Hepatic Toxicity After Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation: Incidence, Characteristics and Risk Factors In a Cohort of 452 Patients.

Hepatic dysfunction is one of the most frequent and less studied complications in the setting of allogeneic stem cell transplantation (Allo). To analyze the incidence, characteristics, risk factors and impact on outcome of hepatic dysfunction in reduced intensity conditioning Allo (Allo-RIC) recipients we conducted a retrospective study in three large Spanish centers.

We analyzed 452 consecutive patients receiving an Allo-RIC between February 1998 and December 2008. Median age was 53 years (range [rg] 18–71). The median follow-up for survivors was 4 years (rg 0.2–10) RIC consisted in fludarabine 150mg/m2 plus melfalan 70–140 mg/m2 or busulfan 8–10mg/kg. Grades of hepatic dysfunction were defined according to the National Cancer Institute criteria (3.0). Severe hepatic toxicity was considered in patients presenting grade III-IV abnormalities after Allo-RIC in at least one of the following: aspartate aminotransferase (AST), alanine aminotransaminase (ALT), gamma glutamyl transpeptidase (GGT), total bilirubin and protrombin time.

A total of 307 patients (68%) developed grade III-IV hepatic toxicity at a median time of 176 days (rg 0–3868) for a cumulative incidence of 69% (95%IC 63–76). A total of 123 (27%), 179 (40%), 140 (31%) and 132 (29%) patients developed grade III-IV levels of AST, ALT, GGT and bilirubin, respectively. Median time of detection of AST, ALT, GGT and bilirubin peaks in days was 177 (rg 0–1200), 168 (rg 0–2253), 452 (rg 257–3126) and 74 (rg 0–783), respectively. Grade III-IV protrombin time abnormalities were found in 23 (5%) patients at a median time of 69 days (11-3868). Main causes of severe hepatic toxicity after Allo were graft versus host disease (GVHD) (n=127, 41%) and pharmacological toxicity (n=32, 10%). In multivariate analysis, risk factors for the development of severe hepatic toxicity were unrelated donors (HR 1.4 [95%CI 1–1.9] p=0.03), use of busulfan in the conditioning regimen (HR 1.3 [95%CI 1–1.7] p=0.04) and high levels of bilirubin and GGT before transplant (HR 2.4 [95%CI 1.6–3.2] p<0.001 and HR 2.7 [95%CI 1.7–4.3] p<0.001, respectively). Patients with severe hepatic toxicity showed higher 4-years non-relapse mortality (NRM) (HR 1.5 [95%CI 1.1–2.1] =0.01) and lower 4-years overall survival (OS) (HR 1.7 [95%CI 1.2–2.5] =0.007). Regarding specific hepatic toxicities, patients with grade III-IV bilirubin levels showed higher NRM and lower OS (HR 3.4 [95%CI 2.3–5.2] p<0.001 and HR 2.5 [95%CI 1.7–3.8] p<0.001, respectively), while patients with grade III-IV protrombin time abnormalities had lower OS (HR 2 [95%CI 1.2–3.4], p=0.005). AST and ALT abnormalities after Allo did not have any impact on NRM and OS. Interestingly, patients with high GGT levels after Allo seemed to have a better outcome with lower NRM and higher OS (HR 0.1 [95%CI 0.1–0.2] p<0.001 and HR 0.2 [95%CI 0.1–0.4] p<0.001, respectively). Regarding GVHD, patients with severe hepatic toxicity did not show higher incidence of acute or chronic GVHD.

Hepatic toxicity is frequent and diverse after Allo-RIC. Grade III-IV bilirubin levels were associated with worse outcome of the procedure while grades III-IV GGT levels seemed to be associated with better outcome. High transaminase levels did not show an impact in our patients.

No relevant conflicts of interest to declare.