Changes In Liver Iron Concentration Research Articles

Successful chelation in beta-thalassemia major in the 21st century.

This century has seen a revolution the management of beta-thalassemia major. Over a 12-year period to 2016, we aimed to analyze the benefits of such advances. In 209 patients, independent of the chelation regimen, ferritin, cardiac T2* and liver iron concentration changes were evaluated. We defined chelation success (ChS) as no iron load in the heart and acceptable levels in the liver. Over 3 early magnetic resonance imagings, the same parameters were assessed in 2 subgroups, the only 2 that had sufficient patients continuing on 1 regimen and for a significant period of time, 1 on deferrioxamine (low iron load patients n = 41, Group A) and 1 on deferoxamine-deferiprone (iron overloaded n = 60, Group B). Finally, 28 deaths and causes were compared to those of an earlier period. The 209 patients significantly optimized those indices, while the number of patients with chelation success, increased from 6% to 51% (P < .0001). In group A, ChS after about 8 years increased from 21 to 46% (P = .006), while in Group B, from 0% to 60% (P < .001) after about 7 years. Deaths over the 2 periods showed significant reduction. Combined clearance of cardiac and liver iron (ChS) is feasible and should become the new target for all patients. This requires, serial magnetic resonance imagings and often prolonged intensified chelation for patients.

Mitapivat Improves Iron Overload in Patients with Pyruvate Kinase Deficiency

Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia. Iron overload is highly prevalent in patients (pts) with PK deficiency regardless of transfusion requirements, suggesting dyserythropoietic features. Iron overload can lead to serious complications including liver cirrhosis, cardiomyopathy, arrhythmia, sudden cardiac death, and endocrine dysfunction. In pts with PK deficiency, ineffective erythropoiesis combined with chronic hemolysis contributes to the manifestation of iron overload. Increased erythropoietic drive leading to erythroferrone-induced hepcidin suppression results in increased iron absorption and abnormal iron metabolism in PK deficiency. Furthermore, transfusions increase the existing burden of iron overload in PK deficiency. Mitapivat (AG-348) is a first-in-class, oral, allosteric activator of the red blood cell wildtype and mutant PK enzyme (PKR) that is approved by the US Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, which has been shown to improve ineffective erythropoiesis and hemolysis. Previously reported data from ACTIVATE (NCT03548220) and its long-term extension (LTE) study (NCT03853798) also showed that treatment with mitapivat improved markers of iron homeostasis in adults with PK deficiency (up to 72 weeks [wks]). Here, we provide longer-term data from the LTE study on the impact of mitapivat on iron homeostasis and iron overload, and also assess liver iron concentration (LIC) changes in pts with iron overload at baseline (BL). Methods: In ACTIVATE (double-blind, placebo [PBO]-controlled study), pts with PK deficiency who were not regularly transfused were randomized 1:1 to receive mitapivat or PBO. Pts who had demonstrated clinical benefit from mitapivat on completion of the fixed-dose period for ACTIVATE (24 wks), or who were assigned to the PBO arm in ACTIVATE, were eligible to continue in the LTE. All pts enrolled in the LTE received mitapivat. Pts from ACTIVATE who continued in the LTE were categorized into the mitapivat-to-mitapivat arm (M/M) or PBO-to-mitapivat arm (P/M). The ACTIVATE/LTE analysis assessed changes from BL over time (up to 96 wks), for both study arms, in markers related to iron homeostasis and overload, including erythroferrone, soluble transferrin receptor (sTfR), hepcidin, and LIC by magnetic resonance imaging. LIC changes over time in pts with evidence of iron overload at BL, were also assessed; pts were considered to have iron overload at BL if they met at least 1 of 3 criteria: BL ferritin >1000 mg/L, BL average LIC >3 mg Fe/g dry weight (dw), or chelation therapy within the last year before study start. For this calculation, BL was defined as the last assessment before start of treatment with mitapivat, and LIC data from pts in the M/M arm were pooled together with data from pts in the P/M arm and summarized over the time they were treated with mitapivat. Results: 80 pts were included in the ACTIVATE/LTE analysis (M/M=40; P/M=40). Meaningful improvements in hepcidin, erythroferrone, sTfR, and LIC values were observed with mitapivat treatment previously; here, we confirm these meaningful improvements are continued up to 96 wks (Table). These measurements were improved early-on, within 24 wks of starting treatment in the M/M arm, but remained relatively unchanged in the P/M arm while on PBO. Similar improvements to the M/M arm were seen in the P/M arm after switching to mitapivat in the LTE. Among pts treated with mitapivat (N=78), 55.1% (n=43) met the criteria for iron overload at BL. These pts showed clinically meaningful and continued improvements in iron overload over time as measured by LIC (median [Q1, Q3] decrease from BL to Wk 96 of mitapivat treatment of -1.95 [-4.85, -0.70] mg Fe/g dw) (Figure). Conclusions: Activation of PKR with mitapivat was associated with meaningful long-term improvements in iron homeostasis and overload. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload in pts with PK deficiency. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Modern management of iron overload in thalassemia major patients guided by MRI techniques: real-world data from a long-term cohort study.

Monitoring liver and cardiac iron stores by magnetic resonance imaging (MRI) enables identifying patients at risk of organ-specific morbidity and better tailoring of iron chelation therapy in thalassemia. Nevertheless, serum ferritin (SF) remains the only tool for monitoring iron status in most resource-poor regions. In this study, we assessed the impact of using MRI techniques to guide iron chelation therapy on iron overload outcomes in a cohort of 99 patients with thalassemia major (TM, mean age at baselines 20.7 ± 6.9years) followed from 2006 to 2019. We also assessed the ability of SF trends to predict changes in consecutive liver iron concentration (LIC) and cardiac T2* (cT2*) measurements. The most commonly used chelator was deferasirox at baseline (65%) and final (72%) assessments. Overall, patients with safe LIC values (< 7mg/g dw) increased from 57 to 77%, and safe cT2* values (> 20ms) increased from 72 to 86%. We obtained the most significant improvement in patients with severe and moderate liver (p = 0.006 and p < 0.001) and cardiac (p < 0.0013 and p < 0.0001) iron overload at baseline. SF trends were in the same direction in 64% of changes in LIC, but only 42% of changes were proportional. Most of the changes in SF (64%) and LIC (61%) could not predict changes in cT2*. Moreover, downward trends in SF and LIC were associated with worsening cardiac iron in 29% and 23.5% of consecutive cT2* measurements. Liver and cardiac MRI-driven oral iron chelation improved the iron status of subjects with TM and demonstrated the importance of using validated MRI techniques in critical clinical decisions.

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 that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study 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 to 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. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

LONG-TERM SAFETY AND EFFICACY OF DEFERIPRONE FOR THE TREATMENT OF CHRONICALLY TRANSFUSED, IRON-OVERLOADED PATIENTS WITH SICKLE CELL DISEASE OR OTHER ANEMIAS

Assess the safety and efficacy of deferiprone (DFP) in chronically transfused, iron-overloaded patients with sickle cell disease (SCD) or other anemias. FIRST was a multicenter, 1-year, noninferiority trial of DFP vs deferoxamine (DFO). Patients ≥2 years of age were randomly assigned 2:1 to receive DFP or DFO. Those who completed FIRST could enter FIRST-EXT, a 2-year extension in which all patients received DFP. Thus, the baseline was the start of FIRST for patients randomized to DFP (up to 3 years for the DFP-DFP group), and the start of FIRST-EXT for patients randomized to DFO in FIRST (up to 2 years for the DFO- DFP group). In both studies, efficacy endpoints were yearly changes from baseline in liver iron concentration (LIC), cardiac MRI T2*, and serum ferritin (SF) level. All adverse drug reactions (ADRs) for both studies were recorded. In FIRST, patients (N = 228) were 46.9% female, mean age was 16.9 (standard deviation [SD] 9.6; range 3–59) years, 84.2% had SCD and 15.8% had other anemias. At 1 year, there were no significant (p > 0.05) differences in change in LIC, cardiac MRI T2*, or SF measures between the DFP and DFO intent-to-treat groups. Common ADRs (≥5% of patients) in the DFP group were abdominal pain, vomiting, pyrexia, increased alanine transaminase, increased aspartate aminotransferase, neutropenia, nausea, and chromaturia; in the DFO group, they were pyrexia and injection site pain. Serious ADRs in the DFP group were neutropenia (2.6%), increased transaminases (1.3%), and agranulocytosis, sickle cell crisis, epididymitis, Propionibacterium infection, bacterial sinusitis (infections not associated with neutropenia), vascular device infection, and migraine (0.7% each); in the DFO group, they were abdominal pain, arthritis, and headache (1.3% each). 134 Patients continued to FIRST-EXT (n = 89 DFP-DFP; n = 45 DFO-DFP): 60.4% were male, mean age was 16.2 (SD 8.6; range 4–47) years, 85.8% had SCD and 14.2% had other anemias. At baseline, all patients had elevated LIC with a mean (SD) of 14.93 (7.61) mg/g dry weight (dw), all had normal cardiac iron with a mean (SD) MRI T2* of 32.69 (17.66) ms, and all but 1 had elevated SF with a mean (SD) of 3894 (2591) μg/L. LIC decreased with mean (SD) reductions of -2.64 (4.64), -3.91 (6.38), and -6.64 (7.72) mg/g dw after 1, 2, and 3 years, respectively (p < 0.01 for all years). Cardiac iron remains in the normal range for all patients. SF levels declined with mean (SD) changes from baseline to years 1, 2, and 3 of -1 (1986), -771 (2171), and -1016 (3617) μg/L, respectively (p < 0.05 for years 2 and 3). No new ADRs (observed in 30.6% of patients) were reported. One patient withdrew due to ADRs of thrombocytopenia and neutropenia, which resolved. Another patient withdrew due to generalized edema and died for reasons unknown 17 days after withdrawal from the study. DFP effectively controlled iron burden in chronically transfused patients with SCD and other anemias, and it was noninferior to DFO. DFP use was associated with reductions in LIC and SF levels. Cardiac MRI T2* remained normal. DFP was well tolerated in patients who received up to 3 years of treatment, with no new safety concerns. We thank Dr. M Badr, Dr. B Inusa, Dr. AAM Adly, Dr. Y Kilinc, C Fradette, and NT Temin for their contribution to the studies. Sponsored by Chiesi Global Rare Diseases; medical writing support provided by Oxford PharmaGenesis Inc., and funded by Chiesi.

Randomized Controlled Trial of the Efficacy and Safety of Deferiprone in Iron-Overloaded Patients with Sickle Cell Disease or Other Anemias

Randomized Controlled Trial of the Efficacy and Safety of Deferiprone in Iron-Overloaded Patients with Sickle Cell Disease or Other Anemias

Effects of Luspatercept on Iron Overload and Impact on Responders to Luspatercept: Results from the BELIEVE Trial

Effects of Luspatercept on Iron Overload and Impact on Responders to Luspatercept: Results from the BELIEVE Trial

Non Invasive Evaluation of Hepatic Iron Concentration By Fibroscan in Transfusion-Dependent Egyptian Patients with Chronic Hemolytic Anemia

Background: Transient elastography (Fibroscan®) is an ultrasound technique used to measure liver stiffness (LS), and thus assess for liver fibrosis, in patients with various chronic hepatic disorders. It can also be used to predict severity in multiple other diseases that might affect LS such as amyloidosis and possibly conditions associated with iron overload.Objectives: To assess the frequency of liver fibrosis in patients with chronic hemolytic anemia using Transient elastography (Fibroscan®), and to determine the reliability of this tool as a non-invasive method to predict hepatic iron content as compared to liver iron concentration (LIC) measured by magnetic resonance imaging (MRI).Patients and methods: Seventy-five transfusion dependent patients (50 β-thalassemia major;25 sickle cell disease) with a mean age of 13.4±5.2 years in addition to 75 -age and sex matched- healthy children were recruited. All subjects underwent assessment of LS in kilopascals (kPa), by Transient elastography measurement using FibroScan (Echosens, Paris, France І). Steady state serum ferritin (SF), and hepatitis B serologies (HBsAg and antiHB core antibodies) were assessed by enzyme linked immunoassay (ELISA). LIC values, within 6 months' duration, as identified by quantitative MRI of hepatic iron stores as a signal intensity ratio method based on T1 and T2* contrast imaging without gadolinium were retrieved. Informed consent was obtained from patients' legal guardians prior to enrollment in the study.Results: The median SF was 2280 ng/ml (84% had values exceeding 1000 ng/ml). The median LIC was 13.86 mg/g dw (78.7% patients showed LIC above 7 mg/g dw). The median cardiac T2* was 30.8 ms (3 patients had values below 20). Fifty-two (69.3%) patients were categorized as F0-1 and 21 (28%) were stage F2, 2 (1.3%) were stage F3, and 2 patients had severe fibrosis. The mean and median fibroscan (FS) values were 6.19 ±1.76 kPa and 5.9 kPa (range 3 to 14.1) respectively. Patients had significantly higher mean FS compared to control group (p ˂0.001). Patients with no or mild fibrosis (F0-1) had lower FS values (5.3kPa) compared to patients with fibrosis grades 2-4 (p ˂0.001). FS values were not affected by disease type (thalassemia or sickle cell disease), age (above 12 years), or HCV sero-positivity. FS values correlated with SF (r=0.410, p˂ 0.001). Simple regression analysis of the two variables suggested that changes in SF were associated with minimal but significant changes in FS values (p=0.04) with good agreement (kappa =0.324, p=0.003). LIC did not differ in relation to grade of fibrosis (p>0.05), did not correlate with FS values (r= 0.014, p=0.908), and no changes in FS were expected with LIC changes on regression analysis (p=0.466) with low agreement between LIC and FS at cutoff value 5.3 kPa (kappa = 0.015, p=0.9). Sensitivity and specificity of FS values to predict LIC were high at cutoff values ranging between 3.2 to 3.75 kPa but decreased markedly at higher cutoff values. On comparing sensitivity and specificity of FS values in prediction of iron overload at different cutoff values by ROC curve, it could not significantly predict iron overload (p=0.7). No correlations were found between LIC and other variables including SF (r=0.2), and changes in SF were not significantly associated with changes in LIC values (p =0.089). However, sensitivity and specificity of SF in predicting LIC were good at cutoff 1003.85 ng/ml but decreased markedly at higher cutoff values. Comparing its sensitivity and specificity to that of SF in the prediction of iron overload at different cutoff values by ROC curve, FS could not predict iron overload accurately (p=0.9) and the degree of agreement between these two variables as indicators of iron overload was low (kappa=0.063, p=0.478).Conclusion: Fibroscan could be a valuable tool to assess the degree of liver fibrosis in patients with elevated SF, but it does not appear to reliably predict LIC in such group of patients especially with severe iron overload. FS values were not affected by disease type, age above 12 years, or HCV sero-positivity. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Iron-chelating effect of silymarin in patients with β-thalassemia major: A crossover randomised control trial.

This study aimed to determine the potential iron-chelating effects of silymarin in patients with β-thalassemia major receiving standard iron-chelation therapy. We evaluated whether addition of silymarin to standard iron-chelation therapy could improve iron burden markers and liver and cardiac function in these patients, via a placebo-controlled, crossover clinical study. Silymarin (140mg) or placebo were administered thrice daily to all patients (n=82) for 12weeks, and after a 2-week washout period, patients were crossed over to the other groups. Silymarin efficacy was assessed by measuring serum iron level, ferritin level, total iron-binding capacity and liver and cardiac function on magnetic resonance imaging. Silymarin treatment resulted in a negative change in the serum iron and ferritin levels and a positive change in the total iron-binding capacity levels (treatment effect, p<.001, p=.06, and p=.05, respectively). Silymarin treatment led to positive changes in cardiac and liver function in both treatment sequences of study; however, this was not statistically significant. There was a negative change in liver iron concentration in both treatment sequences (treatment effect, p=.02). In conclusion, combined iron-chelation and silymarin therapy was effective for improving the iron-burden status in patients with β-thalassemia major.

Longitudinal changes in LIC and other parameters in patients receiving different chelation regimens: Data from LICNET.

The liver remains the primary site of iron storage, with liver iron concentration (LIC) being a strong surrogate of total body iron. MRI-R2 can accurately measure LIC. The LICNET (Liver Iron Cutino Network) was established to diagnostics of liver iron overload by MRI-R2 subjects with hemochromatosis in hematological disorders. The aims of the study were to look at variation in LIC measurements during time across different chelation regimens. This was a cross-sectional study of 130 patients attending 9 Italian centers participating in the LICNET. LIC comparisons over time (T0 and T1 ) were made using t test and/or Wilcoxon test. LIC significantly decreased from MRI1 to MRI2 although at high variance (median change -0.8mg Fe/g dw, range: -29.0 to 33.0; P=.011) and 7.7% of patients shifted from LIC values of high risk (>15mg Fe/g dw) to an intermediate-risk category (7-15mg Fe/g dw). Median change in LIC and correlation with serum ferritin levels (SF), during different chelation regimens, is reported. These findings suggest as longitudinal variation in the LIC is possible, across all chelation regimens. It confirms as SF levels not always can be used for estimating changes in LIC.

Iron Unloading By Therapeutic Phlebotomy in Previously Transfused Children with Sickle Cell Anemia: The Twitch Experience

▪Background: TCD With Transfusions Changing to Hydroxyurea (TWiTCH, ClinicalTrials.gov NCT01425307), an NHLBI-sponsored Phase III multicenter trial, compared transfusions to hydroxyurea for maintaining TCD velocities in children with sickle cell anemia who previously received transfusions for abnormal TCD velocities. Iron overload was treated with serial phlebotomy in children randomized to hydroxyurea. At the first scheduled interim analysis, non-inferiority of hydroxyurea was demonstrated and the study was terminated prematurely.Methods: Participants randomized to hydroxyurea received decreasing volumes of monthly transfusions during hydroxyurea dose escalation to maximum tolerated dose (MTD), averaging 6-7 months. During this transfusion overlap period, no chelation therapy was given. After hydroxyurea MTD was reached, transfusions were discontinued and children started monthly phlebotomy if their entry liver iron concentration (LIC) by MRI-R2 (FerriScan®) was ≥2 mg Fe/g dry weight liver (DWL). The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) with adjustments for anemia (5 mL/kg for Hb 8.0-8.5 g/dL and held if Hb <8.0 g/dL). Phlebotomy was performed over 30 minutes with immediate equal volume normal saline replacement, typically using peripheral venous access. LIC was assessed at study entry, midpoint (12 months), and exit (24 months/early closure). Ferritin was monitored monthly using a centralized laboratory. Iron loading calculations were based on actual transfusion and phlebotomy volumes.Results: Sixty children (mean age 9.7±3.2 years; range 5.2-19.0 years; 48% male) were randomized to the Hydroxyurea Treatment Arm. The average duration of previous transfusions was 4.5±2.8 years. Almost all (51/60, 85%) had previously received chelation, primarily deferasirox, and 48 (80%) were on chelation therapy at study enrollment.Hydroxyurea MTD was achieved in 57 children (95%), and 54 commenced phlebotomy (two had low iron burden with LIC <2 and one had Hb <8.0 g/dL). A total of 914 phlebotomy procedures were scheduled per protocol for these 54 children and 756 (83%) were fully completed. There were 77 procedures cancelled due to anemia and another 81 procedures cancelled due to planned anesthesia (16), provider preference (14), hydroxyurea-related cytopenia (13), intercurrent illness (11), inadequate iv access (9), family request (5) or other (13). In 94% of phlebotomy procedures that were initiated, the full volume was removed; for the remaining 6% (47 procedures), a reduced volume was removed due to loss of venous access (37), symptoms such as headache or lightheadedness (7), or other reasons (3).A total of 18 Adverse Events (17 Grade 2 and one Grade 3) occurred in 14 participants in association with phlebotomy (2.3% prevalence). The most common complication was light headedness/near-syncope (6) followed by anemia (4), hypotension (3), headache (3), and pain at the venous access site (1). One subject had a syncopal episode followed by transient weakness, which was centrally adjudicated as TIA.An average of 53.6±21.8 mL/kg blood was administered in the hydroxyurea-treated arm, which calculates to an average iron loading of 40.1±16.3 mg Fe/kg, while an average of 112 mL/kg of venous blood was removed by phlebotomy, which calculates to an average iron unloading of 36.1±15.7 mg Fe/kg. For the 54 children who received phlebotomy, the average LIC was 12.0± 9.7 mg/g at study entry, 13.4±10.3 at midpoint reflecting overlap transfusions without chelation, and 9.7±8.9 at study exit reflecting serial phlebotomy, for an average net LIC decrease of 2.3±4.1 mg/g. Average serum ferritin at study entry was 3105±741 ng/mL and 1392±1542 ng/mL at study exit. For 39 children who completed all 24 months of treatment before study closure, the overall average LIC decrease was 3.2±3.8 mg/gram DWL and 10 had final LIC measurements <3 mg Fe/g. Calculated net iron loading was not significantly associated with measured changes in LIC or ferritin.Conclusions: In the TWiTCH trial, phlebotomy was a feasible, safe, well-tolerated, and effective treatment for transfusional iron overload in children with sickle cell anemia. Although initial overlap transfusions without chelation limited the phlebotomy effects, in children who reached hydroxyurea MTD and discontinued chronic transfusions, monthly phlebotomy led to net iron unloading and lower LIC, and significantly reduced iron burden. DisclosuresRogers:Apopharma: Consultancy. Kalfa:Baxter/Baxalta/Shire: Research Funding. Kwiatkowski:Sideris Pharmaceuticals: Consultancy; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy. Wood:World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; World Care Clinical: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy. Ware:Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Bayer Pharmaceuticals: Consultancy; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding.

Association Between Cardiac Iron Clereance and Hepatic Siderosis

Introduction. The aim of this multicenter study was to evaluate in thalassemia major (TM) if the cardiac efficacy of the three iron chelators in monotherapy was influenced by hepatic iron levels over a follow up of 18 months.Methods. Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we evaluated prospectively the 98 patients those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans and who showed evidence of significant cardiac iron (global heart T2*<20 ms) at the basal MRI. Iron overload (IO) was measured by T2* multiecho technique. We used cardiac R2* (equal to 1000/T2*) because cardiac R2* is linearly proportional to cardiac iron and hepatic T2* values were converted into liver iron concentration (LIC) values.Results. We identified 3 groups of patients: 47 treated with deferasirox (DFX), 11 treated with deferiprone (DFP) and 40 treated with desferrioxamine (DFO).Percentage changes in cardiac R2* values correlated with changes in LIC in both DFX (R=0.469; P=0.001) and DFP (R=0.775; P=0.007) groups. All patients in these 2 groups who lowered their LIC by more than 50% improved their cardiac iron (see Figure 1).Percentage changes in cardiac R2* were linearly associated to the log of final LIC values in both DFX (R=0.437; P=0.002) and DFP groups (R=0.909; P<0.0001).Percentage changes in cardiac R2* were not predicted by initial cardiac R2* and LIC values.In each chelation group patients were divided in subgroups according to the severity of baseline hepatic iron overload (no, mild, moderate, and severe IO). The changes in cardiac R2* were comparable among subgroups (P=NS) (Figure 2).Conclusion. In patients treated with DFX and DFP percentage changes in cardiac R2* over 18 months were associated with final LIC and percentage LIC changes.In each chelation group percentage changes in cardiac R2* were no influenced by initial LIC or initial cardiac R2*. [Display omitted] [Display omitted] DisclosuresPepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..

Agreement Between R2 and R2* Liver Iron Estimates Is Independent of the Type of Iron Removal Therapy: Results from the Twitch Trial

▪Introduction: TCD with Transfusions Changing toHydroxyurea (TWiTCH Clinical Trials.gov NCT01425307), an NHLBI-sponsored multicenter trial, compared transfusion pluschelation (Standard Arm) tohydroxyurea (HU) plus phlebotomy (Alternative Arm) in children with sickle cell disease at high risk for stroke. Alternative arm patients underwent serial phlebotomy (10mL/kg, maximum 500mL) every 4 weeks after reaching maximal tolerated dose (MTD) of HU and discontinuing transfusions. Changes in liver iron concentration (dLIC), measured as mg Fe per gram dry weight liver, by both MRI R2 (FerriScan) and R2* were key secondary outcome measures. R2 and R2* are two, different MRI techniques that exploit the magnetic properties of tissue iron to estimate iron concentration. We previously reported significant differences between the two approaches at the baselinetimepoint. The purpose of this investigation was to determine the limits of agreement between measurements ofdLIC over a period of one year by R2 and R2* methods in both arms of the study.Methods: MRI R2 and R2* data were collected prior to randomization, and after 1 year (midpoint) and 2 years of therapy (study exit). dLIC between baseline to midpoint and midpoint to study completion was calculated for both R2 and R2* LIC values. Since LIC measurement variability increases with iron burden, each dLIC pair (R2 and R2*) were normalized to the patients iron burden at the start of the observation interval. That is, dLIC from baseline to midpoint was normalized to baseline LIC, while dLIC from midpoint to study end was normalized to midpoint LIC. The geometric mean of LICR2 and LICR2* was used to represent the baseline and midpoint LIC. Bland Altman analysis was performed on measurements of the percent change of dLICR2 and dLICR2* to determine the limits of agreement between the two techniques.Results: R2 measurements were performed in 104 patients at baseline, 94 at midpoint and 99 at study end, while R2* measurements were performed in 101, 87, and 89 patients, respectively. However, missing data limited Bland Altman comparisons ofdLIC to 74 patients between baseline to midpoint and 69 patients from midpoint to study end. Figure 1 (left) plots the measureddLIC using R2 (vertical axis) against the measureddLIC change by R2* (horizontal axis) for the Standard Arm participants. Dots represent LIC change over the first year and open circles represent LIC changes over the second year. The dotted line represents perfect agreement. Figure 1 (right) demonstrates the corresponding relationship for the patients in the Alternative Arm.Although the alternative arm appears to have greater disagreement, this represents an artifactcause by the transient increases in LIC that occurred as patients bridged from standard to alternative therapy. Iron chelationwas stopped when patients began hydroxyureabut patients required an overlap period of transfusions for stroke prophylaxis. Figure 2 demonstrates the difference in dLIC measured by R2 and R2*, expressed as a percentage of starting LIC, plotted against the starting LIC value. The standard arm (open circles) and alternative arms (dots) completely overlap. 95% limits of agreement between the two measures ofdLIC were -45.7% to 63.7% (light lines). At LIC values > 8.3 mg/g,dLIC predicted by R2 was larger than predicted by R2*, while the converse was true for LIC values below 8.3 mg/g, similar to our published baseline findings for LIC measurements.Conclusions: LIC by R2 and R2* tracked one another closely over time in patients in both study arms. These data indicate that either technique can be used with confidence to monitor patients on iron removal therapy (chelation or phlebotomy), but that the techniques should not be interchanged. [Display omitted] [Display omitted] DisclosuresWood:Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Vifor: Consultancy; Biomed Informatics: Consultancy; World Care Clinical: Consultancy; Ionis Pharmaceuticals: Consultancy; World Care Clinical: Consultancy; AMAG: Consultancy; AMAG: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Biomed Informatics: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy. St Pierre:Resonance Health: Consultancy, Equity Ownership. Piccone:Novartis: Other: Speaker. Hankins:Novartis: Research Funding. Rogers:Apopharma: Consultancy. Ware:Bayer Pharmaceuticals: Consultancy; Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding.

Effectiveness of red blood cell exchange, partial manual exchange, and simple transfusion concurrently with iron chelation therapy in reducing iron overload in chronically transfused sickle cell anemia patients.

Chronic transfusion therapy (CTT) is indicated for stroke prevention in children with sickle cell anemia (SCA) and is complicated by iron overload and alloimmunization. CTT is performed by simple transfusion (ST), partial manual exchange (PME), or erythrocytapheresis (RCE). Although small case series have demonstrated RCE in combination with iron chelation therapy stabilizes and/or decreases ferritin, there are no reports comparing the effect of ST, PME, and RCE on liver iron concentration (LIC). CTT modality effect on serum ferritin and LIC were compared in SCA patients on iron chelation, with hemoglobin (Hb)S goal of 30%. Medical records of SCA patients on CTT and deferasirox (≥25 mg/kg/day) were retrospectively reviewed. Mean HbS%, change in ferritin and LIC, and alloimmunization rate were determined for each CTT group. Twenty-eight patients were included; six crossed over (one from ST to PME, one from ST to PME then to RCE, three from ST to RCE, and one from PME to RCE) to include 36 transfusion modality intervals. Median pretransfusion HbS% levels were 32.7% (ST), 36.2% (PME), and 34.7% (RCE; p = 0.732). Median ferritin changes were +15 (-17 to +45), +38 (+24 to +105), and -91 (-141 to -48) ng/mL/month (p = 0.003), and median LIC changes (available in 22 patient transfusion modality intervals) were +1.3 (-1.6 to +4.3), +2.3 (-6.5 to +8.9), and -5.7 (-10.7 to -0.5) mg/g/year (p = 0.024) in ST, PME, and RCE, respectively. There was no significant difference in alloimmunization rate between ST/PME and RCE groups. We recommend RCE plus chelation as an effective method for reducing iron overload, while maintaining HbS at 30% to 35%.

Efficacy and Safety of Deferasirox in Chinese Patients with Non-Transfusion-Dependent Thalassemia: 1-Year Results from the Thetis Study

▪Background: Although non-transfusion-dependent thalassemias (NTDT) and non-transfusion-dependent congenital or chronic anemias are found in Southern China, they are relatively rare diseases in China and there are little data evaluating iron chelation in Chinese patients. This 1-year analysis from the THETIS study investigated the efficacy and safety of deferasirox in a large subpopulation of Chinese patients. Early escalation of deferasirox doses (max: 30 mg/kg/day) was evaluated according to liver iron concentration (LIC).Methods: THETIS is an open-label, single-arm, multicenter, Phase IV, 5-year study with the primary endpoint after 1 year of treatment. For this subanalysis, Chinese patients ≥10 years of age with iron overload (LIC ≥5 mg Fe/g dry weight [dw] and serum ferritin [SF] ≥300 ng/mL) were enrolled. Exclusion criteria included: blood transfusions within 6 months of study enrollment or anticipated regular transfusions (unplanned transfusions allowed), Hb S/β thalassemia, active hepatitis B/C, cirrhosis, history of clinically relevant ocular and/or auditory toxicity; on two consecutive measurements: alanine aminotransferase >5× the upper limit of normal (ULN), serum creatinine >ULN, creatinine clearance ≤40 mL/min, or urine protein/urine creatinine ratio >1.0 mg/mg. All patients started deferasirox at 10 mg/kg/day. At week 4, deferasirox was increased according to baseline LIC (LIC >15, 20 mg/kg/day; LIC >7-≤15, 15 mg/kg/day; LIC ≥5-≤7, 10 mg/kg/day). At week 24, deferasirox was adjusted further: LIC >15, +5-10 mg/kg/day (max 30 mg/kg/day); LIC >7-≤15, +5 mg/kg/day (max 20 mg/kg/day); LIC ≥3-≤7, same dose. If LIC <3 or SF <300, therapy was held and restarted at the previously effective dose when LIC ≥5 and SF ≥300 (max 10 mg/kg/day). This sub-analysis evaluated absolute change in LIC and SF from baseline to week 52.Results: 68 Chinese patients were enrolled (median age 26.0, range 10-63 years) with Hb H disease (n=35), β thalassemia intermedia (n=21) or Hb E/β thalassemia (n=12). Most patients received prior transfusions (n=56/68, 82.4%); 20/68 (29.4%) patients received prior chelation. 57/68 (83.82%) patients completed 1 year. Patients who discontinued were most commonly lost to follow-up (n=4) or withdrew consent (n=3, personal or logistical reasons). Mean actual daily deferasirox dose ± standard deviation (SD) over 1 year (considering dose adjustments), was 16.21 ± 5.61 mg/kg/day.Mean LIC ± SD at baseline was 17.75 ± 12.37 mg Fe/g dw in Chinese patients, which decreased to 9.35 ± 6.83 mg Fe/g dw at week 52 (absolute change from baseline, -8.51 ± 8.58 mg Fe/g dw [95% CI -10.69 to -6.33]). Patients with higher LIC at baseline experienced a greater reduction in LIC by week 52 (Figure).Furthermore, 48 (70.6%) Chinese patients achieved an absolute decrease in LIC of ≥3 mg Fe/g dw, and 46 (67.6%) patients achieved a ≥30% relative reduction in LIC at the last assessment. At week 52, LIC was <3 mg Fe/g dw in 5 (7.4%) patients. Median SF (range) decreased in Chinese patients from a baseline of 1580 (333-6638) ng/mL to 872 (267-4315) ng/mL at week 52 (absolute median change, -423 [-5307 to -1669] ng/mL). At week 52, SF was <300 ng/mL in 1 (1.5%) patient.Adverse events (AE) regardless of causality were reported in 40 (58.8%) Chinese patients. Drug-related AEs were reported in 18 (26.5%) Chinese patients, most commonly gastrointestinal (abdominal discomfort, n=2; diarrhea and hematochezia, n=1 each) or skin related (rash, n=3; eczema, n=1). No patients discontinued because of AEs. One death occurred during the study (pneumonia leading to cardiac failure) that was not suspected to be drug-related. No patient had two consecutive serum creatinine increases of >33% above baseline or >ULN. No patient discontinued treatment due to notable liver or renal laboratory values.Conclusions: Deferasirox at 10 mg/kg/day escalated to a maximum of 30 mg/kg/day effectively reduced iron burden in Chinese patients. AEs were consistent with the known safety profile for deferasirox. Early dose escalation at week 4 and further adjustment at week 24 ensured that patients with iron overload achieved clinically relevant reductions in iron burden. These results were in alignment with the THETIS primary efficacy analysis, supporting early dose escalation of deferasirox to optimize chelation in more heavily iron-overloaded Chinese NTDT patients. [Display omitted] DisclosuresCappellini:Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Zhu:Novartis: Employment. Wang:Novartis: Employment. Qi:Novartis: Employment. Taher:Novartis: Honoraria, Research Funding.

Correlation of Hepatocyte Iron Score and Liver Iron Ratio with Alanine Aminotransferase in Patients with Beta Thalassemia Receiving Iron Chelation Therapy for at Least 3 Years

Background: Chronic blood transfusions impact the liver due to accumulation of iron, leading to tissue damage, collagen formation and portal fibrosis. Long-term chelation therapy has been shown to be associated with stability or improvement of liver fibrosis and necroinflammation in heavily iron-overloaded patients with β thalassemia, independently of reductions in liver iron concentration (LIC) (Deugnier et al Gastroenterology 2011;141:1202-1211). It was also shown that changes in alanine aminotransferase (ALT, an indicator of hepatocellular damage) mirrored changes in LIC, with significant decreases in ALT seen in LIC responders. Here, we evaluated the effect of long-term chelation therapy on hepatocyte iron score (HIS), and the correlation of HIS and liver iron ratio (LIR) with ALT, to determine if the location of iron within the liver impacts liver function.Methods: Study design, inclusion and exclusion criteria for studies 107 and 108 have been described previously (Deugnier et al, 2011). β thalassemia patients who had liver biopsy assessment at start of deferasirox treatment and after at least 3 years, were included in this analysis. Iron deposits were assessed according to size, cellular and lobular locations in Rappaport's acinus leading to three different scores: HIS (range 0-12), sinusoidal iron score (SIS, range 0-4) and portal iron score (PIS, range 0-4). The LIR, used to assess the relative amount of hepatocytic to total liver iron, was calculated as HIS/(HIS + SIS + PIS) x 100%. LIC was determined by liver biopsy. Correlation between ALT and HIS, and ALT and LIR was assessed using Pearson correlation coefficients. Baseline (BL) in these analyses refers to start of deferasirox treatment. Patients who received deferoxamine during the first year are referred to as the crossover cohort. Assessments were performed according to LIC response (see Table).Results: Of 671 β thalassemia patients enrolled, 470 received chelation therapy for at least 3 years. Of these patients, 219 had histological biopsy data at BL and after at least 3 years of treatment. For all patients (n=219), mean absolute change ± standard deviation (SD) in HIS from BL (16.7 ± 7.4) to end of study (EOS; 11.8 ± 7.8) was -5.0 ± 9.3 (95% confidence interval [CI]; -6.3, -3.8), with a mean relative change of -18.1% (95% CI; -27.7, -8.5). In the crossover cohort (n=94), the mean absolute change in HIS from BL (15.1 ± 7.1) to EOS (11.6 ± 8.0) was -3.8 ± 9.3 (95% CI; -5.8, -1.8), with a mean relative change of -10.4% (95% CI; -26.8, 6.0).Among LIC responders, the mean absolute change of HIS from BL (18.6 ± 7.4) to EOS (9.9 ± 7.2) was -8.7 ± 7.6 (95% CI; -10.1, -7.4); mean relative change -43.5% (95% CI; -51.7, -35.4). Among LIC non-responders, the mean absolute change of HIS from BL (13.0 ± 5.9) to EOS (14.4 ± 7.9) was 1.6 ± 8.2 (95% CI; -0.3, 3.5); mean relative change 26.9% (95% CI; 6.9, 47.0; Table).Correlation of HIS versus ALT: At BL and EOS, HIS showed a weak positive correlation with ALT in LIC responders (n=125, R=0.27 and n=126, R=0.31, respectively) and moderate correlation in non-responders (n=72, R=0.36 and n=72, R=0.43). Similarly, absolute change in HIS showed a weak correlation with change in ALT in LIC responders (n=125; R=0.17) with a moderate correlation in non-responders (n=72; R=0.44; Figure).Correlation of LIR versus ALT: At BL and EOS, LIR showed no correlation with ALT in LIC responders (n=121; R=-0.07 and n=122; R=0.04, respectively) and non-responders (n=70; R=-0.14 and n=70; R=-0.05, respectively). Absolute change in LIR showed a weak negative correlation with change in ALT in LIC responders (n=121; R=-0.25) and no correlation in non-responders (n=70; R=0.02).Discussion: Long-term iron chelation therapy is associated with improvement of liver function as measured by ALT in iron-overloaded patients with β thalassemia. Absolute change in HIS correlated with change in ALT in both LIC responders and non-responders. Although this correlation was weak to moderate, this finding supports the importance of excess iron removal from hepatocytes in order to improve ALT levels. By contrast, LIR which represents the proportion of HIS to total liver iron, showed no correlation. These results suggest that the improvement in liver function seen during chelation therapy may partly be due to the decrease in iron stored in hepatocytes. Further studies are warranted to investigate the mechanisms by which iron chelation therapy may improve liver function. [Display omitted] [Display omitted] DisclosuresCappellini:Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kattamis:ApoPharma: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Han:Novartis: Employment. El-Ali:Novartis: Employment. Porter:Celgene: Consultancy; Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Optimising iron chelation therapy with deferasirox for non-transfusion-dependent thalassaemia patients: 1-year results from the THETIS study

Efficacy and safety of iron chelation therapy with deferasirox in iron-overloaded non-transfusion-dependent thalassaemia (NTDT) patients were established in the THALASSA study. THETIS, an open-label, single-arm, multicentre, Phase IV study, added to this evidence by investigating earlier dose escalation by baseline liver iron concentration (LIC) (week 4: escalation according to baseline LIC; week 24: adjustment according to LIC response, maximum 30mg/kg/day). The primary efficacy endpoint was absolute change in LIC from baseline to week 52. 134 iron-overloaded non-transfusion-dependent anaemia patients were enrolled and received deferasirox starting at 10mg/kg/day. Mean actual dose±SD over 1year was 14.70±5.48mg/kg/day. At week 52, mean LIC±SD decreased significantly from 15.13±10.72mg Fe/g dw at baseline to 8.46±6.25mg Fe/g dw (absolute change from baseline, −6.68±7.02mg Fe/g dw [95% CI: −7.91, −5.45]; P<0.0001). Most common drug-related adverse events were gastrointestinal: abdominal discomfort, diarrhoea and nausea (n=6 each). There was one death (pneumonia, not considered drug related). With significant and clinically relevant reductions in iron burden alongside a safety profile similar to that in THALASSA, these data support earlier escalation with higher deferasirox doses in iron-overloaded non-transfusion-dependent anaemia patients.

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

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).

Insights into Relationships Between Serum Ferritin and Liver Iron Concentration Trends during 12 Months of Iron Chelation Therapy with Deferasirox – a Post-Hoc Analysis from the Epic Study

▪BackgroundSerum ferritin is regularly used to assess response to chelation therapy and correlates significantly with liver iron concentration (LIC) particularly when LIC is <7 mg Fe/g dry weight (dw) and serum ferritin is <4000 ng/mL. The absence of a serum ferritin decrease in the first months of a new chelation regime may be interpreted as a lack of response with respect to decreasing body iron load. However, sequential LIC determination (where available) has indicated that many of these patients do indeed have a decrease in LIC. This clinical experience requires greater understanding, particularly the nature of the LIC and serum ferritin relationship at baseline serum ferritin values ≥4000 ng/mL.The aim of this post-hoc analysis of the EPIC study was to gain insight into the relationship between serum ferritin and LIC in response to deferasirox over 1 year, in a large patient cohort, so that serum ferritin trends can be more clearly interpreted and evidence-based practical guidance be given for patients with transfusion-dependent thalassemia (TDT).MethodsTDT patients were recruited from 25 sites, received 1-year of deferasirox treatment and had serum ferritin and R2 magnetic resonance imaging (R2-MRI)-assessed LIC measurements at baseline and 1 year. Summary statistics are provided for serum ferritin and LIC responders (decrease, any change from baseline <0) and nonresponders (increase or no change, any change from baseline ≥0), and for baseline serum ferritin categories (≥4000 vs <4000 ng/mL).ResultsOf the 374 patients analyzed in the EPIC liver MRI substudy, 317 had TDT, of which 72.7% (n=226) had a serum ferritin response and 27.3% (n=85) had no response. Importantly, after 1 year LIC decreased in approximately half of serum ferritin nonresponders (51.8%; n=44; Table) and in 79.6% of serum ferritin responders (n=180). Median (min, Q1, Q3, max) change in LIC (mg Fe/g dw) was –5.4 (–38.5, –11.7, –0.9, 15.4) in serum ferritin responders and –0.2 (–18.4, –2.6, 2.7, 19.6) in nonresponders. Median (range) transfusional iron intake (mg/kg/day) was similar in serum ferritin responders (0.30 [0.01–1.49]) and nonresponders (0.37 [0.02–1.00]). Median deferasirox dose (mg/kg/day) was higher in serum ferritin responders than nonresponders (28.1 [9.8–40.4] vs 23.7 [9.7–37.9]).Evaluation of responses by baseline serum ferritin showed that a greater proportion of serum ferritin responders with baseline serum ferritin <4000 ng/mL also had decreased LIC (88.7% [n=102]; Table), compared with serum ferritin responders with baseline serum ferritin ≥4000 ng/mL (70.3% [n=78]). However, serum ferritin baseline category had no effect on the proportion of patients who decreased LIC despite having no serum ferritin response (52.6% [n=30], <4000 ng/mL; 50.0% [n=14], ≥4000 ng/mL; Table). There was little change in median LIC in serum ferritin nonresponders after 1 year regardless of baseline serum ferritin value (–0.3 [–13.5–18.7] for <4000 ng/mL and 0.2 [–18.4–19.6] for ≥4000 ng/mL).Assessment by change in serum ferritin and LIC quadrants indicated that patients without serum ferritin or LIC response had the lowest baseline median (range) serum ferritin and LIC (2155 [480–9725] ng/mL; 11.9 [1.8–37.5] mg Fe/g dw; n=41), and received a lower median deferasirox dose (23.7 [9.7–36.0] mg/kg/day). Overall, median LIC decrease (mg Fe/g dw) was smaller in patients with baseline serum ferritin <4000 ng/mL (n=172) than in those with serum ferritin ≥4000 ng/mL (–2.8 [–38.5–18.7] vs –4.9 [–31.1–19.6]; n=139). Median iron intake was similar between groups.Discussion and conclusionsA decrease in LIC was seen in ~80% of serum ferritin responders after 1 year of deferasirox; a greater proportion of serum ferritin responders (88%) decreased LIC when baseline serum ferritin was <4000 ng/mL. Importantly, among patients with no serum ferritin response up to half may be responding with respect to iron balance, indicating that a lack of serum ferritin response should be interpreted with caution. However, since a decrease in serum ferritin predicts a decrease in LIC in 80% of patients, MRI measurement (where available) should be prioritized for patients with serum ferritin increase/no change. Overall, serum ferritin response can help predict LIC response, but in some patients treated with deferasirox, serum ferritin may not accurately reflect removal of iron from the body. [Display omitted] DisclosuresPorter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy; Cerus: Membership on an entity’s Board of Directors or advisory committees; Alnylam: Membership on an entity’s Board of Directors or advisory committees. Taher:Novartis: Honoraria, Research Funding. Sutcharitchan:Novartis: Research Funding. Aydinok:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Chakravarty:Novartis: Employment. El-Ali:Novartis: Employment.

Deferasirox for iron chelation in multitransfused children with sickle cell disease; long-term experience in the East London clinical haemoglobinopathy network.

Deferasirox (DFX) has been licensed for iron chelation in patients with sickle cell disease (SCD), but there is limited data on its long-term efficacy and safety in children. This retrospective study included 62 regularly transfused children managed in the East London and Essex Clinical Haemoglobinopathy Network (mean age 9.2 ± 3.2 yr). Efficacy measurements consisted of monthly serum ferritin (SF) and annual R2 MRI-estimated liver iron concentration (LIC), and safety markers included serum creatinine and alanine aminotransferase (ALT). The mean duration of DFX treatment was 2.5 ± 1.4 yr, and mean dose at 36 months was 25 mg/kg/d. Mean SF at initiation of treatment was 2542 ± 952 ng/mL and increased to 4691 ± 2255 ng/mL at 36 months (P = 0.05). Mean LIC on first scan was 10.3 mg/g dry weight and did not decrease significantly on follow-up scans. There was a significant correlation between relative change in LIC and in SF (R(2) = 0.66, P < 0.001). Reversible transaminitis episodes, probably due to drug-induced hepatitis, were noted in 53% of patients. Responses to an adherence and acceptability questionnaire indicated that more than 50% of children had difficulties in taking DFX, commonly because of unpleasant taste. Our results show that more than 50% of children with SCD have inadequate control of iron overload with DFX. It is not clear whether this is because of frequent dose interruptions, poor tolerability and adherence, or poor efficacy of the drug. We recommend further studies to confirm these findings and to optimise iron chelation in this population.