Risk Assessment of Complications Prevalence in Italian Chelated Transfusion Dependent Thalassemia Patients

Introduction. Thalassemia and hemoglobin disorders are an emerging global health burden, accounting for about 3.4% of deaths in children less than 5 years of age. The current therapeutic management of transfusion dependent thalassemia (TDT) patients is based on regular blood transfusions and iron chelation therapy (CT). Chelation treatment aims to decrease iron stores or correct iron imbalance, and constitutes a major improvement for all people with TDT. Therefore, standards for the treatment of children and adults with TDT have been developed. The three main chelators used in current clinical practice are deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX). The main findings concerning the effectiveness and safety profiles of DFO, DFP, and DFX have been described extensively elsewhere. However, no large cohorts of TDT patients have been evaluated for the role of CT on the prevalence of the composite complications defined as cardiac, liver complication or even death.

The aim of this study was to evaluate the effect of CT, from the onset of the diagnosis, on the prevalence of the composite complications defined as cardiac, liver complication or even death.

Methods. This was a retrospective study on 1511 TDT Italian patients treated with DFO, DFP and DFX. The 2006 was selected as baseline time because of the year when all three chelators were available. The Kaplan-Meir (K-M) survival curves and log-rank tests were considered for assessing the differences among survival probabilities of patients treated with DFP versus DFO and DFP vs DFX. Furthermore, Multivariate Cox Regression Models (MCRMs) were performed to estimate the risk for composite complications, including both type of CT and all considered prognostic variables. By a stepwise backward selection, all predictors not statistically significant, were systematically removed from the full model containing all the prognostic variables (5% level). All statistical analyses were carried out using R software (R Core Team (2021).

Results. A statistically significant difference between the DFO and DFP groups, for comparing the risk of composite complication, was observed (p<0.0001). The estimated K-M survival curve was higher for patients treated with DFP in comparison with those treated with DFO. This suggested as patients treated with DFP had a lower risk to have a composite complication. This result was also observed considering the estimated risk for cardiac complication between the two groups (p<0.0001). A statistically significant difference was shown between DFX vs DFP (p=0.02) only for the risk of cardiac complication, suggesting as the risk of cardiac complication was higher for patients treated with DFX in comparison with DFP. The final MCRM estimating the risk for composite complications, chosen by stepwise backward selection method, suggested that seven variables had prognostic significance: CT (DFO vs DFP), sex, age at diagnosis, serum ferritin (SF), ALT, and ejection fraction (EF). There was significantly greater risk for composite complications of patients treated with DFO vs DFP, for female in comparison with male and this risk was associated with higher levels of SF and ALT and lower levels of EF and age at diagnosis.

Conclusions. DFP showed advantage over DFO in K-M survival curves and log-rank test both for the composite and for the cardiac complication. In the same model, DFP showed advantage over DFX for cardiac and similar effect for the composite complications . Using MCRM, DFP confirmed advantage over DFO with similar result in comparison with DFX. Overall, this study suggested, as oral chelation with DFP had advantage over DFO and it confirmed to have more efficacy for cardiac complication over DFX.