Liver Complications after Allogeneic Hematopoietic Stem Cell Transplantation: Descriptive Longitudinal Study Using Liver Parameters Monitoring and Their Impact on Transplantation Outcomes Using a Prediction Score

The indications and use of allogeneic hematopoietic cell transplantation (allo-HCT) have rapidly grown and become a standard procedure for many patients with hematological malignancies. Although the overall outcomes have significantly improved over the past two decades, liver-related complications are often encountered after transplantation and are a large component of the associated overall morbidity and mortality and account for up to 15% of transplantation-related mortality (TRM). The differential diagnosis include drug toxicity, infectious complications, graft versus host disease (GVHD), sinusoidal obstruction syndrome (SOS), metabolic conditions, and development of neoplastic conditions. The principal aim of our study was to evaluate in a longitudinal analysis, the variation of different liver biological parameters, their correlation with liver complications and their impact on transplantation outcomes. Our secondary objective was to establish a score that allows the prediction of liver complications in order to avoid severe evolution.

We included in this study 417 patients who underwent allo-HCT between years 2009 and 2015. There were 245 (59%) males and 172 (41%) females, with a median age at allo-HCT of 49 years (18-69). The major diagnoses were acute leukemias (N=210, 50%), myelodysplastic syndromes (N=64, 15%) and lymphomas (N=60, 14%). Before transplantation, 256 (61%) patients were in complete remission or in "chronic" phase. HC donors were identical siblings in 35% of cases, matched unrelated in 28%, mismatched unrelated in 33% and haploidentical in 4%. Cells source was peripheral blood in 47%, bone marrow in 39% and cord blood in 14% of patients. Conditioning regimens were of reduced intensity in 52% and myeloablative in 48% of transplantations.

A liver screening including bilirubin, alkaline phosphatase, transaminases (ASAT, ALAT) and GGT, was performed twice a week during the first 4 weeks after transplantation, once a week during the second and third months and once a month until the end of the first year, then, once every 3 months during the second year. In case of abnormalities, further analyses were performed including ultrasound and liver biopsy when needed.

Acute GVHD grade ≥II was observed in 160 patients [81 grade II: 19 gut, 61 skin and 1 Liver; 79 grade III-IV: 14 gut grade III & 21 grade IV, 33 skin grade III & 4 grade IV, 3 liver grade III & 4 grade IV]. The cumulative incidence of acute GVHD grade II-IV and grade III-IV at 3 months were 26% [22-31] and 14% [11-18] respectively. Chronic GVHD developed in 133 patients (75 limited & 53 extensive) with a cumulative incidence of 15% (12-19) and 31% (26-35) at 1 & 2 years respectively.

Liver complications observed until 3 months after allo-HCT included 10 GVHD (2 grade I, 1 grade II, 3 grade III and 4 grade IV), 14 SOS, 158 EBV reactivations, 158 CMV reactivations and 101 HHV6 reactivations. The median time of SOS occurrence was 15 days [11-25] with cumulative incidence of 3.12% at 3 months. The median time of EBV, CMV and HHV6 reactivations was 49 days, 43 days and 41 days respectively with a cumulative incidence of 37%, 33% and 20% respectively at 3 months. Over 60 000 results for biological parameters were analyzed and allowed the establishment of a scoring system for each parameter able to predict the occurrence of liver complications notably SOS and acute GVHD. The score took into consideration a parameter value over the normal, its percentage compared to normal value and the way of its evolution over time or its kinetics. The analysis showed significant impact of bilirubin score on SOS (HR=3.9 [2.3-6.4], p<0.001); bilirubin and GGT scores on acute gut GVHD (HR= 11.5 [4.1-32.4], p<0.001 & HR= 2.4 [1.03-5.8], p=0.042 respectively); bilirubin, ASAT and ALAT scores on acute liver GVHD.

After a median follow-up of 14 months, 215 (52%) patients are alive and 202 (48%) died with 110 (26%) from TRM causes and 92 (22%) from relapse. Median survival was 30 [23-37] months with a survival probability at 3 years of 46% [41-52]. The median PFS was 14 [11-20] months with a PFS probability 3 years of 38% [33-43]. In multivariate analysis, ASAT and bilirubin high scores have significantly worsened OS.

In conclusion, we showed a very interesting scoring system that can predict liver complications by monitoring the biological parameters which could prevent morbidity and consequent mortality and leads to optimal allo-HCT outcomes.