Both iron chelation combination regimens were equally effective in reducing iron overload and improving QoL.DFP/DFX combination proved superior in improving cardiac T2*, treatment compliance, and patients satisfaction with no greater adverse events.
Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload and requires chelation therapy. The iron chelator deferiprone is often used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study (NCT02041299) assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was −4.04 (0.48) mg/g dry weight for deferiprone vs −4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, −0.76, 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia.
Iron overload is inevitable in patients who are transfusion dependent. In young children with transfusion-dependent thalassemia (TDT), current practice is to delay the start of iron chelation therapy due to concerns over toxicities, which have been observed when deferoxamine was started too early. However, doing so may increase the risk of iron accumulation that will be manifested as toxicities later in life. This study investigated whether deferiprone, a chelator with a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. Recently diagnosed TDT infants (N = 64 their age ranged from 10 to 18 (median 12) months, 54.7% males; receiving ≤6 transfusions; serum ferittin (SF) >400 to < 1000 ng/mL were randomized to "early start deferiprone" (.ES-DFP) at a low dose (50 mg/kg/day) or to "delay chelation" (DC), and remained in the study until their serum ferritin (SF) level reached ≥1000 μg/L. 61 patients continued the study Levels of transferrin saturation (TSAT) and labile plasma iron (LPI) were measured as well. By approximately 6 months postrandomization, 100% of the subjects in DC group had achieved SF > 1000 µg/L and TSAT > 70% compared with none in the ES-DFP group. LPI level > 0.6 µM was observed in 97% vs. 40% of the DS and ES groups, respectively, (P < 0.001). The time to reach SF > 1000 µg/L was delayed by 6 months in the ES-DFP group (P < 0.001) without escalating DFP dose. No unexpected, serious, or severe adverse events were seen in the ES-DFP group.
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.
Long-term safety and efficacy data on the iron chelator deferiprone in sickle cell disease (SCD) and other anemias are limited. FIRST-EXT was a 2-year extension study of FIRST, a 1-year, randomized non-inferiority study of deferiprone versus deferoxamine in these populations. Patients who entered FIRST-EXT continued to receive, or were switched to, deferiprone. Altogether, 134 patients were enrolled in FIRST-EXT (mean age: 16.2 years), with mean (SD) exposure to deferiprone of 2.1 (0.8) years over the 2 studies. The primary endpoint was safety. Secondary endpoints were change in liver iron concentration (LIC), cardiac T2*, serum ferritin, and the proportion of responders (≥20% improvement in efficacy measure). The most common adverse events considered at least possibly related to deferiprone were neutropenia (9.0%) and abdominal pain (7.5%). LIC (mg/g dry weight) decreased over time, with mean (SD) changes from baseline at each time point (year 1: −2.64 [4.64], year 2: −3.91 [6.38], year 3: −6.64 [7.72], all P<0.0001). Mean serum ferritin levels (µg/L) decreased significantly after year 2 (−771 [P=0.0008]) and year 3 (−1016 [P=0.0420]). Responder rates for LIC and serum ferritin increased each year (LIC: year 1, 46.5%; year 2, 57.1%; year 3, 66.1%; serum ferritin: year 1, 35.2%; year 2, 55.2%; year 3, 70.9%). Cardiac T2* remained normal in all patients. In conclusion, long-term therapy with deferiprone was not associated with new safety concerns and led to continued and progressive reduction in iron load in individuals with SCD or other anemias. #NCT02443545.
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