High Tacrolimus Trough Concentrations Is an Early Predictor of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Allogeneic Hematopoietic Cell Transplantation in Children.

Introduction Veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) is potentially a fatal complication of hematopoietic cell transplantation (HCT). Prompt diagnosis and initiation of treatment is associated with improved survival. Platelet refractoriness, elevated serum creatinine, and high tacrolimus trough concentrations have predicted onset of VOD in adult patients earlier than the Baltimore and modified Seattle criteria. Data on ability of tacrolimus trough concentrations to predict onset of VOD in pediatric HCT patients are lacking. Objective Compare the correlation of high tacrolimus trough concentrations with the day of diagnosis of VOD in pediatric HCT patients. Methods This single-center IRB approved, retrospective study included patients undergoing allogeneic HCT between 2009 and 2023 who received tacrolimus and developed VOD. Patient demographics, tacrolimus trough levels and dose changes, day of VOD diagnosis by the European Society of Blood and Marrow Transplantation (EBMT) pediatric criteria, modified Seattle criteria, and Baltimore criteria were collected. Data are presented as median and interquartile range (IQR). Results Forty patients with a median age of 2.1 years (IQR: 0.8, 11.7) received an allogeneic HCT for malignant (29/40 =72.5%) and non-malignant disorders (11/40 =27.5%). Busulfan/cyclophosphamide (21/40 =52.5%) or busulfan/fludarabine (6/40 =15%) based conditioning regimens were the most commonly used with 13/40 (32.5%) categorized as others. Tacrolimus + methotrexate (21/40 =52.5%) was the most common graft-versus-host disease prophylaxis followed by tacrolimus + mycophenolate (11/40 =27.5%). Unexplainable elevated tacrolimus trough concentrations were observed at a median of day +8 (IQR: 6, 10) after transplant with VOD being diagnosed at a median of day +10 (IQR: 9, 13), day +11 (IQR: 8, 15), and day +14 (IQR: 12, 16) using the EBMT, modified Seattle, and Baltimore criteria, respectively (figure). Tacrolimus trough concentrations were elevated at a median of 2, 4, and 5 days before VOD was diagnosed based on EBMT, modified Seattle, or Baltimore criteria, respectively. A median tacrolimus trough concentration of 15.4 ng/mL (IQR: 13.6, 17.5) was observed in 40/40 (100%) patients prior to VOD diagnosis. Trough concentrations kept rising to as high as 17.5 ng/mL (IQR: 16, 21) and remained elevated for 9 days (IQR: 3, 12), with doses held in 20/40 (50%) patients for a median of one day (IQR: 0, 3). Tacrolimus dose reduction was necessary in all patients (40/40, 100%) with a median dose decrease of 73% (IQR: 64%, 88%). Conclusion Unexplainable, elevated tacrolimus trough concentrations were observed in 100% pediatric HCT patients earlier than the VOD diagnosis. This observation should not only help in the earlier diagnosis of VOD, but also in initiation of early treatment with defibrotide.