Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label, noninferiority study

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.

Download Full-text

Deferasirox Decreases Liver Iron Concentration in Iron-Overloaded Patients with Myelodysplastic Syndromes, Aplastic Anemia and Other Rare Anemias

Acta Haematologica ◽

10.1159/000381893 ◽

2015 ◽

Vol 134 (4) ◽

pp. 233-242 ◽

Cited By ~ 9

Author(s):

Yutaka Kohgo ◽

Akio Urabe ◽

Yurdanur Kilinç ◽

Leyla Agaoglu ◽

Krzysztof Warzocha ◽

...

Keyword(s):

Aplastic Anemia ◽

Myelodysplastic Syndromes ◽

Iron Concentration ◽

Dry Weight ◽

Japanese Patients ◽

Efficacy And Safety ◽

Liver Iron Concentration ◽

Open Label ◽

Liver Iron ◽

Therapeutic Goals

Iron overload in transfusion-dependent patients with rare anemias can be managed with chelation therapy. This study evaluated deferasirox efficacy and safety in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemias. A 1-year, open-label, multicenter, single-arm, phase II trial was performed with deferasirox (10-40 mg/kg/day, based on transfusion frequency and therapeutic goals), including an optional 1-year extension. The primary end point was a change in liver iron concentration (LIC) after 1 year. Secondary end points included changes in efficacy and safety parameters (including ophthalmologic assessments) overall as well as in a Japanese subpopulation. Overall, 102 patients (42 with MDS, 29 with AA and 31 with other rare anemias) were enrolled; 57 continued into the extension. Mean absolute change in LIC was -10.9 mg Fe/g dry weight (d.w.) after 1 year (baseline: 24.5 mg Fe/g d.w.) and -13.5 mg Fe/g d.w. after 2 years. The most common drug-related adverse event was increased serum creatinine (23.5%), predominantly in MDS patients. Four patients had suspected drug-related ophthalmologic abnormalities. Outcomes in Japanese patients were generally consistent with the overall population. Results confirm deferasirox efficacy in patients with rare anemias, including a Japanese subpopulation. The safety profile was consistent with previous studies and ophthalmologic parameters generally agreed with baseline values (EUDRACT 2006-003337-32).

Download Full-text

Deferasirox (Exjade®, ICL670) Treatment of Inadequately Chelated β-Thalassemia Patients from the Middle East: The ESCALATOR Trial.

Blood ◽

10.1182/blood.v106.11.3840.3840 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3840-3840 ◽

Cited By ~ 1

Author(s):

Ali Taher ◽

Amal El-Beshlawy ◽

Abdullah Al Jefri ◽

Mohsen El Alfy ◽

Kusai Al Zir ◽

...

Keyword(s):

Iron Overload ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelator ◽

Oral Iron ◽

Study Cohort ◽

Liver Iron ◽

Transfusion Therapy ◽

Once Daily ◽

Oral Iron Chelator

Abstract Iron overload is a potentially life-threatening consequence of multiple blood transfusions. Effective iron chelation therapy reduces morbidity and saves lives. Many patients are unable to comply with current treatments, deferoxamine (DFO) or deferiprone (L1), because they cannot tolerate the parenteral infusion regimen required for DFO, because of adverse events (AEs), or because they do not respond to treatment. The objective of the ESCALATOR trial is to evaluate the effectiveness of deferasirox, an investigational once-daily oral iron chelator in advanced clinical development, in reducing liver iron concentration (LIC) in patients with β-thalassemia unable to be properly treated with DFO and/or L1. During a 1-year treatment period, patients will receive deferasirox at a daily dose of 20 mg/kg. Reduction of LIC is the primary endpoint, as assessed by biopsy at baseline and study end. Secondary efficacy variables include serum ferritin (SF) and other potential surrogate markers of iron overload such as concentration of labile plasma iron (LPI) in a subgroup of patients. Safety assessments include AEs and comprehensive laboratory evaluations. To date, 232 patients have initiated treatment at seven centers in five countries (Egypt, Saudi Arabia, Lebanon, Oman, Syria). Demographics, relevant medical history and baseline iron burden parameters are described in the table. Importantly, baseline SF values were significantly correlated with LIC (R=0.63; P<0.0001). The last patient’s last visit will be in June 2006. Age 2 to <16 years (n=159) Age ≥16 years (n=73) All patients (n=232) Mean ± SD; †n=14 Female:male, n 79:80 35:38 114:118 Race (caucasian:oriental:other), n 59:81:19 11:41:21 70:122:40 BMI*, kg/m2 17.4 ± 2.6 21.6 ± 3.2 18.7 ± 3.4 Weight*, kg 29.4 ± 9.9 54.7 ± 9.7 37.3 ± 15.3 Hepatitis B or C, n 43 29 72 Splenectomy, n 46 53 99 Transfusions in previous year*, n 15.5 ± 4.5 14.3 ± 3.7 15.1 ± 4.3 Total volume transfused in previous year*, mL 5265 ± 2469 7446 ± 2953 5873 ± 2784 Years on chelation therapy*, n 6.2 ± 3.5 12.7 ± 4.8 8.2 ± 4.9 Proportion of life on transfusion therapy*, % 89.3 ± 13.9 89.0 ± 14.1 89.2 ± 14.0 Liver pathology grading (modified HAI scale) Grade 0–6 143 64 207 Grade 7–12 4 0 4 Grade 13–18 0 0 0 LIC, mg Fe/g dw Mean ± SD 17.1 ± 8.5 20.0 ± 10.0 18.0 ± 9.1 Median (min, max) 16.6 (2.9, 38.2) 19.0 (2.9, 48.9) 17.5 (2.9, 48.9) SF, ng/mL Mean ± SD 3957 ± 2342 4564 ± 4117 4148 ± 3019 Median (min, max) 3356 (914, 13539) 3335 (956, 23017) 3346 (914, 23017) LPI†,μmol/L Mean ± SD - - 1.03 ± 0.80 Median (min, max) - - 0.82 (0, 2.65) The ESCALATOR study cohort is a highly challenging population with varied chelation response and transfusion history. The magnitude of LIC and SF, which were well correlated, reflects the severity of iron overload in patients unable to maintain adequate chelation using DFO or L1. This study will provide important insights into the clinical management of iron overload with the well tolerated, once-daily oral iron chelator deferasirox in this difficult-to-treat population.

Download Full-text

Efficacy and Safety of Deferasirox (Exjade®) during 1 Year of Treatment in Transfusion-Dependent Patients with Myelodysplastic Syndromes: Results from EPIC Trial

Blood ◽

10.1182/blood.v112.11.633.633 ◽

2008 ◽

Vol 112 (11) ◽

pp. 633-633 ◽

Cited By ~ 13

Author(s):

Norbert Gattermann ◽

Mathias Schmid ◽

Matteo Della Porta ◽

Kerry Taylor ◽

John F Seymour ◽

...

Keyword(s):

Abdominal Pain ◽

Iron Overload ◽

Myelodysplastic Syndromes ◽

Iron Concentration ◽

Study Drug ◽

Dry Weight ◽

Multicenter Trial ◽

Efficacy And Safety ◽

Contributing Factors ◽

Liver Iron

Abstract Background: Many patients (pts) with myelodysplastic syndromes (MDS) [particularly those with Low- or Int-1-risk] are susceptible to iron overload from ongoing blood transfusions and increased dietary iron absorption. Deferasirox (Exjade®) has shown efficacy in maintaining or reducing body iron (assessed by liver iron concentration [LIC] and serum ferritin [SF]) in MDS pts. More recently, the efficacy and safety of deferasirox in pts with various underlying anemias, including MDS, was evaluated in the large EPIC study. Data for MDS pts are presented here. Methods: The EPIC study was a 1-yr, openlabel, single-arm, multicenter trial. Pts with transfusion-dependent MDS and SF ≥1000 ng/ mL, or SF <1000 ng/mL but requiring >20 transfusions or 100 mL/kg of blood and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw), received an initial deferasirox dose of 10–30 mg/kg/day. SF was assessed monthly and protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 mths based on SF trends and safety markers. Primary efficacy endpoint was the change in SF from baseline at 12 mths. Safety assessments included monitoring of adverse event (AE) and laboratory parameters. Results: 341 MDS pts (204 M, 137 F; mean age 67.9 yrs, range 11–89 yrs) with median baseline SF of 2730 (range 951–9465) ng/mL were enrolled. Mean transfusion duration was 3.6 yrs, and pts received a mean of 116.4 mL/kg of blood in the previous yr. Almost half (48.4%) of all pts had not received any prior chelation therapy; 40.0% had previously received deferoxamine (DFO), 4.1% deferiprone, 7.0% combination DFO/ deferiprone, and 0.3% other therapy. Overall, mean actual dose of deferasirox over 1 yr of treatment was 19.2±5.4 mg/kg/day. At 12 mths, there was a significant reduction in median SF from baseline (by LOCF: –253.0 ng/mL; P=0.0019). Median SF (range) ng/mL values at baseline, 3, 6, 9 and 12 mths were 2729.5 (951–9465; n=336), 2358.0 (534–46569; n=263), 2209.5 (357–10066; n=230), 2076.0 (358–25839; n=197) and 1903.5 (141–10155; n=174), respectively. Overall, 48.7% of pts (n=166) discontinued therapy. Reasons for withdrawal included AEs [n=78, 23% (n=44, 13% for drug-related AEs)], consent withdrawal (n=33, 10%), unsatisfactory therapeutic effect (n=6, 2%), lost to follow-up (n=2, <1%), death (n=26, 8%, none treatment-related as per investigators’ assessments) and other (n=21, 6%). Most common investigator-assessed drug-related AEs were diarrhea (n=110, 32%), nausea (n=45, 13%), vomiting (n=26, 8%), abdominal pain (n=26, 8%), upper abdominal pain (n=25, 7%), rash (n=23, 7%), and constipation (n=21, 6%). Only 25 pts discontinued study drug for drug-related GI AEs. Most AEs were mild-to-moderate (95%) in severity. In total, 14.7% had two consecutive serum creatinine values >33% above baseline (in normal range), 10.6% had two values above ULN, and 24.9% had both two consecutive values >33% and >ULN; 19 pts had dose decreases and 10 dose interruptions due to abnormal creatinine; there were no progressive increases. One patient (<1%) with normal baseline alanine aminotransferase had an increase that exceeded >10xULN on two consecutive visits. Conclusions: In this large cohort of MDS pts with iron overload, deferasirox provided significant reduction in SF levels over 1-yr treatment with appropriate dose adjustments every 3 mths based on SF trends and safety markers. The AE profile in this study is consistent with previously reported deferasirox data in MDS pts. The discontinuation rate was higher in this subgroup. Investigations are ongoing to assess possible contributing factors including associated comorbidities, age of pts, and others.

Download Full-text

Extrahepatic Iron Deposition In Chronically Transfused Children With Sickle Cell Anemia – Baseline Findings From The Twitch Trial

Blood ◽

10.1182/blood.v122.21.2238.2238 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2238-2238 ◽

Cited By ~ 2

Author(s):

John C. Wood ◽

Alan Cohen ◽

Banu Aygun ◽

Hamayun Imran ◽

Lori Luchtman-Jones ◽

...

Keyword(s):

Iron Overload ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Iron Concentration ◽

Dry Weight ◽

Iron Deposition ◽

Liver Iron ◽

Transfusion Therapy ◽

Upper Limits

Abstract Introduction Chronic transfusion therapy is the standard of care for children with sickle cell anemia (SCA) and abnormal transcranial Doppler velocities. Although effective, monthly transfusions are costly, inconvenient, and produce iron overload in the liver and extrahepatic organs. The TWiTCH study (ClinicalTrials.gov NCT01425307) is a randomized clinical trial to determine whether hydroxyurea therapy leads to comparable time averaged TCD velocities as conventional transfusion therapy, while reducing somatic iron stores. We report baseline data on iron burden in the spleen, pancreas, and kidneys from the TWiTCH cohort. Methods Pediatric patients from 22 centers underwent screening R2* assessment of the liver, spleen, pancreas, and kidneys. All sites used a 1.5 Tesla magnet, torso phased array coils, and a multiple echo gradient echo sequence with a minimum echo time ≤1.3 ms. Images were analyzed centrally at Children’s Hospital Los Angeles; core laboratory staff were blinded to patient, site, and visit data. Raw R2* values were used as iron surrogates for spleen, pancreas, and kidney. All statistics were performed by the TWiTCH Data Coordinating Center. Results A total of 113/159 enrolled patients (mean age 8.8 ± 6.3 years) successfully completed baseline abdominal R2* assessment (Table 1). Patients had received chronic transfusions for 4.2 ± 2.4 years and iron chelation for 3.2 ± 2.2 years. Serum ferritin values ranged from 191 to 10593 ng/ml (2655.6 ± 1668.1 ng/ml). All subjects had liver iron detectable by R2*, with 51.3% having liver iron concentration (LIC) >7 mg/g, and 13.3% >15 mg/g of dry weight. Splenic R2* could be assessed in 80/113 (71%) subjects, with the remainder having surgical splenectomy or autoinfarction. Splenic R2* revealed splenic tissue was comparable to liver tissue containing on average 13.1 mg Fe/g of dry weight. Pancreas R2* was greater than the upper limits of normal in 39.3% but no values exceeded 100 Hz (the level associated with pancreas dysfunction, pituitary iron accumulation, and cardiac iron deposition in thalassemia patients). LIC was the only significant predictor of pancreas R2* (r2 = 0.06, p=0.001). Kidney R2* was above the upper limits of normal in 79.5% of the patients and demonstrated preferential cortical distribution. Kidney R2* positively correlated with lactate dehydrogenase levels (p < 0.001), positive correlated with LIC R2* (p=0.005) and negatively correlated with hemoglobin level(p = 0.01) with a combined r2 of 0.29. No association was found with total bilirubin or reticulocyte count. Discussion This represents the first multicenter study documenting the prevalence and extent of extrahepatic iron deposition in children with SCA receiving chronic transfusions. Splenic iron deposition was common but uncorrelated with LIC,, suggesting different kinetics of iron loading transport. Clinically-significant pancreatic iron deposition was not observed. Renal R2* tracked with intravascular hemolysis markers, rather than LIC or ferritin, consistent with tubular uptake of filtered cell-free hemoglobin. Overall, chronically transfused children with SCA have greater splenic and renal iron deposition, but much milder pancreatic iron overload, than that observed in transfused thalassemia patients. Disclosures: Wood: Novartis: Honoraria; Apopharma: Honoraria, Patents & Royalties; Shire: Consultancy, Research Funding. Off Label Use: Hydroxyurea is FDA-approved for use in adults but not children. Thompson:Amgen: Research Funding; Eli Lilly: Research Funding; Glaxo Smith Kline: Research Funding; ApoPharma: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; bluebird bio: Research Funding.

Download Full-text

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up

Blood ◽

10.1182/blood-2010-11-316646 ◽

2011 ◽

Vol 118 (4) ◽

pp. 884-893 ◽

Cited By ~ 117

Author(s):

M. Domenica Cappellini ◽

Mohamed Bejaoui ◽

Leyla Agaoglu ◽

Duran Canatan ◽

Marcello Capra ◽

...

Keyword(s):

Adverse Events ◽

Iron Concentration ◽

Iron Chelation ◽

Dry Weight ◽

Thalassemia Major ◽

Efficacy And Safety ◽

Liver Iron ◽

Median Serum

Abstract Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

Download Full-text

Ineffective Erythropoiesis in β-Thalassemia Is Characterized by Increased Iron Absorption Mediated by down Regulation of Hepcidin and up Regulation of Ferroportin.

Blood ◽

10.1182/blood.v108.11.1543.1543 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1543-1543 ◽

Cited By ~ 1

Author(s):

Sara Gardenghi ◽

Maria Marongiu ◽

Pedro Ramos ◽

Ella Guy ◽

Laura Breda ◽

...

Keyword(s):

Iron Overload ◽

Iron Content ◽

Iron Absorption ◽

Hematological Parameters ◽

Iron Concentration ◽

Dry Weight ◽

Heme Iron ◽

Ineffective Erythropoiesis ◽

Transfusion Therapy ◽

Expression Levels

Abstract Progressive iron overload occurs in β-thalassemia as a result of increased gastrointestinal absorption. Our goal is to investigate the relationship between ineffective erythropoiesis (IE), iron-related genes and organ iron distribution in mice that exhibit levels of anemia consistent with thalassemia intermedia (th3/+) and major (th3/th3), as we described previously. The th3/th3 mice die in 8 weeks due to severe anemia but can be rescued by transfusion therapy. We analyzed up to 90 animals at 2, 5 and 12 months, as appropriate. We monitored various hematological parameters, tissue iron content and quantitative-PCR levels of Hamp, Fpn1, Smad4, Cebpa, Hfe, Tfr1 and other genes involved in iron metabolism in liver, spleen, kidney, heart and duodenum. At 2 months, th3/th3 mice had the highest total body iron content and highest degree of IE. The total iron was 53.6±21.0, 406.1±156.1, 657.7±40.3 μg in the spleen, and 107.5±35.7, 208.5±24.9 and 1298.7±427.5 μg in the liver of +/+, th3/+ and th3/th3, respectively (n≥5 per genotype). However, if the organ size was not taken in account, the iron concentration in the spleen of th3/+ was higher, in average, than that of th3/th3 mice (3.8±1.5 and 2.9±0.5 μg/mg), while in the liver was the opposite (0.6±0.1 and 5.1±2.0 μg/mg of dry weight, P<0.001). Heme and non-heme iron analyses provided similar results. Surprisingly, the distribution of iron within organs also differed. In th3/+ mice, the hepatic iron was almost exclusively located in Kupffer cells, whereas in th3/th3 mice in parenchymal cells. Our data suggest that Hamp is responsible for the increased iron absorption, being reduced to 20% and 70% in 2 month-old th3/+ and th3/th3 mice compared to +/+ animals (P<0.001). Hfe was reduced by 50% (P<0.05) in the liver of the animals that expressed low Hamp levels, indicating that Hfe could be directly responsible for Hamp regulation or share the same regulatory pathway. Low levels of Smad4 and Cebpa were observed only in the liver of mice with the lowest Hamp expression (P<0.05), indicating that these proteins might contribute to further decreased Hamp synthesis. In addition, while Tfr1 in th3/+ mice was 40% lower in the liver, it was up-regulated (400%) in th3/th3 mice (P<0.001), which may explain why iron is increased more in the liver of th3/th3 mice. In 5 and 12 month-old th3/+ mice, the surprising observation was the normal expression level of Hamp. However, in the duodenum, the Fpn1 RNA and protein levels were augmented (300%, P<0.001). In transfused th3/+ and th3/th3 animals, Hamp, Hfe, Cbpa and Smad4 expression levels were normalized or increased, while Tfr1 was down-regulated in both groups, which may explain the increased splenic iron deposition in these animals. Our data suggest that IE, together with the relative expression levels of Hamp and Tfr1, is largely responsible for the organ iron overload observed in young thalassemic mice. However, in older mice, it is the increase of Fpn1 levels in the duodenum that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the genesis of iron overload in β-thalassemia.

Download Full-text

Iron Stores in Patients with Myelodysplasia and Aplastic Anemia.

Blood ◽

10.1182/blood.v108.11.3726.3726 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3726-3726

Author(s):

Peter Nielsen ◽

Tim H. Bruemmendorf ◽

Regine Grosse ◽

Rainer Engelhardt ◽

Nicolaus Kroeger ◽

...

Keyword(s):

Risk Factor ◽

Iron Overload ◽

Aplastic Anemia ◽

Myelodysplastic Syndromes ◽

Iron Concentration ◽

Dry Weight ◽

Iron Toxicity ◽

Intervention Threshold ◽

Liver Iron Concentration ◽

Liver Iron

Abstract Patients with myelodysplastic syndromes (MDS), osteomyelofibrosis (OMF), or severe aplastic anemia (SAA) suffer from ineffective erythropoiesis due to pancytopenia, which is treated with red blood cell transfusion leading to iron overload. Especially in low-risk patients with mean survival times of > 5 years, potentially toxic levels of liver iron concentration (LIC) can be reached. We hypothesize that the higher morbidity seen in transfused patients may be influenced by iron toxicity. Following a meeting in Nagasaki 2005, a consensus statement on iron overload in myelodysplastic syndromes has been published, however, there is still no common agreement about the initiation of chelation treatment in MDS patients. In the present study, a total of 67 transfused patients with MDS (n = 20, age: 17 – 75 y), OMF (n = 4, age: 48 – 68 y), SAA (n = 43, age: 5 – 64 y) were measured by SQUID biomagnetic liver susceptometry (BLS) and their liver and spleen volumes were scanned by ultrasound at the Hamburg biosusceptometer. Less than 50 % were treated with DFO. LIC (μg/g-liver wet weight, conversion factor of about 6 for μg/g-dry weight) and volume data were retrospectively analyzed in comparison to ferritin values. Additionally, 15 patients (age: 8 – 55 y) between 1 and 78 months after hematopoietic cell transplantation (HCT) were measured and analyzed. LIC values ranged from 149 to 8404 with a median value of 2705 μg/g-liver, while serum ferritin (SF) concentrations were between 500 and 10396 μg/l with a median ratio of SF/LIC = 0.9 [(μg/l)/(μg/g-liver)] (range: 0.4 to 5.2). The Spearman rank correlation between SF and LIC was found to be highly significant (RS = 0.80, p < 0.0001), however, prediction by the linear regression LIC = (0.83± 0.08)·SF was poor (R2 = 0.5) as found also in other iron overload diseases. Although iron toxicity is a long-term risk factor, progression of hepatic fibrosis has been observed for LIC > 16 mg/g dry weight or 2667 μg/g-liver (Angelucci et al. Blood2002; 100:17–21) within 60 months and significant cardiac iron levels have been observed for LIC > 350 μmol/g or 3258 μg/g-liver (Jensen et al. Blood2003; 101:4632-9). The Angelucci threshold of hepatic fibrosis progression was exceeded by 51 % of our patients, while 39 % were exceeding the Jensen threshold of potential risk of cardiac iron toxicity. The total body iron burden is even higher as more than 50 % of the patients had hepatomegaly (median liver enlargement factor 1.2 of normal). A liver iron concentration of about 3000 μg/g-liver or 18 mg/g-dry weight has to be seen as latest intervention threshold for chelation treatment as MDS patients are affected by more than one risk factor. A more secure intervention threshold would be a LIC of 1000 μg/g-liver or 4 – 6 mg/g-dry weight, corresponding with a ferritin level of 900 μg/l for transfused MDS patients. Such a LIC value is not exceeded by most subjects with heterozygous HFE-associated hemochromatosis and is well tolerated without treatment during life-time. Non-invasive liver iron quantification offers a more reliable information on the individual range of iron loading in MDS which is also important for a more rational indication for a chelation treatment in a given patient.

Download Full-text

Phlebotomy to Reduce Iron Overload in Patients Cured of Thalassemia by Bone Marrow Transplantation

Blood ◽

10.1182/blood.v90.3.994.994_994_998 ◽

1997 ◽

Vol 90 (3) ◽

pp. 994-998 ◽

Cited By ~ 1

Author(s):

Emanuele Angelucci ◽

Pietro Muretto ◽

Guido Lucarelli ◽

Marta Ripalti ◽

Donatella Baronciani ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Iron Overload ◽

Marrow Transplantation ◽

Iron Concentration ◽

Transferrin Saturation ◽

Dry Weight ◽

Liver Iron ◽

Before And After ◽

Upper Level

In thalassemia after successful bone marrow transplantation (BMT), iron overload remains an important cause of morbidity. After BMT, patients have normal erythropoiesis capable of producing a hyperplastic response to phlebotomy so that this procedure can be contemplated as a method of mobilizing iron from overloaded tissues. A phlebotomy program (6 mL/kg blood withdrawal at 14-day intervals) was proposed to 48 patients with prolonged follow-up (range, 2 to 7 years) after BMT. Seven patients were not submitted to the program (five because of refusal and two because of reversible side effects). The remaining 41 patients (mean age, 16 ± 2.9 years) were treated for a mean period of 35 ± 18 months. All were evaluated before and after 3 ± 0.6 years of followup. Values are expressed as mean ± standard deviation (SD) or as median with a range (25 to 75 percentile). Serum ferritin decreased from 2,587 (2,129 to 4,817) to 417 (210 to 982) μg/L (P < .0001), total transferrin increased from 2.34 ± 0.37 to 2.7 ± 0.58 g/L (P = .0001), transferrin saturation decreased from 90% ± 14% to 50% ± 29% (P < .0001). Liver iron concentration evaluated on liver biopsy specimens decreased from 20.8 (15.5 to 28.1) to 4.2 (1.6 to 14.6) mg/g dry weight (P < .0001). Aspartate transaminase decreased from 2.7 ± 2 to 1.1 ± 0.6 (P < .0001) and alanine transaminase from 5.2 ± 3.4 to 1.7 ± 1.2 (P < .0001) times the upper level of normality. The Knodell score for liver histological activity decreased from 6.9 ± 3 to 4.9 ± 2.8 (P < .0001). These data indicate that phlebotomy is safe, efficient, and widely applicable to ex-thalassemics after BMT.

Download Full-text

Estimation and quantification of liver iron concentration by magnetic resonance imaging

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20194589 ◽

2019 ◽

Vol 7 (11) ◽

pp. 4266

Author(s):

Vipul V. Chemburkar ◽

Archit A. Gupta ◽

Devdas S. Shetty ◽

Ruchi R. Agarwal

Keyword(s):

Iron Overload ◽

Wide Spectrum ◽

Iron Concentration ◽

Dry Weight ◽

Accurate Estimation ◽

Liver Iron Concentration ◽

Liver Iron ◽

Cross Sectional ◽

Male Predominance ◽

Duration Of Disease

Background: Liver iron overload is considered to be the histological hallmark of genetic hemochromatosis. The accurate estimation of iron overload is important to establish the diagnosis of hemochromatosis. The aim of the present study was to estimate T2* liver value, quantify liver iron concentration (in milligram of iron per gram dry weight) and find out the appropriate therapy for patients with iron overload according to severity index.Methods: A cross-sectional observational study was carried out in Department of Radio Diagnosis, at B.Y.L. Nair Hospital and medical college, Mumbai from June 2017 to August 2018. A total of 50 cases were enrolled for the present study.Results: Male predominance (66.0%) was seen. Mean duration of disease among the studied cases was 10.52±6.06 years, with minimum and maximum duration of disease of 1 and 26 years respectively. Eight percent had compliance to visit and treatment among the enrolled cases.Conclusions: MRI was concluded to be potentially useful non-invasive method for evaluating liver iron stones in a wide spectrum of haematological and liver diseases.

Download Full-text

Phase III Evaluation of Once-Daily, Oral Therapy with ICL670 (Exjade®) Versus Deferoxamine in Patients with β-Thalassemia and Transfusional Hemosiderosis.

Blood ◽

10.1182/blood.v104.11.3619.3619 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3619-3619 ◽

Cited By ~ 4

Author(s):

Maria Cappellini ◽

Mohamed Bejaoui ◽

Silverio Perrotta ◽

Leyla Agaoglu ◽

Antonios Kattamis ◽

...

Keyword(s):

Quantum Interference ◽

Safety Data ◽

Study Drug ◽

Dry Weight ◽

Phase Iii ◽

Outcome Variable ◽

Efficacy And Safety ◽

Open Label ◽

Liver Iron ◽

Once Daily

Abstract ICL670 (deferasirox) is an investigational once-daily oral iron chelator that has demonstrated the ability to induce sustained, clinically relevant reductions in liver iron content (LIC) in heavily transfused patients with β-thalassemia and iron overload. The efficacy and safety of ICL670 is being assessed in a multicenter, randomized, open-label Phase III study in comparison with deferoxamine (DFO) in patients aged ≥2 years with β-thalassemia and transfusional hemosiderosis. Between March and November 2003, 587 patients began treatment (296 on ICL670; 291 on DFO) in the following 12 countries : Italy (200), Turkey (87), Tunisia (68), US (48), Greece (46), Germany (27), Argentina (24), Belgium (24), Brazil (20), UK (18), Canada (13) and France (12). Based on LIC at baseline (2–3, >3–7, >7–14 and >14 mg Fe/g dw), patients were randomized in a 1:1 ratio to receive either oral ICL670 once daily at doses of 5, 10, 20 or 30 mg/kg, respectively, or subcutaneous DFO at doses of 20–60 mg/kg/day for 5 days/week. Treatment was for one year initially, to be followed by an extension phase during which patients randomized to DFO may switch to ICL670. LIC, the primary outcome variable, was assessed at baseline by liver biopsy or, in some children, non-invasively by magnetic susceptometry using a Superconducting QUantum Interference Device (SQUID). LIC will be reassessed after 12 months of therapy in each patient using the same methodology as at baseline. Liver biopsies are analyzed at a single center (Rennes, France) and SQUID assessments are performed in 3 centers (Turin, Italy; Hamburg, Germany; Oakland, US). At baseline, median (25–75th percentiles) LIC was 13.0 mg Fe/g dw (7.2–21.0) by biopsy and 5.6 (4.0–7.7) in those patients assessed by SQUID. Total body iron balance will be assessed to determine the relative chelation efficacies of ICL670 and DFO. A summary of patient demographics and baseline characteristics (median values or no. of pts) is given in the table. ICL670 has been well tolerated with mild, transient gastrointestinal complaints as the main AEs with a suspected relationship to study drug. As of May 2004, 8 patients on ICL670 and 2 on DFO had discontinued therapy due to AEs. The key efficacy and safety data from the initial 12 months of therapy for all randomized patients will be available late November 2004. Treatment group (by initial dose) ICL670 (n=296) Deferoxamine (n=291) 10 mg/kg n = ≤ 94 20 mg/kg n = 83 30 mg/kg n = 119 <35 mg/kg n = 51 35-<50 mg/kg n = 119 ≥ 50 mg/kg n = 121 Age (yrs) median 15 15 15 15 14 17 No. of pts 2 - <16 years 49 44 60 26 63 56 No. of ≥ pts 16 yrs 45 39 59 25 56 65 No. of males/females 44/50 41/42 54/65 32/19 50/69 61/60 LIC (mg Fe/g dry weight) 4.7 10.6 21.8 4.5 9.1 19.5 No. of pts with biopsy/SQUID* 60/34 69/14 117/0* 36/15 93/26 119/2 Serum ferritin (ng/ml) 1881 1954 3250 1546 2037 2383

Download Full-text