Deferasirox: appraisal of safety and efficacy in long-term therapy

Abstract

Deferasirox is a once-daily, oral iron chelator that is widely used in the management of patients with transfusional hemosiderosis. Several Phase II trials along with their respective extension studies as well as a Phase III trial have established the efficacy and safety of this novel agent in transfusion-dependent patients with β-thalassemia, sickle-cell disease and bone marrow-failure syndromes, including myelodysplastic syndrome and aplastic anemia. Data from various clinical trials show that a deferasirox dose of 20 mg/kg/day stabilizes serum ferritin levels and liver iron concentration, while a dose of 30–40 mg/kg/day reduces these parameters and achieves negative iron balance in red cell transfusion-dependent patients with iron overload. Across various pivotal clinical trials, deferasirox was well tolerated, with the most common adverse events being gastrointestinal disturbances, skin rash, nonprogressive increases in serum creatinine, and elevations in liver enzyme levels. Longer-term extension studies have also confirmed the efficacy and safety of deferasirox. However, it is essential that patients on deferasirox therapy are monitored regularly to ensure timely management for any adverse events that may occur with long-term therapy.

Iron Overload in Myelodysplastic Syndromes: Pathophysiology, Consequences, Diagnosis, and Treatment

“…Further prospective evaluation of deferasirox in the TELESTO trial (ClinicalTrials.gov identifier: NCT00940602) is needed to confirm these data and further define the use of ICT in MDS patients (Shenoy et al, 2014;Taran & Taran, 2015). Life expectancy, transfusion burden, and evidence of iron excess (elevated SF), as well as any related patient comorbidities, are currently the main factors to consider when deciding on ICT in the absence of more rigorous evidence-based guidelines (Chaudhary & Pullarkat, 2013). l…”

“…Consistent with the mechanism of action of hepcidin, RARS patients in this study tended to have the highest levels of toxic nontransferrin bound iron (NTBI; 1.59 µM) while levels in the RAEB and CMML patients were lower (0.03 and 0.19 µM, respectively; p = .058; Santini et al, 2011). Thus, patients with MDS are at risk for IO prior to their becoming transfusion dependent, due to the disease processes seen in MDS, which results in reduced hepcidin production by the liver and increased iron absorption from the gut, ultimately leading to IO ( Figure 1B; Chaudhary & Pullarkat, 2013;Sebastiani et al, 2016;Steensma & Gattermann, 2013). This is an important observation as most of the current concerns in MDS patients may be focused exclusively on transfusion dependence and less so on the disease process.…”

“…In this study, the median overall survival was 3.1 years among the nonchelated patients vs. 10.5 years in those chelated for more than 6 months (p < .001); importantly, median survival was not different for those weakly chelated (fewer than 6 months) and those who were not chelated at all. The management of AEs associated with ICT and the degree of IO is therefore essential to achieve efficacy and benefit (Chaudhary & Pullarkat, 2013). A recent study showed that the effectiveness of deferasirox, measured by the decrease in SF (or LIC via MRI, if available), was significantly better in adherent patients (defined as those with a 90% or greater medication possession ratio) vs. nonadherent patients, and the median adherence rate in this small "real-world" sample (N = 35) was 92% (Escudero-Vilaplana, Garcia-Gonzalez, Osorio-Prendes, Romero-Jimenez, & Sanjurjo-Saez, 2016).…”

Iron Chelation Therapy With Deferasirox in the Management of Iron Overload in Primary Myelofibrosis

“…Deferasirox (DSX) is the principal option currently available for oral ICT 21. DSX has been demonstrated to decrease NTBI, to maintain or reduce body iron (as assessed by serum ferritin) and to have a good tolerability profile with no severe adverse effects in pre-treated or therapy-naïve MDS patients 21,22.…”

“… 21 DSX has been demonstrated to decrease NTBI, to maintain or reduce body iron (as assessed by serum ferritin) and to have a good tolerability profile with no severe adverse effects in pre-treated or therapy-naïve MDS patients. 21 , 22 This oral ICT also seems to induce a hematologic improvement that leads to a significant reduction or complete interruption of blood transfusions in MDS patients, in addition to improving the survival. 23 Hematologic responses also in term of increase in platelet and neutrophil count have been observed in MDS setting.…”