Verification of the Prediction Accuracy of a Biomarker-Based Prognostic for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) After Hematopoietic Cell Transplantation (HCT)

Abstract

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT), especially in severe cases. Patient outcomes are improved with prompt treatment; however, diagnosing this disease is challenging as many clinical symptoms of VOD/SOS overlap with other post-HCT complications. A biomarker-based prognostic test for the assessment of VOD/SOS risk, termed "VODCheck" was developed in a previous study but has not yet been validated. This study aimed to validate the accuracy of VODCheck as a prognostic test for VOD/SOS in an independent cohort of patients. VODCheck incorporates hyaluronan (HA), angiopoietin-2 (ANG-2), and thrombomodulin (TM) based on their association with VOD/SOS, their analytical characteristics, and their ability to complement each other in a multivariate prognostic model. To validate VODCheck we measured plasma biomarker levels from a subset of patients enrolled in the control arm of a phase 3 study that tested VOD/SOS prophylaxis. We used a hierarchical design with prespecified primary (day 7), secondary A (day 15), and secondary B (day 1) hypotheses to verify the prognostic accuracy of VODCheck post-HCT. The cases of VOD/SOS (n = 22) were age-matched ∼1:3 with controls (n = 65). VODCheck was prognostic of VOD/SOS risk at all 3 time points with an area under the curve (AUC) of .815 (P < .001) for day 7, .836 (P < .001) for day 15, and .706 (P = .002) for day 1 post-HCT. A multivariate analysis confirmed the prognostic accuracy of VODCheck after adjustment for confounders such as age, VOD/SOS risk status, primary disease, and ozogamicin treatment. VODCheck was validated as an independent predictor of risk for VOD/SOS within 15 days post-HCT and appears to provide clinicians with actionable information to improve patient care.

Keywords: Biomarkers; Defibrotide; Sinusoidal obstruction syndrome; Veno-occlusive disease.