Two-year long safety and efficacy of deferasirox film-coated tablets in patients with thalassemia or lower/intermediate risk MDS: phase 3 results from a subset of patients previously treated with deferasirox in the ECLIPSE study

Abstract

Background: Despite the proven benefits of iron chelation therapy (ICT) in the management of chronic iron overload and related complications, compliance to long-term ICT is challenging. Results from the ECLIPSE study, an open-label, randomized, multicenter, 2-arm, phase 2 study evaluated the safety of deferasirox dispersible tablet and film-coated tablet (FCT) formulations in patients with transfusion-dependent thalassemia (TDT) or very low, low, or intermediate risk myelodysplastic syndrome (MDS) treated over 24 weeks. Methods: The aim of the current study (a 2-year, open-label, multicenter, single-arm, phase 3 study) is to evaluate the long-term safety and efficacy of deferasirox FCT in a subset of patients with TDT or lower/intermediate-risk MDS treated for 2 years after the completion of 24 weeks of treatment with deferasirox in the ECLIPSE phase 2 study. Results: Of 53 patients enrolled, 34 (64.2%) completed treatment and study. Adverse events (AEs) reported in most patients (~ 70%) were of mild to moderate severity. Headache and diarrhea were the most frequently (> 25%) reported AEs. None of the serious AEs (including 1 death) were considered treatment related. No new safety signal was identified, and long-term safety of deferasirox FCT was consistent with the known safety profile of deferasirox. No major concerns associated with gastrointestinal tolerability, renal safety, or hematological abnormalities (thrombocytopenia/neutropenia) were reported during the 2 years. Patients receiving deferasirox FCT had a treatment compliance (by pill count) of ~ 90% and persistence (continuous use for ≥ 30 days) of > 95%. Reduction in serum ferritin level was almost consistent starting from week 2 across all post-baseline time points (relative reduction: month 6, 19%; month 12, 29%).

Pharmacological and clinical evaluation of deferasirox formulations for treatment tailoring

“…Compliance to DFX DT was already close to optimal in the considered series and was slightly but consistently higher for FCT, confirming what was expected from previous reports about the acceptability of this formulation 21 , 23 , 32 , 33 . The evaluation of the impact of DFX FCT on compliance for patients with non-optimal adherence to therapy or a possible psychological role of novelty itself in long-term treatment is beyond the scope of this work.…”

“…Further studies will be required to properly investigate and address the characteristics of these factors. The decrease in FTN observed in patients that took a FCT dose above the mean of all doses administered during the study (ΔFTN = − 504 ± 1216 ng/mL/year at mean dose of 20.2 mg/kg, N = 21) is consistent with the long-term results from patients that took part in the ECLIPSE study (ΔFTN = − 618 ± 1013 ng/ml in 12 months at mean dose of 21.3 mg/kg, N = 36) 32 . Altogether, these results indicate and confirm that DFX FCT is reliable in terms of dose adjusting and effects, thus suggesting the possibility of its better scalability compared to DT, as already observed in the PK analysis for this formulation.…”

“…Different studies are available for FCT and none of them extensively evaluated its effects on renal function in a direct confrontation with DT at the indicated corresponding dose. The ECLIPSE study was limited to 24 weeks 21 and its long-term extension considered FCT only, evaluating sCr, creatinine clearance, and urinary protein/creatinine ratio for up to 2 years in a larger group of patients with very different diagnoses 32 , reporting no major concerns about renal safety. A single-centre study analyzed the switch from DFX DT to FCT in 74 patients with thalassaemia and other transfusion-dependent conditions from all ages and reported a modest rise in mean sCr, with 6 patients (8%) having a sCr increase of > 30% from baseline, and 5 out 6 returning to the normal range by dose adjustment 22 .…”

Allogeneic stem cell transplantation may overcome the adverse impact of myelofibrosis on the prognosis of myelodysplastic syndrome

“…Based on the clinical practice guidelines [ 1 , 24 – 26 ] for MDS, patients with lower-risk MDS were treated with either immunoregulatory therapy (including lenalidomide and cyclosporine) or supportive care alone (including transfusion, erythropoiesis-stimulating agents and iron chelation). If patients had transfusion dependence, they would be given hypomethylating agents (HMA) or allo-HSCT when appropriate donors existed.…”

An update on the US adult thalassaemia population: a report from the CDC thalassaemia treatment centres

“…Oral dispersible as well as film-coated tablet formulations of deferasirox are now available and have shown improved compliance. 6 A new twice daily formulation of deferiprone for transfusional iron overload offers more convenience. 7 Luspatercept, an injectable transforming growth factor-beta (greek B) binding recombinant protein based on activin A, was approved in 2020 and has reduced transfusion requirements in thalassaemia intermedia (TI) and TM.…”