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&lt;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.

Background and Objectives Shortage of blood during the severe acute respiratory syndrome‐COV‐2 (SARs‐COV‐2) pandemic impacted transfusion practice. The primary aim of the study is to assess management of acute haemolytic crisis (AHC) in glucose‐6‐phosphate dehydrogenase(G6PD)‐ deficient children during SARs‐COV‐2 pandemic, and then to assess blood donation situation and the role of telemedicine in management. Methods Assessment of G6PD‐deficient children attending the Emergency Department (ER) with AHC from 1 March 2020 for 5 months in comparison to same period in the previous 2 years, in three paediatric haematology centres. AHC cases presenting with infection were tested for SARs‐COV‐2 using RT‐PCR. Children with Hb (50–65 g/L) and who were not transfused, were followed up using telemedicine with Hb re‐checked in 24 h. Results A 45% drop in ER visits due to G6PD deficiency‐related AHC during SARs‐COV‐2 pandemic in comparison to the previous 2 years was observed. 10% of patients presented with fever and all tested negative for COVID‐19 by RT‐PCR. 33% of patients had Hb < 50 g/L and were all transfused. 50% had Hb between 50 and 65 g/L, half of them ( n = 49) did not receive transfusion and only two patients (4%) required transfusion upon follow up. A restrictive transfusion strategy was adopted and one of the reasons was a 39% drop in blood donation in participating centres. Conclusion Fewer G6PD‐deficient children with AHC visited the ER during SARs‐COV‐2 and most tolerated lower Hb levels. Telemedicine was an efficient tool to support their families. A restrictive transfusion strategy was clear in this study.

5292 Objective: Repeated blood transfusion my lead to peroxidative tissue injury in thalassemia ptients due to secondary iron overload. The aim of the study was to assess the effects of antioxidant vitamins on the oxidative stress, antioxidant status, erythrocytes, hemoglobin derivatives. Also to demonstrate their effects on hepatic status in multitransfused beta-thalassemia major patients. Methods: The study was a prospective follow up study. It involved thirty β-thalassemia major patients aged 4–17 years (15 males and 15 females) recruited from Hematology Oncology Department, Ain Shams University. They were compared to a 20 healthy age and sex matched subjects served as controls. Patients were treated with oral dose of vitamin E (400 mg/day if patient weight < 20 kg and 600 mg/day in patient weight at least 20 kg), low dose of vitamin C (100 mg/day) and vitamin A (25000 IU/ week) for twelve months. Investigations were performed before and after 6 and twelve months of therapy: liver transaminases, serum ferrittin, hepatitis status for HBV, HCV, hepatic fibroscan elastography (TE) for assessment of liver fibrosis and hepatic MRI R2* to measure liver iron concentration (LIC). Assessment of the oxidant /antioxidant capacity by measuring: reduced glutathione, malondialdehyde, ascorbic acid, catalase enzyme, superoxide dismutase, glutathione reductase as well as glutathione peroxidase determination. Results: All patients were on iron chelation therapy: 12 patients received deferiprone (DFP) (75 mg/kg per day orally), 8 patients received deferoxamine (DFO) (30–50 mg/kg per day subcutaneously at least 5 times/week), and 10 patients received a combination of DFO (30–50 mg/kg per day, 2–3 days/week) and DFP (75 mg/kg per day, 7 days/week). In the studied thalassemics 40.0% and 54% were HCV RNA and hepatitis B surface antigen positive. The basal levels of vitamin A, E and C were 3.1, 4, and 2.6 times significantly lower in thalassemia patients compared to controls(p<0.001). Malondialdehyde concentration was 3.4 times higher while reduced glutathione level was 3.2 times lower in studied thalassemics compared to controls(p=0.02,p=0.04). Levels of vitamin A, C, E, reduced glutathione and hemoglobin were significantly elevated during the study period on antioxidant therapy(P=0.03, P=0.02, P<0.001)).This was paralleled by a significant decline in the oxidative-stress marker malondialdehyde (7.87±2.2,8.2±3,11.6±4.1nmol/L;at baseline, after 6 and 12 ms therapy respectively, p<0.001) and serum ferritin levels(2887±1009,2456±1122,2114±990 μg/L, p=0.05). After twelve months of vitamins treatment, there were highly significant improvements of enzymatic antioxidants parameters as compared with before treatment in thalassemia patients. Alanine transaminase, aspartate transaminase, superoxide dismutase and glutathione peroxidase were significantly decreased(p<0.001) while catalase and glutathione reductase activities were significantly elevated(p<0.005). The extent of hemolysis of erythrocytes in studied patients decreases markedly after treatment compared to baseline (p<0.001).There was significant improvement of hepatic fibrosis after 12ms of therapy as 20% of patients had high TE values (FibroScan>12kPa) at baseline compared to 16% after 12 ms therapy (P=0.04).And 56% of patients had value of (>6kPa) at baseline compared to 66%, 70% at 6 and 12months therapy respectively(p=0.03). Levels of liver iron concentration were progressively decreased during the study period compared to baseline (22.4±6.7, 19.4±4.8, 14.4±3.6 mg/gm) in MRI R2* at baseline, after 6 and 12 months therapy respectively<0.001. CONCLUSIONS: Antioxidants vitamins are effective in clinical practice for regulation of antioxidant status as well as improvement of liver iron concentration and hepatic fibrosis in multitransfused thalassemia major patients. Disclosures: No relevant conflicts of interest to declare.

Iron toxicity is the main risk factor for morbidity and mortality in patients with transfusion-dependent thalassemia. Current practice is to start chelation therapy only after 10-20 transfusions, or when the serum ferritin (SF) level rises above 1,000 μg/L. This delay is aimed at minimizing the risk of chelation toxicity that was observed with the use of deferoxamine in children with low iron stores. Deferiprone has lower affinity for iron than deferoxamine and data from clinical trials on its use in patients without systemic iron overload indicate a safety profile for its use in those conditions. The current trial was designed to evaluate the safety of the early use of low-dose deferiprone in newly diagnosed pediatric thalassemia and to evaluate if it can postpone iron overload. Sixty-four children recently diagnosed with thalassemia major who had begun receiving blood transfusions every 3-4 weeks to keep pre-transfusion Hb above 10 gm/dl, had not yet started iron chelation therapy and had SF ≥ 400 μg/L or transferrin saturation (TSAT) ≥ 70% or labile plasma iron (LPI) ≥ 0.2 µM were randomized to start deferiprone (DFP) at a dose normally considered to be sub-therapeutic (50 mg/kg/day) or no chelation (NC). Age at 1st transfusion was 8.1 ± 1.7 for DFP-treated and 8.1 ± 1.6 months for NC children. The percentage of patients with LPI ≥ 0.6 µM, SF ≥ 1000 μg/L or TSAT ≥ 70% in each study arm was assessed at 6 months and 12 months. Patients with confirmed SF ≥1000 ng/mL were withdrawn from the study and placed on a standard chelation regimen. Results. Two patients (DFP) were lost to follow after baseline measurements, 1 patient (NC) withdrew consent at baseline, and 10 patients (5 DFP, 5 NC) have yet to complete all follow up visits. All NC patients had been removed from the trial prior to completing 7 months of follow-up 12 due to confirmed SF ≥ 1000 μg/L. Mean ± SD time of follow up was 10.4± 4.9 and 5.9 ± 2.5 months for DFP and NC, respectively. Most common adverse events in patients on DFP versus NC were diarrhoea (19% vs 13%, p= 0.73), vomiting (13% vs 13%, p=1.00), abdominal colic (13% vs 13%), increased liver enzymes (6% vs 3%, p=1.00) and neutropenia (neutrophil count between 1,000-1,500 x 109/L) (6% vs 6%). All adverse events were mild in severity and did not require interruption of DFP use. There were no cases of agranulocytosis or of moderate neutropenia, no arthralgia and no serious infections in DFP-treated patients. Preliminary efficacy results are presented in the table. DFP therapy was associated with a significant reduction in the rate of iron accumulation as measured by SF (P<0.0001) (Figure 1), LPI (P<0.001) (Figure 2) and TSAT (P<0.001). LPI ≥ 0.6 µM appeared as early as after 5 transfusions in NC children and was delayed to at least 10 transfusions with DFP therapy. TSAT ≥ 70% appeared after 10 transfusions in NC children and was delayed to at least 17 transfusions with DFP therapy. The results of this study show that LPI and TSAT may reach values ≥ 0.6 µM and ≥ 70%, respectively, after 5 -10 transfusions in children with TM and all NC children had SF ≥ 1000 μg/L after 8-9 transfusions. A sub-therapeutic dose regimen of deferiprone for a mean of 10 months in children with TM and low iron overload was not associated with safety concerns and able to significantly reduce the rate of iron accumulation as measured by SF and the appearance of high levels of LPI and of TSAT. Table Table. Disclosures Berdoukas: ApoPharma Inc: Consultancy. Tricta:ApoPharma Inc: Employment.