In a study of patients with high-risk thalassemia major (TM), researchers found that a conditioning regimen involving reduced exposure to a component, treosulfan, was linked to some poorer outcomes following hematopoietic stem cell transplantation (HCT). This is according to study results presented in a poster at the 2022 Tandem Meetings by Aswin Anand Pai of Christian Medical College in Vellore, India, and colleagues.

An active metabolite of treosulfan is an epoxide compound called 2S,3S-1,2-epoxybutane-3,4-diol-4-methanesulfonate (S,S-EBDM). This metabolite had previously been described as showing an association with the development of sinusoidal obstruction syndrome in patients with TM who had undergone HCT, the researchers explained in their poster. They undertook the current study with an aim of assessing dose-exposure-response relationships for treosulfan and S,S-EBDM in patients with TM.

Patients in this single-center study had high-risk TM and were undergoing HCT with a conditioning regimen that included treosulfan, fludarabine, and thiotepa. The researchers evaluated plasma levels of treosulfan and S,S-EBDM and analyzed pharmacokinetic parameters related to these compounds. Analyses involved evaluating relationships between treosulfan or S,S-EBDM pharmacokinetics and various HCT-related outcomes, in addition to genetic factors that may relate to treosulfan pharmacokinetics.

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A total of 77 patients were evaluated. The 1-year rate of graft rejection was 6.5% in these patients, and 25% patients experienced sinusoidal obstruction syndrome. Fatalities occurred in 16% of patients owing to multiple causes. The 1-year overall survival rate was 84%, and the 1-year event-free survival rate was 82%.

When considering treosulfan pharmacokinetics, a possible trend toward graft rejection with lower treosulfan exposure was observed. Graft rejection trended toward occurring in patients with a lower area-under-the-curve (AUC) for treosulfan, compared with a higher AUC in patients without graft rejection. The hazard ratio for this analysis was 0.13 (95% CI, 0.02-1.15; P =.06).

When the treosulfan/S,S-EBDM exposure ratio was >19, there was a significantly lower incidence of sinusoidal obstruction syndrome (0%, compared with 25%; P =.002). A treosulfan AUC of >2400 mg*h/L was associated with a trend toward better overall survival (94%, compared with 80%; P =.19), and a trend toward better event-free survival (94.7%, compared with 77.6%; P =.1). The researchers also found that certain genetic polymorphisms appeared related to treosulfan and S,S-EBDM pharmacokinetics.

The researchers concluded that greater exposure to treosulfan was linked to better outcomes with HCT, while increased exposure to S,S-EBDM was linked to greater incidence of sinusoidal obstruction syndrome. They also considered optimal dosing of treosulfan to be important and suggested a prospective study involving therapeutic monitoring-guided conditioning with treosulfan is appropriate.

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Pai AA, Panetta JC, Standing JF, et al. Lower treosulfan systemic exposure predicts graft rejection in patients with beta thalassemia major undergoing allogeneic hematopoietic cell transplantation. Presented at: 2022 Tandem Meetings; April 23-26, 2022. Abstract 303.