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.