory48%24%<0.0001Tacrolimus level, median [IQR]at VOD/SOS diagnosis9.3[6.7-12.5]7.2[5.3-9.6]<0.0001D-39.05[6.8-12.6]7.58[5.9-9.9]<0.0001D-58.85[7-10.8]7.5[5.9-10.2]0.0035D-78.8[6-11.7]7.3[5.75-9.25]0.0002Tacrolimus level outside of target rangeat VOD/SOS diagnosis57%43%0.007D-352%40%0.03D-542%39%0.59D-755%32%<0.0001INR at VOD/SOS diagnosis, median [IQR]1.35[1.2-1.6]1.1[1.1-1.2]<0.0001 Open table in a new tab