BLOG: GSTA1*B polymorphism may be prognostic for treosulfan-based HCT in beta-thalassemia
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Key takeaways:
- This is the first study to investigate treosulfan pharmacogenetics in a large uniform cohort of patients with beta-thalassemia.
- GSTA1*B polymorphism affects treosulfan metabolism, increasing its active metabolite monoepoxide 2S, 3S-1,2-epoxybutane-3,4-diol-4-methanesulfonate (S, S-EBDM) exposure, causing early toxicities, graft-versus-host disease, increased transplant-related mortality and inferior thalassemia-free survival.
- GSTA1*B polymorphism could be a plausible prognostic biomarker for the treosulfan based-hematopoietic cell transplant setting.
A treosulfan-based reduced-toxicity conditioning regimen has significantly improved hematopoietic cell transplantation outcomes for patients with high-risk thalassemia major and hematologic malignancies.
However, complications related to regimen-related toxicities, mixed chimerism and graft rejection limit its success.
We previously explored the pharmacokinetics and pharmacogenetics of treosulfan and its active metabolite monoepoxide 2S, 3S-1,2-epoxybutane-3,4-diol-4-methanesulfonate (S, S-EBDM), where we observed that NAD(P)H Quinone Dehydrogenase-1 (NQO1) and Glutathione S-transferase (GST) polymorphisms contributed significant variability in Treo/S, S-EBDM pharmacokinetics that influenced regimen-related toxicities after HCT.
We also recently proposed a therapeutic cutoff for treosulfan exposure for better HCT outcomes.
In a more recent study, we assessed the impact of these genetic polymorphisms on early clinical outcomes, including transplant-related mortality 100 days after transplant (TRM+100) and 1-year thalassemia-free survival.
We screened NQO1 (rs10517) and GST (GSTA1*B) polymorphisms in all patients with thalassemia major who underwent HCT between January 2012 and June 2022 who received a fludarabine/treosulfan/thiotepa-based conditioning regimen. We used Cox regression analysis to estimate the influence of these genetic polymorphisms on TRM D+100 and 1-year thalassemia-free survival.
Among 314 patients, 180 (57.4%) carried variant genotypes for GSTA1*B polymorphism and 84 (26.8%) carried variant genotypes for GSTA1*B & NQO1 polymorphism.
Patients with variant genotypes for GSTA1*B polymorphism had a significantly higher TRM+100 (P = .01) and inferior 1-year thalassemia-free survival (P = .01). Results showed no association between NQO1 polymorphism and HCT outcomes.
Patients carrying variant genotypes for GSTA1*B polymorphism had significantly higher TRM+100 (82.2% vs. 92.4%; P = .01) and inferior thalassemia-free survival (73.5% vs. 86.4%; P = .009).
Multivariate analysis adjusted for known clinical risk factors revealed only a trend towards higher TRM+100 (HR=1.95; 95% CI, 0.92-4.13) and inferior thalassemia-free survival (HR = 1.77; 95% CI, 0.97-3.23) among patients with GSTA1*B variants.
The study further strengthens our previous findings on treosulfan pharmacokinetics and pharmacogenetics. It is possible that GSTA1*B polymorphism affects treosulfan metabolism, increasing S, S-EDBM exposure causing early toxicities and graft-versus-host disease, resulting in high transplant-related mortality and inferior thalassemia-free survival.
We continue to explore the functional relevance of this variant in treosulfan metabolism.
References:
- Pai AA, et al. Biol Blood Marrow Transplant. 2018. Volume 3, Issue 3, Supplement. Page S80.
- Pai AA, et al. Blood. 2019;134(Supplement_1): 1977.
- Pai AA, et al. Transplant Cell Ther. 2022. Volume 28, Issue 3, Supplement. Page S237.
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