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Differential effects of the type of iron chelator on the absolute number of hematopoietic peripheral progenitors in patients with β-thalassemia major.

ABSTRACT: Several studies have established an association between iron chelation therapy with deferasirox and hematopoietic improvement in patients with myelodysplastic syndromes. There are no data from patients with β-thalassemia major. In a cross-sectional study, we evaluated the absolute number of several hematopoietic peripheral progenitors (colony-forming unit-granulocyte/macrophage, erythroid burst-forming units, colony-forming unit-granulocyte/erythrocyte/macrophage/megakaryocyte, and long-term culture-initiating cells) in 30 patients with β-thalassemia major (median age 29.5 years, 40% males) and 12 age-matched controls. For the β-thalassemia major patients, data on splenectomy status, the type of iron chelator used, and serum ferritin levels reflecting changes in iron status on the chelator were also retrieved. All patients had to be using the same iron chelator for at least 6 months with >80% compliance. The absolute number of all hematopoietic peripheral progenitors was higher in β-thalassemia major patients than in controls, and varied between splenectomized and non-splenectomized patients (lower number of erythroid burst-forming units and higher numbers of colony-forming unit-granulocyte/macrophage, colony-forming unit-granulocyte/erythrocyte/macrophage/megakaryocyte, and long-term culture-initiating cells). The number of erythroid burst-forming units was significantly higher in patients taking deferasirox (n=10) than in those taking either deferoxamine (n=10) or deferiprone (n=10) (P<0.05). After adjusting for age, sex, splenectomy status, and serum ferritin changes, the association between a higher absolute number of erythroid burst-forming units in deferasirox-treated patients than in patients taking deferoxamine or deferiprone remained statistically significant (P=0.011). In conclusion, in β-thalassemia major patients, compared with other iron chelators, deferasirox therapy is associated with higher levels of circulating erythroid burst-forming units. This variation is independent of iron status changes and is more likely to be due to the type of chelator.

SUBMITTER: Forni GL

PROVIDER: S-EPMC3659986 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.

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Differential effects of the type of iron chelator on the absolute number of hematopoietic peripheral progenitors in patients with β-thalassemia major.

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