The Risk Factors Associated with Liver Injury and the Impact of Liver Injury On Transplant Related Mortality in Pediatric Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

In adults, hepatic complications following allogeneic hematopoietic stem cell transplantation (AlloHSCT) are associated with significant morbidity and transplant related mortality (TRM). However, there is a paucity of parallel data on the incidence of, and risk factors for, liver injury (LI) and the impact of LI on TRM in pediatric AlloHSCT recipients. Methods: We compared total bilirubin, direct bilirubin and alanine aminotransferase values pre-AlloHSCT and at 1month, day +100  and 12 months post-AlloHSCT in 248 patients following myeloablative conditioning (MAC) or reduced toxicity/reduced intensity conditioning (RTC/RIC). Liver injury was defined as ≥ Grade 2 toxicities according to the NCI CTCAE 3.0/4.0 or total bilirubin 1.95mg/dL (1.5 times above upper limit of normal). Univariate and multivariate logistic regression models were used to identify risk factors for the incidences of LI and TRM. Results: 248 eligible patients received MAC (n=109) or RTC/RIC AlloHSCT (n=139). The incidence of LI at 1 month post-AlloSCT was significantly higher in MAC vs. RTC/RIC AlloHSCT based on total bilirubin levels (21.9% vs. 7.8%; p=0.0067). There was no significant difference in LI pre-AlloHSCT, LI  at day +100 and 12 months post-AlloHSCT between the two groups. The TRM among patients with LI at 1 month post-AlloHSCT was as 64.2% (CI₉₅  49%, 79.4%) compared to 19% (CI₉₅ 11.8, 26.1%) (p<.0001) for those who did not have LI at 1 month post- AlloHSCT. On multivariate analysis, only bloodstream bacterial infections (p=0.0059) and invasive fungal infections (p=0.0020) were significant risk factors for developing LI at 1 month. On multivariate analysis for risk factors for TRM, only LI at 1 month post-AlloHSCT (p=0.0001), primary graft failure (p=0.0096) and bloodstream bacterial infections (p=.0328) were significant. However, LI prior to AlloHSCT conditioning was not associated with higher TRM. Conclusions: TRM among pediatric patients with LI at 1 month post-AlloHSCT is extremely high, with infections being the primary risk factor for LI.