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A 5’UTR polymorphism in NT5E gene but not fludarabine systemic exposure influences HCT outcome in patients with high-risk β-thalassemia major
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  • Aswin Pai,
  • Ezhilpavai Mohanan,
  • John Panetta,
  • Balaji Balakrishnan,
  • Raveen Stephen Illangeswaran,
  • Bharathi Rajamani,
  • Kavitha Lakshmi,
  • Eunice Edison,
  • Anu Korula,
  • Fouzia A,
  • Aby Abraham,
  • Biju George,
  • Alok Srivastava,
  • Vikram Mathews,
  • Poonkuzhali Balasubramanian
Aswin Pai
Christian Medical College

Corresponding Author:[email protected]

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Ezhilpavai Mohanan
Christian Medical College
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John Panetta
St. Jude Children's Research Hospital
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Balaji Balakrishnan
Christian Medical College
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Raveen Stephen Illangeswaran
Christian Medical College
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Bharathi Rajamani
Christian Medical College
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Kavitha Lakshmi
Christian Medical College
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Eunice Edison
Christian Medical College
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Anu Korula
Christian Medical College
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Fouzia A
Christian Medical College
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Aby Abraham
Christian Medical College
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Biju George
Christian Medical College
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Alok Srivastava
Christian Medical College
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Vikram Mathews
Christian Medical College
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Poonkuzhali Balasubramanian
Christian Medical College
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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.