A 5’UTR polymorphism in NT5E gene but not fludarabine systemic exposure
influences HCT outcome in patients with high-risk β-thalassemia major
Abstract
Aim Although the fludarabine (F-araA)-treosulfan based toxicity reduced
conditioning regimen has improved hematopoietic cell transplantation
(HCT) outcome in patients with high-risk beta-thalassemia major (TM),
rejection and regimen related toxicities (RRT) are still of major
concern. This study aims to assess the role of F-araA pharmacokinetics
(PK) and pharmacogenetics (PG) in a uniform cohort of patients with TM.
Methods All patients with TM who receiving F-araA based regimen prior to
HCT between September 2010 and 2019 were enrolled in this study. F-araA
plasma levels were analyzed using LC-MS/MS. Selected polymorphisms in
genes encoding for the enzymes (NT5E (Ecto-5’-nucleotidase) and DCK
(Deoxycytidine kinase) involved in the metabolism of F-araA were
screened. The influence of F-araA PK and PG on clinical outcomes were
evaluated. Results F-araA PK showed wide inter-individual variation (27
and 19 fold in F-araA AUC and CL) which was explained by a promoter
polymorphism (rs2295890) in the NT5E gene. Patients carrying the NT5E
promoter variant showed no graft rejection (0% vs 7.7%, p=0.07) or
Sinusoidal Obstruction Syndrome (0% Vs 19%, p=0.0007) and a trend to
better EFS (87.5% vs 75.7%, p=0.1). F-araA systemic exposure was not
associated with HCT outcome. Conclusion Our results suggest that the
NT5E promoter polymorphism could be a predictive biomarker in F-araA
based HCT setting in TM, however extensive functional studies are
warranted to validate the clinical utility of this finding.