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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
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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.

Peer review status:IN REVISION

15 Jan 2021Submitted to British Journal of Clinical Pharmacology
18 Jan 2021Assigned to Editor
18 Jan 2021Submission Checks Completed
18 Jan 2021Reviewer(s) Assigned
04 Feb 2021Review(s) Completed, Editorial Evaluation Pending
08 Feb 2021Editorial Decision: Revise Major