Incidence, Risk Factors for Early Hepatotoxicity and Its Impact on Survival in Patients with Myelofibrosis Undergoing Allogeneic Hematopoietic Cell Transplantation
Authors: Wong Kit Man , Atenafu Eshetu G , Kim Dennis Dong Hwan , Kuruvilla John , Lipton Jeffrey H. , Messner Hans A. , Gupta Vikas 
Published: October 2019

Abstract
Abstract 1951
Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for myelofibrosis (MF), but it is associated with significant morbidity and mortality. Hepatotoxicity is an important regimen-related toxicity of HCT. MF is a myeloproliferative disorder with several features that may impair hepatic function and predispose to liver injury. These include extramedullary hematopoiesis, increased hepatic iron overload from blood transfusions, portal hypertension, and splanchnic vein thrombosis (SVT). It is hypothesized that patients with MF are at high risk of acute hepatocellular injury after allogeneic HCT due to existing hepatic impairment and/or underlying risk factors for hepatotoxicity. We conducted a retrospective chart review of consecutive patients (pts) with MF who underwent HCT from 1981 to 2011 to assess the incidence of liver toxicity, risk factors and its impact on survival. 53 pts were identified: idiopathic MF, 39; post-polycythemia vera (PV) MF, 4; post-essential thrombocytopenia (ET) MF, 10. 94% of the transplants were performed after 1995.
The International Prognostic Scoring System (IPSS) at the time of HCT included intermediate 2 risk (34%) and high risk (55%). Pre-HCT transfusion dependency according to Gale criteria was observed in 60% pts. 11 pts (21%) had a significant history of hepatoportal disease (i.e. SVT, biopsy proven hepatic iron overload, evidence of portal hypertension). Conditioning intensity was myeloablative in 66% and reduced in 34%. Mean baseline values of bilirubin, AST and serum albumin were 14uM (4–38), 24U/L (8–90) and 39g/L (30–49), respectively.
The incidence of mild (34.2mM to 102.6mM), moderate (102.6mM to 342mM) and severe (greater than 342mM) hyperbilirubinemia in the first 6 weeks post-HCT was 32%, 40% and 4%, respectively. The frequency of transaminitis (AST >2x ULN) was 29%. On average, albumin decreased by 9 +/− 4g/L, where a reduction of 10g/L or greater was observed in 44% of patients. There were 18 cases (35%) of hepatic veno-occlusive disease.
In a bivariate analysis, older age at HCT, female gender and longer disease duration were significantly associated with AST elevation, while a history of hepatoportal disease predicted hyperbilirubinemia. The etiology of MF (i.e. idiopathic, post-PV, post-ET), IPSS, transfusion dependency, degree of hepatosplenomegaly, donor match and conditioning intensity had no impact on hepatocellular injury.
Significantly lower overall survival was associated with moderate/severe hyperbilirubinemia (p 0.02) and severe AST elevation (p 0.02). The hazard ratios for non-relapse mortality (NRM) for moderate/severe rises in bilirubin and AST were 4.36 and 7.24, respectively.
Our study shows a high risk of early hepatotoxicity in MF patients undergoing HCT. Early hepatotoxicity is an important cause of NRM and inferior survival in this population. These findings are useful in patient counseling and improving the selection of patients with MF for HCT, as well as in monitoring those at risk for acute hepatocellular injury in the post-HCT setting.

Disclosures:
Gupta: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.