Comparison Of Two Combination Iron Chelation Regimens, Deferiprone and Deferasirox Versus Deferiprone and Deferoxamine, In Pediatric Patients With β-Thalassemia Major

Abstract

Background Patients with severe iron overload may require a more rapid and efficient therapy for reduction in iron burden than what can be provided with chelation monotherapy. Combined chelation using deferoxamine (DFO) and deferiprone (DFP) is widely used to treat such patients, but the inconvenience of parenteral administration of DFO reduces the effectiveness of this regimen in many patients. Minimal data are available on the safety and efficacy of combined two orally active chelator agents. Aim To compare the safety, efficacy, compliance, treatment satisfaction, and quality of life (QoL) associated with two combination chelation regimens: DFP and DFO versus DFP and deferasirox (DFX). Methods This was a randomized, open-label trial registered as (NCT01511848) conducted at 2 treatment centers in patients aged 10 to 18 years with β-thalassemia major and severe iron overload (serum ferritin > 2500 μg/ L on chelation monotherapy, with 50% uptrend over the last 12 months). Patients were randomly allocated to one of two 12-month treatment regimens. All patients received DFP at a dose of 75 mg/kg/day, divided into 2 doses taken orally at 8 am and 3 pm. Those in Arm 1 additionally received DFO at a dose of 40 mg/kg/d delivered via subcutaneous infusion pump, starting at 10 pm, while those in Arm 2 additionally received a dose of DFX 20 mg/kg/d, taken orally at 10 pm. The primary efficacy endpoints were the difference between treatment groups in the change from baseline to 12 months of serum ferritin (SF) levels, liver iron concentration (LIC), and cardiac MRI. Secondary efficacy endpoints were the change from baseline to 12 months in QoL, using the Medical Outcomes Study Short Form health survey (SF-36). Serum ferritin was measured every 3 months, and liver and cardiac MRI T2* assessments were conducted every 6 months. Changes in all 3 measures were compared using 2-way ANOVA for repeated measures. The safety endpoint was the occurrence of serious adverse events during the study period. In addition, patients had complete blood count every 2 weeks, and monthly detailed clinical examinations that included blood sampling for serum creatinine, albumin/creatinine ratio, and liver function tests. Audiometric and ophthalmological assessments were conducted at baseline and 12 months. Assessments of compliance and of patient-reported outcomes (PROs) were assessed at weeks 424 and at end of study. Results A total of 96 patients were randomized. The arms were comparable with respect to baseline demographics, with a mean age of 14.9±1.8 years in Arm 1 and 15.1±1.9 years in Arm 2 (p=0.27), and with 65.2% males in Arm 1 and 66.6% males in Arm 2 (p=0.76). Forty of 46 patients (87%) in Arm 1 and 46 of 48 patients (92%) in Arm 2 completed all 12 months of treatment. Reasons for discontinuation were skin infection and pain at infusion sites in Arm 1,and decrease in SF < 1000 μg/ L in Arm 2. Efficacy findings: Table 1 shows the changes in SF, LIC, and cardiac MRI values at baseline and at completion of 1 year on therapy. Safety findings: No serious adverse events were reported during the study in either treatment group. The number of adverse effects reported was comparable in both arms. Compliance: Treatment compliance was significantly higher in Arm 2 than in Arm 1(95% vs. 80%, respectively<0.001). Satisfaction: Significantly more patients in Arm 2 than in Arm 1 reported being satisfied with treatment at both 6 months (92% vs. 64%, respectively; p<0.001) and 12 months (88% vs. 59%, respectively; p<0.001). QoL: Improvement in QoL was seen in significantly more patients in Arm 2 than in Arm 1 (85% vs. 60%, respectively; p<0.001). Conclusion Data from this randomized prospective study show that while both forms of combination therapy, DFP with DFX and DFP with DFO, were effective in reducing iron overload in multi-transfused β-thalassemia major, patients who received DFP and DFX showed a higher decline in serum ferritin, greater improvement in cardiac T2*, higher treatment satisfaction, better compliance, and more improvement in QoL than did patients who received DFP and DFO, with no increased toxicity. Disclosures: No relevant conflicts of interest to declare.

Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization

“…Combination of the orally active DFX with DFO has also had some clinical evaluation (Lal et al , ) and is the subject of further prospective trials (Aydinok et al , ). The combination of two orally active chelators, DFP with DFX, would be more appealing to patients than therapies involving parenterally administered DFO but clinical experience is limited (Elalfy et al , ).…”

Current approach to iron chelation in children

“…Small studies have explored the combination of DFX and DFO or DFP, showing a rapid reduction in systemic and myocardial iron and the potential of a synergistic or additive effect on iron removal (Farmaki et al , ; Lal et al , ). Recent preliminary data from a prospective randomized 1‐year study suggested SF, cardiac T2*, compliance and quality of life were improved in children with TM who received DFP and DFX compared to those who received DFP and DFO (El‐Alfy et al , ). The first results from a large prospective study show that combined therapy of DFX and DFO resulted in an improvement in cardiac T2* during 12 months of treatment with a considerable decrease in LIC in patients with transfusional severe cardiac and liver iron (Aydinok et al , ).…”

Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

“…Ten were multicentre trials (Calvaruso 2015; Elalfy 2015; Galanello 2006; Maggio 2009; Olivieri 1997; Pennell 2006; Pennell 2014; Taher 2017; Tanner 2007; Vichinsky 2007) and ranged from two centres in one country (Calvaruso 2015; Elalfy 2015; Olivieri 1997) to 44 centres in multiple countries (Vichinsky 2007). Six were single-centre trials (Aydinok 2007; Bahnasawy 2017; Badawy 2010; El Beshlawy 2008; Hassan 2016, Mourad 2003).…”

“…The number of participants enrolled in the trials ranged from 24 (Aydinok 2007) to 213 (Maggio 2009). Sample-size calculations were reported in eight trials (Calvaruso 2015; Elalfy 2015; El Beshlawy 2008; Maggio 2009; Pennell 2006; Pennell 2014; Tanner 2007; Vichinsky 2007).…”

“…Where we identified data as being missing or unclear in the published literature, we contacted trial authors directly. We contacted three authors for additional trial information (Antmen 2013; Badawy 2010; Elalfy 2015) and have received one response stating that the trial data were not available at this time (Badawy 2010). We recorded the number of participants lost to follow-up for each trial.…”