Incidence and Predictors of Late-Occurring Cirrhosis in Long-Term Survivors of Allogeneic Hematopoietic Cell Transplantation (HCT)

Background: There is a paucity of knowledge regarding the incidence and predictors of late-occurring cirrhosis that may be due to early post-HCT hepatic complications or late-occurring risk factors such as iron overload, chronic GvHD, or persistent infectious hepatitis in HCT survivors; furthermore, there is limited information regarding the epidemiology of cirrhosis in HCT survivors after the implementation of universal blood product screening for Hepatitis C in 1992.

Methods: Individuals with late-occurring (≥1 year post-HCT) cirrhosis, utilizing World Health Organization criteria, were selected from 1+year survivors of allogeneic HCT performed at a single institution between 1976 and 2007. The National Hospital Discharge Survey was used to compare the HCT cohort with age-, sex-, and HCT year-specific rates of cirrhosis in the general population. Cox proportional hazards regression analysis was used to calculate relative risk (RR) estimates and 95% confidence intervals (CI), adjusted for relevant covariates.

Results: Thirty nine cases of cirrhosis were identified in a cohort of 1,737 HCT survivors, followed for a median of 6.1y (1-33). Median age at HCT:  33.8y (0.6-74.9); median time to cirrhosis: 6.0y (1-25.6); 64% were male; 41% Hispanic; 62% underwent HCT<1992; Hepatitis C infection was present in 56.4%.  Cumulative incidence of cirrhosis was 1.6% at 10 yrs and 4.6% at 20 yrs post-HCT. The cohort was at a 15-fold increased risk of cirrhosis (standardized incidence ratio [SIR] 15.0, CI:10.8-20.3) when compared to the general population. The risk was highest for patients who underwent HCT<1992 (SIR=27.9, CI:18.2-40.6); the risk remained elevated among those transplanted ≥1992 (SIR=8.7, CI:5.0-13.8). Absolute excess risk for the entire cohort was 26.2 per 10,000 person-years of follow-up. Multivariable analysis adjusted for age, gender, race/ethnicity, diagnosis, treatment era, HCT conditioning, and GvHD, revealed older age at HCT (>40 yrs [RR=5.9, p<0.01]) and total body irradiation (TBI [RR=14.4, p=.01]) to be independent risk factors for cirrhosis. Five-year survival following diagnosis of cirrhosis was 38.2% (primary cause of death: liver failure in 84.6%)

Conclusions: The incidence of cirrhosis increases with time from HCT. While the risk is higher among those transplanted before 1992, recent HCT recipients remain at increased risk. Older age at HCT and conditioning with TBI significantly increase risk of cirrhosis. These data form the basis for targeted surveillance and early intervention in survivors at highest risk for late-occurring hepatic disease.