Introduction
Hematopoietic cell transplantation (HCT) is the only proven curative modality available for patients with β-thalassemia major (TM). The ideal conditioning regimen for these patients, particularly those at high risk1 remains to be defined. A toxicity reduced conditioning regimen containing Treosulfan (Treo), Fludarabine (F-araA) and Thiotepa has significantly improved transplant outcomes compared to the historical Busulfan/cyclophosphamide (Bu/Cy) based myeloablative regimen in patients with high-risk TM 1,2. However, graft rejection, RRTs, and Graft Versus Host Disease (GvHD)3,4 are still a major concern. Limited inconclusive data is available on the PK, pharmacogenetics (PG) and pharmacodynamics of F-araA 5–11 or Treo 12–19 in patients undergoing HCT with this regimen in patients with varying diagnoses. All these studies including ours have shown wide inter-individual variation in F-araA and Treo PK but none of the variables tested explained this variation. In our recent report on F-araA PK in patients with aplastic anemia/Fanconi anemia9, a promoter polymorphism (rs2295890G>C) in the 5’ectonucleotidase (NT5E /CD73) gene, which is involved in the conversion of prodrug Fludarabine monophosphate to F-araA significantly explained this variation.
While the role of conditioning regimen drug exposure on HCT outcome has been extensively evaluated with respect to Bu/Cy regimen resulting in targeted dose adjustment of Bu to improve outcome20–23, no such effort has yet been made for toxicity reduced conditioning regimen containing Treo/Flu/Thiotepa. Here we evaluated the PK and PG of F-araA and the role of these variables in influencing the inter-individual variability in PK and its influence on HCT outcome in a uniform cohort of patients with high-risk TM.