Liver Iron Concentration Levels Research Articles

Improvement in Iron Burden in Patients with Transfusion-Dependent β-Thalassemia (TDT) Treated with Betibeglogene Autotemcel (Beti-cel) Gene Therapy: Up to 9 Years of Follow-up

Introduction: Beti-cel is an approved, one-time gene therapy treatment for adult and pediatric patients with TDT. Beti-cel consists of autologous hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene (β A-T87Q), which produces functional hemoglobin (Hb) and addresses the underlying genetic cause of TDT. While transfusion independence (TI) remains a critical component for assessing patient response to gene therapy, other measures, including markers of iron overload, are important for evaluating the impact of therapy and management of disease burden over time. Previously, we demonstrated that iron markers stabilized in patients who achieved TI and stopped chelation therapy. Here, we report iron management outcomes in patients who completed either a phase 1/2 or phase 3 beti-cel parent study and subsequently enrolled in the long-term follow-up study. Methods: Patients with TDT who completed a parent beti-cel study (phase 1/2 studies: HGB-204 [NCT01745120]; HGB-205 [NCT02151526]; phase 3 studies: HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) could enroll in a long-term study (LTF-303 [NCT02633943]) for up to an additional 13 years of follow-up. In these studies, TI was defined as a weighted average Hb ≥9 g/dL without packed red blood cell transfusions for ≥12 months. Iron removal therapy was at the discretion of the treating physician. Liver and cardiac magnetic resonance imaging evaluated liver iron concentration (LIC) and cardiac T2*; serum ferritin and transferrin receptor (TfR) were assessed at regular intervals according to protocol. Results:As of January 30, 2023, 63 patients received beti-cel; median (range) follow-up was 60.1 (23.8-109.5) months. In phase 3 studies, 37/41 (90%) patients achieved TI and maintained TI through the last follow-up, which was 5+ years for 10 patients ( Figure 1). In phase 1/2 studies, 15/22 (68%) patients achieved TI; 14 of these patients maintained TI through the last follow-up, which was up to 9 years. One patient no longer meets protocol-defined TI as a result of Hb level <9g/dL at year 6 due to acute health events unrelated to β-thalassemia, which were not attributed to loss of beti-cel treatment effect. In total, 51 patients across phase 1/2 and 3 studies achieved and maintained TI through last follow-up with 35/51 (69%) patients off chelation. Thirty of 51 patients had an LIC measurement at month 48. Of these 30 patients, 21 had an LIC <5 mg/g at month 48 post infusion. Among these 21 patients, 5 never restarted chelation after infusion (2 received phlebotomy only), 11 restarted chelation and then were able to discontinue after iron stores normalized (1 also received phlebotomy), and 5 continue to receive chelation (none had phlebotomy). The other 9 patients who had an LIC measurement at month 48 had an iron burden ≥5 mg/g. All 9 of these patients restarted chelation; 4 were able to discontinue (2 had phlebotomy) and 5 continue to receive chelation (1 had phlebotomy). Analysis of iron marker stabilization after discontinuation of chelation will be presented. The median (range) change from baseline in LIC levels at month 48 was -3.9 (-22.3 to 10.5) mg Fe/g dry weight; the median (range) change from baseline in serum ferritin was -2119.0 (-7211 to 3889) pmoL/L. Reductions from baseline in serum TfR were observed at month 36; cardiac T2* remained stable at month 48 ( Table 1). Safety of beti-cel treatment largely reflected the known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen. Conclusion: In this analysis with up to 9 years of follow up, patients treated with beti-cel who achieved TI also demonstrated sustained improvements in iron burden, and the majority of patients were able to stop chelation. Collectively, these results demonstrate the long-term durability and stability of response after beti-cel gene therapy in patients with TDT.

MRI for Quantitative Determination of Iron in the Liver and Heart in Patients with Primary and Secondary Hemochromatoses in Association with Serrum Ferritin: Single-Stage Observational Study

Background. An extremely small number of studies have been devoted to the study of differences in LIC (liver iron concentration) and MIC (myocardium iron concentration) indicators, as well as their correlation with each other and with ferritin levels in patients with various nosological forms. Aims to study the relationship of ferritin, LIC and MIC levels in patients with various causes of hemochromatosis (hereditary hemochromatosis (HH), aplastic anemia (AA), primary myelofibrosis (PMF), thalassemia (TL), myelodysplastic syndrome (MDS)). Methods. The design of the study is a singlestage observational one. The study included 91 patients with primary hemochromatosis and secondary transfusion-dependent hemochromatosis receiving regular blood transfusion and iron chelate therapy from 2015 to 2018. The studies were carried out on 1.5 T MR-scanner Magnetom Espree (Siemens, Germany), and myocardial iron concentration (MIC) was calculated using the formula MIC = 45 (T2*) 1.22. Liver iron concentration (LIC) was calculated using the formula LIC = 0.03 R2* + 0.74. The ferritin level was determined by enzyme immunoassay. Statistical processing of the results obtained was carried out using the SPSS software package. Results. Connections between LIC and ferritin (r = 0.867; p 0.001), MIC and ferritin (r = 0.759; p = 0.004) and LIC and MIC (r = 0.737; p = 0.006) were found in patients with primary hemochromatosis, while in patients with secondary hemochromatosis significant correlations were found only between LIC and MIC (r = 0.503; p 0.001), while the relationship was average. Links between LIC and ferritin were found in patients with AA (r = 0.656; p = 0.040), an average relationship, in patients with TL (r = 0.714; p = 0.020), an average relationship. The relationship between MIC and ferritin was revealed in patients with AA (r = 0.703; p = 0.050), an average relationship, in patients with TL (r = 0.757; p = 0.018), an average relationship. At the same time, in patients with MDS and PMF in this study, there was no association between ferritin and LIC, ferritin and MIC. Conclusions. In patients with hereditary hemochromatosis, LIC and MIC are associated with ferritin, and MIC is also associated with LIC (medium bond). In patients with iron overload due to thalassemia, an average correlation between LIC and ferritin, MIC and ferritin was revealed. In patients with iron overload due to aplastic anemia, an average correlation between LIC and ferritin, MIC and ferritin was revealed.

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.

Determinants Of Tissue Iron Loading In Transfused and Non-Transfused β-Thalassemia and Sickle Cell Disease Patients – Biomarkers Of Iron Regulation and Inflammation

IntroductionTransfused thalassemia (Thal) and sickle cell disease (SCD) patients develop tissue iron loading and organ injury. Even non-transfused Thal patients develop iron overload and iron-induced organ injury. In general, Thal patients are known to have greater extra-hepatic iron loading than SCD patients. This study investigated biomarkers that could modulate tissue iron loading in Thal and SCD. Patients and MethodsSeventy-eight Thal and SCD patients were enrolled including transfused (17 Tx Thal, and 19 Tx SCD) and non-transfused (12 nTx Thal and 16 nTx SCD). The following were analyzed: markers of erythroid expansion GDF15 and sTfR; markers of iron regulation and loading including hepcidin, NTBI, transferrin saturation, serum ferritin, ferritin/hepcidin and liver iron concentration (LIC); and a marker of inflammation, high sensitivity C-reactive protein (CRP). LIC was measured by SQUID Ferritometry®. Serum hepcidin was determined by competitive ELISA (Intrinsic LifeSciences, La Jolla, CA). ResultsLIC is similar between Tx Thal, nTx Thal and Tx SCD patients. Only nTx SCD patients had lower levels of LIC. However, all thal patients had an 83% increase in GDF15 levels and 87% higher NTBI levels (p<0.001) compared to all SCD patients. nTx thal had lower NTBI compared to TX thal despite similar LIC and not being on chelation therapy. Also sTfR was 80% higher in nTx thal and SCD compared to Tx Thal. Inflammation, on the other hand, as measured by CRP was 62% higher in all SCD patients (p=0.038) relative to all thal. Also Tx SCD patients had a strong negative relationship between NTBI and sTfR (r=-0.598, p=0.018) indicating that both inflammation and erythropoietic drive may be important in extra-hepatic tissue iron loading. Tx Thal and SCD patients had at least 70% higher levels of hepcidin. nTx thal had 93% higher levels of the ratio of ferritin to hepcidin (p=0.023). NTBI and LIC were found to positively correlate in nTx Thal patients (r=0.788, p=0.012), whereas no correlation between NTBI and LIC was found in Tx Thal patients. In nTx Thal, GDF15 is also negatively correlated with hepcidin (r=-0.631, p=0.038). In Tx SCD, GDF15 positively correlates with hsCRP (r=0.784, p=0.001). Tx SCD patients also show positive correlations between GDF15 and LIC (r=0.692, p=0.003) and serum ferritin (r=0.545, p=0.024). Finally, there is a negative relationship between GDF15 and hemoglobin in both Tx Thal and nTx Thal (r=-0.574, p=0.016 ; r=-0.643, p=0.033, respectively). ConclusionsThe data presented here suggests that more effective erythropoiesis in nTx SCD, Tx SCD and nTx Thal seems to protect from excess NTBI and possible extra-hepatic iron loading. In Tx SCD the positive correlation between CRP and GDF15 and the negative correlation between NTBI and sTfR suggests both inflammation and effective erythropoiesis may be important in extra-hepatic iron loading. Furthermore, GDF15 could be related to ineffective erythropoiesis while sTfR is reflecting effective erythropoiesis in this study cohort. Disclosures:Walter:Novartis: Research Funding. Nemeth:Intrinsic LifeSciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Ganz:Intrinsic LifeSciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Porter:Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Harmatz:Novartis: Research Funding; Shire: Consultancy, Honoraria, Research Funding, travel, travel Other.

Correlation Between Serum Ferritin and Viral Hepatitis in Thalassemia Patients

Serum ferritin is an acute phase protein; importantly, its level is noticeably increased in response to iron overload and systemic inflammation. The iron overload status in thalassemia patients has been recognized as a potential way to measure liver iron concentration (LIC) levels using magnetic resonance imaging (MRI). The aim of this study was to investigate the effect of chronic viral hepatitis on the level of serum ferritin in patients with thalassemia. A cross-sectional study was conducted involving chronic viral hepatitis infection. Mean serum ferritin and LIC levels were recorded. The LIC values were used to divide the patients into two groups; a higher LIC group (>5 mg Fe/g) and a lower LIC group (<5 mg Fe/g). Mean serum ferritin levels were then compared between the two LIC groups. We identified 32 thalassemia patients comprising of 13 chronic viral hepatitis patients, seven patients with hepatitis B virus (HBV), and six patients with hepatitis C virus (HCV). With regard to the group with higher LIC values, the mean serum ferritin levels in the hepatitis group were significantly higher than for those in the non hepatitis group (1776 ± 488 vs. 967 ± 860 ng/mL, p = 0.03). Furthermore, the linear correlation between the mean serum ferritin levels and the viral load in the non transfusion-dependent thalassemia (NTDT) group were found to be significantly correlated (r = 0.7, p = 0.04). Chronic viral hepatitis was determined to be a possible casualty of disproportionately high ferritin levels in the NTDT group.

The serum ferritin levels and liver iron concentrations in patients with alpha-thalassemia: is there a good correlation?

ABSTRACT Introduction Liver iron overload is common in patients with thalassemia. In patients with beta-thalassemia, the correlation between serum ferritin and liver iron concentration is well established. The correlation between serum ferritin levels and liver iron concentrations in patients with alpha-thalassemia remains limited. Methods This is a cross-sectional study in patients with alpha-thalassemia aged ≥ 18 years old at Srinagarind Hospital, Khon Kaen University, Thailand. Liver iron concentration (LIC) was evaluated by the MRI-T2* technique. Linear logistic regression analysis was used to determine the correlation between serum ferritin levels and liver iron concentrations. Results One hundred and thirty-one of the MRI-T2* measurements from 65 patients with alpha-thalassemia were evaluated. Patients with non-deletional alpha-thalassemia had higher LIC compared to patients with deletional alpha-thalassemia. The serum ferritin levels were relatively low at the same levels of LIC in patients with non-deletional alpha-thalassemia compared to deletional alpha-thalassemia. Conclusions The correlation of serum ferritin levels and LIC was modest and different among alpha-thalassemia genotypes. A different serum ferritin threshold is needed to guide iron chelation therapy in patients with alpha-thalassemia. Evaluation of liver iron concentration is necessary for patients with alpha-thalassemia, especially in patients with non-deletional alpha-thalassemia.

Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety Comparison of Deferasirox Formulations for Treatment Tailoring

Introduction: The majority of published data about Deferasirox (DFX) are obtained on the dispersible formulation (DFX DT). A film-coated formulation (DFX FCT) with higher bioavailability is now approved and used in most countries, in tablets containing 30% less active principle. However, only few reports exist about long-term effects of DFX FCT and no independent comparison of the two formulations is available. Hypothesizing a bioavailability even higher than described, we conducted a study comparing PK/PD and safety of both formulations in a cohort of patients with congenital anemias. Methods: Clinical records of patients treated at our referral Centre in the period from 2011 to March 2019 were reviewed, identifying patients that performed a 24-hours PK profile for both DFX formulations and completed at least 1 year of continuous treatment for each one. Data about PK (drug dose, maximum plasma concentration (Cmax), Area Under Curve (AUC)), PD (serum ferritin (FTN), Liver Iron Concentration (LIC) by biosusceptometry) and safety (ALT, AST, creatinine, eGFR, protein/creatinine ratio) were collected. Acute Kidney Injury (AKI) was defined according to guidelines as previously described (Bird, 2018). Estimated compliance was also considered. Serum DFX concentrations were measured by HPLC (De Francia et al, 2012). For PD and safety analysis, study time was defined as the period between two subsequent LIC measures; timeframes closest to the beginning of the therapy were selected. Wilcoxon matched-pairs test, Chi-square test and Spearman r index were used to analyze differences and correlations between DFX DT and DFX FCT treatments, with a significance threshold of 0.01. Results: Seventy-four patients diagnosed of β-thalassemia major (61), β-thalassemia intermedia (11), Diamond-Blackfan anemia (1) and Stomatocytosis (1) met inclusion criteria for PK analysis. DFX was tested at a mean dose of 26.1 (DT) and 15.5 mg/kg (FCT; -41%), with a Cmax of 71.0 and 101.5 μMol/L (+43%) and an AUC of 855.0 and 1301.3 (+52%), respectively. Cmax and AUC correlated significantly with dose for both formulation, but highly for FCT (r(dose-Cmax) = 0.41 and 0.58, r(dose-AUC) = 0.37 and 0.52 for DT and FCT, respectively), suggesting a stronger association between administered dose and systemic bioavailability (Fig.1). Forty-nine out of 74 patients, with at least 1-year follow-up for each formulation, were further analyzed for PD and safety. Actual administered dose was adjusted if indicated, but no significant differences were observed from doses tested at PK. LIC and FTN levels did not change significantly during treatments; as expected, the rate of iron overload variation (ΔLIC) was proportional to the iron overload at baseline for both formulations, but this correlation was stronger for FCT (Tab.1). Mean compliance was high with both formulations but improved significantly with DFX FCT (DT=89.3%; FCT=91.6%; p=0.001). Liver enzymes, creatinine, eGFR and protein/creatinine ratio at the end of treatments did not differ from baseline. AKI episodes were experienced in both formulations at rates comparable or higher than described (Diaz-Garcia, 2014 and Bird, 2018), but significantly lower with DFX FCT (DT=1.47; FCT=0.49 episodes/patient/year; p=0.0083). Overall kidney function was maintained at the end of the study for both treatments. Discussion: This study presents a direct and extended comparison of DFX formulations from real-word experience. DFX FCT, even at doses lower than recommended (-41% instead of -30%) was superior to DT in terms of PK and comparable in overall PD after 1 year of observation. Here described for the first time, DFX FCT also resulted to be superior in terms of scalability, i.e. it showed better correspondence between administered dose and serum concentration and between the baseline iron burden and the rate of iron elimination during treatment. Acute renal impairment was confirmed to be a major complication of DFX treatment, however AKI prevalence was significantly lower for FCT and, consistently, a significant dose-dependent association was observed for FCT, but not DT. Altogether, our results suggest that FCT formulation is more bioavailable than expected and could improve chronic treatment with DFX, underlining the critical role of personalized dose tailoring and monitoring to maximize the delicate balance between effectiveness and safety . Disclosures Longo: Blue Bird Bio: Consultancy. Piga:Celgene Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Acceleron Pharma: Research Funding.

PB2047 COMPARATIVE ANALYSIS OF DEFERASIROX DISPERSIBLE TABLETS VS FILM‐COATED TABLETS IN SEVERE CONGENITAL ANEMIAS: RESTROSPECTIVE STUDY IN A TERTIARY HOSPITAL

Background:Several congenital anemias are defined by ineffective erythropoiesis, sometimes even exarcerbated by chronic hemolysis, which in combination with periodic transfusions required on the most severe forms lead to iron overload in the organism, which settle on body tissues leading to their disfunction, with significant impact on morbimortality.Iron chelators aim to decrease iron load, as well as prevent or delay long term complications. Deferasirox (DF) is an oral chelator whose efficacy and security had been well defined since its approval. New film‐coated formulation proved similar efficacy as well as better palatability and tolerance on the ECLIPSE trial, achieving better treatment compliance.Aims:Conducting a comparative study between deferasirox dispersable tablets (DF‐D) versus film‐coated tablets (DF‐FC) amidst severe congenital anemias, analyzing chelating capacity as well as treatment compliance and side effects in both formulations.Methods:Retrospective case series. We collected data from patients diagnosed with severe congenital anemias and active follow up visits in our hospital, who were treated with DF‐D as well as DF‐FC over 12 months each. Qualitative variables are presented as absolute frequencies and percentages; and the quantitative ones as median and standard deviation. Exact Fisher test was performed when comparing qualitative variables, and Mann Whitney test when analyzing quantitative ones. Data was analized by SPSS Statistics.Results:We collected data from 7 patients: 6 of them diagnosed as thalassemia major and 1 as Blackfan Diamond anemia. 85,7% of our patients were female and 14,3% were male, median age 44 years old.Mean red blood cells concentrates tranfused were 20 units per year for both formulations. Median DF dosing was 1500 mg over DF‐D treatment and 1080 mg over DF‐FC treatment, which translates into equivalent dosing given DF‐FC better bioavailability.We got 6,2% mean increasing percentage of serum ferritin levels with DF‐D versus 1,3% with DF‐FC; however, when analyzing liver iron concentration (LIC) we observed an 8,3% decrease in iron load with DF‐D as opposite to 39,7% with DF‐FC, as well as a similar decrease in cardiac iron concentration (CIC) comparing both formulations (9,5% with DF‐D vs 6,5% with DF‐FC).71,4% patients showed poor treatment compliance over DF‐D treatment, due to the development of side effects, outlining digestive disturbances (80%) and less frequently renal impairment or nonspecific disturbances (10% each), conditioning a change in therapy in 40% of cases. We did not find adherence problems with DF‐FC formulation, side effects rate decreased to 28,6% and no patient required a change in therapy.Summary/Conclusion:Our data revealed a high rate of side effects associated with DF‐D, mainly digestive disturbances, conditioning poor therapeutic adherence as well as changes to treatment in 40% of our patients. New formulation substantially decreased side effects rate, no patients required a change in treatment and we found a 100% therapy compliance.imageSerum ferritin levels showed an slight increase over both treatments, with hardly any diffence between the two, which did not correlate with LIC levels, that showed a significant decrease in iron load, or cardiac deposits. In our opinion this data could be explained given ferritin low specificity quantifying iron load, whose levels fluctuate with inflammatory or infectious states; as compared to LIC and CIC estimation by magnetic resonance imaging, which have shown higher reliability when quantifying iron burden.

Erythropoiesis and Iron Homeostasis in Non-Transfusion-Dependent Thalassemia Patients with Extramedullary Hematopoiesis.

Background Extramedullary hematopoiesis (EMH) is common in non-transfusion-dependent thalassemia (NTDT) patients. Clinical presentations of EMH vary as MRI screening is not feasible. Hence, serum biomarkers are used to predict the risk of EMH. Materials and Methods 52 NTDT patients, including 26 EMH (+) and 26 EMH (-), together with 26 healthy controls, were enrolled in this case-control study from 2013 to 2016. EMH was confirmed by computed tomography or MRI. Demographic, transfusion, genetic, laboratory, and liver iron concentration (LIC) data, as well as clinical complications, were analyzed. Results EMH (+) patients had significantly higher serum ferritin (SF), growth differentiation factor 15 (GDF15), and erythropoietin (EPO) levels compared with EMH (-) patients and controls. The levels of erythroferrone (ERFE), hepcidin, and sTfR did not differ significantly between EMH (+) and EMH (-) patients (p>0.05). In NTDT patients, serum ERFE was not related to SF, LIC, hepcidin, sTfR, EPO, GDF15, and Hb levels. GDF15, EPO concentrations, and GDF15 to sTfR and GDF15 to EPO ratios are able to determine the presence of EMH with considerable sensitivity and specificity. Conclusions GDF15, EPO, and GDF15 to EPO and GDF15 to sTfR ratios are potential biomarkers for the early prediction of NTDT in patients who are at risk for EMH.

Jadenu® Substituting Exjade® in Iron Overloaded β-Thalassemia Major (BTM) Patients: A Preliminary Report of the Effects on the Tolerability, Serum Ferritin Level, Liver Iron Concentration and Biochemical Profiles.

IntroductionDue to the chronic nature of chelation therapy and the adverse consequences of iron overload, patient adherence to therapy is an important issue. Jadenu ® is a new oral formulation of deferasirox (Exjade ®) tablets for oral suspension. While Exjade® is a dispersible tablet that must be mixed in liquid and taken on an empty stomach, Jadenu ® can be taken in a single step, with or without a light meal, simplifying administration for the treatment of patients with chronic iron overload. This may significantly improve the compliance to treatment of patients with β-thalassemia major (BMT). The aim of this study was to evaluate the drug tolerability and the effects of chelation therapy on serum ferritin concentration, liver iron concentration (LIC) and biochemical profiles in patients with BMT and iron overload.Patients and MethodsTwelve selected adult patients BMT (mean age: 29 years; range:15–34 years) were enrolled in the study. All patients were on monthly regular red cell transfusion therapy to keep their pre-transfusional hemoglobin (Hb) level not less than 9 g/dL. They were on Exjade® therapy (30 mg/kg per day) for two years or more before starting Jadenu® therapy (14–28 mg/kg/day). The reason for shifting from Deferasirox® to Jadenu® therapy was lack of tolerability, as described by patients, such as nausea, vomiting, diarrhea, stomach pain. Most of them also reported that Deferasirox® was not palatable. Lab investigations included monthly urine analysis and measurement of their serum concentrations of creatinine, fasting blood glucose (FBG), serum ferritin, alkaline phosphatase (ALP), alanine transferase (ALT), aspartate transferase (AST) and albumin concentrations. LIC was measured using FerriScan ®. Thyroid function, vitamin D and serum parathormone, before and one year after starting Jadenu ® therapy, were also assessed.ResultsApart from some minor gastrointestinal complaints reported in 3 BMT patients that did not require discontinuation of therapy, other side effects were not registered during the treatment. Subjectively, patients reported an improvement in the palatability of Jadenu® compared to Exjade® therapy in 8 out of 12 BMT patients. A non-significant decrease in LIC measured by FerriScan® and serum ferritin levels was observed after one year of treatment with Jadenu®. A significant positive correlation was found between serum ferritin level and LIC measured by the FerriScan® method. LIC and serum ferritin level correlated significantly with ALT level (r = 0.31 and 0.45 respectively, p < 0.05). No significant correlation was detected between LIC and other biochemical or hormonal parameters.ConclusionsOur study shows that short-term treatment with Jadenu ® is safe but is associated with a non-significant decrease in LIC and serum ferritin levels. Therefore, there is an urgent need for adequately-powered and high-quality trials to assess the clinical efficacy and the longterm outcomes of new deferasirox formulation.

SEVERE LIVER IRON CONCENTRATIONS (LIC) IN 24 PATIENTS WITH Β-THALASSEMIA MAJOR: CORRELATIONS WITH SERUM FERRITIN, LIVER ENZYMES AND ENDOCRINE COMPLICATIONS

IntroductionChronic blood transfusion is the mainstay of care for individuals with β-thalassemia major (BTM). However, it causes iron-overload that requires monitoring and management by long-term iron chelation therapy to prevent endocrinopathies and cardiomyopathies, which can be fatal. Hepatic R2 MRI method (FerriScan®) has been validated as the gold standard for evaluation and monitoring liver iron concentration (LIC) that reflects the total body iron-overload. Although adequate oral iron chelation therapy (OIC) is promising for the treatment of transfusional iron-overload, some patients are less compliant with it, and others suffer from long-term effects of iron overload.ObjectiveThe aim of our study was to evaluate the prevalence of endocrinopathies and liver dysfunction, in relation to LIC and serum ferritin level, in a selected group of adolescents and young adult BTM patients with severe hepatic iron overload (LIC from 15 to 43 mg Fe/g dry weight).Patients and MethodsTwenty-four selected BTM patients with severe LIC, due to transfusion-related iron-overload, followed at the Haematology Section, National Centre for Cancer Care and Research, Hamad Medical Corporation of Doha (Qatar), from April 2015 to July 2017, were retrospectively evaluated. The prevalence of short stature, hypogonadism, hypothyroidism, hypoparathyroidism, impaired fasting glucose (IFG), diabetes, and adrenal insufficiency was defined and assessed according to the International Network of Clinicians for Endocrinopathies in Thalassemia (ICET) and American Diabetes Association criteria.ResultsPatients’ most common transfusion frequency was every three weeks (70.8%). At the time of LIC measurements, their median age was 21.5 years with a mean age of 21.7 ± 8.0 years. Mean LIC was 32.05 ± 10.53 mg Fe/g dry weight (range: 15 to 43 mg Fe/g dry weight), and mean serum ferritin level was 4,488.6 ± 2,779 μg/L. LIC was correlated significantly with serum ferritin levels (r = 0.512; p = 0.011). The overall prevalence of short stature was 26.1% (6/23), IFG was 16.7% (4/24), sub-clinical hypothyroidism was 14.3% (3/21), hypogonadotropic hypogonadism was 14.3% (2/14), diabetes mellitus was 12.5% (3/24), and biochemical adrenal insufficiency was 6.7% (1/15). The prevalence of hepatitis C positivity was 20.8% (5/24). No case of clinical hypothyroidism, adrenal insufficiency or hypoparathyroidism was detected in this cohort of patients. The prevalence of IFG impaired fasting glucose was significantly higher in BTM patients with very high LIC (>30 mg Fe/g dry liver) versus those with lower LIC (p = 0.044). The prevalence of endocrinopathies was not significantly different between the two groups of patients with LIC above and below 15 mg Fe/g dry weight.ConclusionsA significant number of BTM patients, with high LIC and endocrine disorders, still exist despite the recent developments of new oral iron chelating agents. Therefore, physicians’ strategies shall optimize early identification of those patients to optimise their chelation therapy and to avoid iron-induced organ damage. We believe that further studies are needed to evaluate if serial measurements of quantitative LIC may predict the risk for endocrine complications. Until these data are available, we recommend a close monitoring of endocrine and other complications, according to the international guidelines.

An Automated Segmentation of R2* Iron-Overloaded Liver Images Using a Fuzzy C-Mean Clustering Scheme.

The objectives of this study were to develop and test an automated segmentation of R2* iron-overloaded liver images using fuzzy c-mean (FCM) clustering and to evaluate the observer variations. Liver R2* images and liver iron concentration (LIC) maps of 660 thalassemia examinations were randomly separated into training (70%) and testing (30%) cohorts for development and evaluation purposes, respectively. Two-dimensional FCM used R2* images, and the LIC map was implemented to segment vessels from the parenchyma. Two automated FCM variables were investigated using new echo time and membership threshold selection criteria based on the FCM centroid distance and LIC levels, respectively. The new method was developed on a training cohort and compared with manual segmentation for segmentation accuracy and to a previous semiautomated method, and a semiautomated scheme was suggested to improve unsuccessful results. The automated variables found from the training cohort were assessed for their effectiveness in the testing cohort, both quantitatively and qualitatively (the latter by 2 abdominal radiologists using a grading method, with evaluations of observer variations). A segmentation error of less than 30% was considered to be a successful result in both cohorts, whereas, in the testing cohort, a good grade obtained from satisfactory automated results was considered a success. The centroid distance method has a segmentation accuracy comparable with the previous-best, semiautomated method. About 94% and 90% of the examinations in the training and testing cohorts were automatically segmented out successfully, respectively. The failed examinations were successfully segmented out with thresholding adjustment (3% and 8%) or by using alternative results from the previous 1-dimensional FCM method (3% and 2%) in the training and testing cohorts, respectively. There were no failed segmentation examinations in either cohort. The intraobserver and interobserver variabilities were found to be in substantial agreement. Our new method provided a robust automated segmentation outcome with a high ease of use for routine clinical application.

Relationship between liver iron concentration determined by R2-MRI, serum ferritin, and liver enzymes in patients with thalassemia intermedia

BackgroundIron overload is a risk factor affecting all patients with thalassemia intermedia (TI). We aimed to determine whether there is a relationship of serum ferritin (SF) and alanine aminotransferase (ALT) with liver iron concentration (LIC) determined by R2 magnetic resonance imaging (R2-MRI), to estimate the most relevant degree of iron overload and best time to chelate in patients with TI.MethodsIn this cross-sectional study, 119 patients with TI (mean age years) were randomly selected and compared with 120 patients who had a diagnosis of thalassemia major (TM). Correlations of LIC, as determined by R2-MRI, with SF and ALT levels, were assessed in all participants. A P-value <0.05 was considered statistically significant.ResultsSF and LIC levels were lower in patients with TI than in those with TM; only ferritin values were significant. We found a statistically significant relationship between SF and LIC, with cut-off estimates of SF in patients with TI who had splenectomy and those who entered puberty spontaneously (916 and 940 ng/mL, respectively) with LIC >5 mg Fe/g dry weight (P<0.0001). A significant relationship was also found for patients with TI who had elevated ALT level (63.5 U/L), of 3.15 times the upper normal laboratory limit, using a cut-off for LIC ≥5 mg Fe/g dry weight.ConclusionWe determined the cut-off values for ALT and SF indicating the best time to start iron chelation therapy in patients with TI, and found significant correlations among iron overload, SF, and ALT.

GNPAT rs11558492 is not a Major Modifier of Iron Status: Study of Italian Hemochromatosis Patients and Blood Donors

Background and AimHFE-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, GNPAT rs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls. Material and MethodsAllele and genotype frequencies were analysed and compared with those reported in Exome Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrho-sis. ResultsGNPAT rs11558492 minor allele (G) frequency (MAF) was 20.3% in HFE-HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in HFE-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis. ConclusionsOur findings indicate that GNPAT rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in HFE-HH patients.

GNPAT rs11558492 is not a Major Modifier of Iron Status: Study of Italian Hemochromatosis Patients and Blood Donors.

HFE-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, GNPAT rs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls. Allele and genotype frequencies were analysed and compared with those reported in Exome Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrhosis. GNPAT rs11558492 minor allele (G) frequency (MAF) was 20.3% in HFE-HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in HFE-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis. Our findings indicate that GNPAT rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in HFE-HH patients.

Iron Overload Status in Patients with Non-Transfusion-Dependent Thalassemia in China

▪Background: Non-transfusion-dependent thalassemia (NTDT) is a genetic disorder most commonly including beta-thalassemia intermedia (Beta-TI), HbE/Beta thalassemia (HbE/Beta thalassemia), and hemoglobin H disease (HbH disease). NTDT patients can be at risk of iron overload due to increased intestinal iron absorption triggered by chronic anemia, ineffective erythropoiesis and, possibly, decreased serum hepcidin. Despite NTDT is popular in southern China, there is little data evaluating iron overload in Chinese patients. This study aimed at investigating the occurrence, prevalence and severity of iron overload in Chinese population with NTDT.Methods: We evaluated the serum ferritin (SF), liver iron concentration (LIC) and cardiac T2* in 158 NTDT patients (83 with HbH disease, 45 with Beta-TI and 30 with HbE/Beta thalassemia) in China. The median age was 22 years old. The main characteristics of these patients along with the main results of the study were summarized in Table 1. Blood samples were obtained for the assessment of hemoglobin (Hb) and serum ferritin (SF) levels. LIC was assessed by using validated R2 magnetic resonance imaging [MRI] (FerriScan®). Cardiac iron level was measured by MRI T2*. Patients were scanned with MRI 1.5 T (Siemens Avanto, Germany). The study was performed at the First Affiliated Hospital of Guangxi Medical University. LIC < 3mg Fe/g dw and cardiac T2* > 20ms was considered normal. Abnormal LIC can be divided into mild: 3-7mg Fe/g dw, moderate: 7-15mg Fe/g dw, severe: >15mg Fe/g dw. All patients or parents/guardians provided their written informed consent to participate in this study. The study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University.Results: The median SF level of 158 NTDT patients was 1,037(27.0-19,704) ng/ ml. LIC was detected in 155 patients (98.1%) and the median LIC value was 8.9(0.6-43) mg Fe/g dw. There were 15 patients (60%) (8 with HbH disease, 5 with Beta-TI and 2 with HbE/Beta thalassemia)<10 years old found liver iron overload. The youngest patient with liver iron overload was 5 years old with 5.6mg Fe/g dw in LIC. Cardiac T2*was assessed in 111 patients (70.2%) and the median cardiac T2* was 32.8(7.5-75.1)ms. The 7 patients (4.4%) (4 with HbH disease and 3 with Beta-TI) had cardiac T2*=<20ms. There was a significant correlation between LIC and SF (r=0.809, p<0.001). No correlation between LIC and Hb, cardiac T2* values can be verified.There was a significant correlation between LIC and age (r=0.497, p<0.001)(Fig 1). The levels of LIC in patients > 30-year old group are significantly higher than those in other groups (Fig 2).The patients with Beta-TI and HbE/Beta thalassemia showed a statistically significant lower Hb and higher values of SF and LIC than those of HbH disease patients.Conclusions: Chinese NTDT patients have a high prevalence of iron overload. The iron overload in patients with Beta-TI and HbE/Beta thalassemia are more serious than those in HbH disease patients. The age of patient is a risk factor of iron overload in NTDT patient. Patients > 30 years old have a high burden of iron overload. Our data shows that the first assessment of MRI LIC should be performed as early as 5 years old. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Features and Morbidities of Hb H Disease in Taiwan

Introduction Patients with non-transfusion-dependent thalassemia experience a wide array of clinical complications despite their independence from frequent, regular red blood cell transfusions. They have the higher incidence of osteoporosis, extramedullary hematopoeisis (EMH), hypogonadism, cholelithiasis, thromboembolic disease, pulmonary hypertension, silent cerebral ischemia, and leg ulcers. Thalassemia is highly prevalent in Taiwan and Hb H disease is predominant. But limited data are available about clinical features and morbidities. Here, we studied clinical features and morbidities in Taiwanese patients with Hb H disease.Methods & Results We collected 90 patients with Hb H disease in three hospitals since 2014 Nov till 2016 July. Male to female were 43/59. The mean age was 33.1 years ( from 0.5 to 92.3 years). Two cases died of pulmonary hypertension and old age at 31 years old and 87 years old. Alfa-globin gene genotype studies were done in 44 cases. The (- -(SEA)) type of α(0)-thalassemia mutation was detected in all patients. Twenty- four (57.1%) cases were deletional (α(3.7)/ α(4.2)/unknown 19/4/1) and 20 (42.9%) were nondeletional (CS/RS 18/2) type. The mean of Hemoglobin (Hb) and serum ferritin level were 8.7 g/dL and 730 ng/mL. We also revealed the positive correlation between age and serum ferritin level. The liver iron concentration (LIC) were 6.694 mg Fe/g dw (n=35). The Hb, ferritin and LIC level were not different between deletional and non- deletional groups. They received the transfusion management : 1 with regular transfusion ≦ 6 weeks interval, 5 with irregular transfusion ≧ 6 weeks interval, 27 with occasional transfusion and 57 without transfusion. Fifteen cases received splenectomy. There were significantly higher prevalence for transfusion frequency and splenectomy in non-deletional group. The prevalence of morbidities were 16/79 for cholelithiasis, 12/90 for thromboembolic event, 4/90 for heart failure symptoms ( 2 for pulmonary hypertension), 5/90 for arrhythmia, 3/90 for bone fracture, 5/20 for osteoporosis and 0 for renal stone. There were non-significantly higher prevalence for morbidities in non-deletional group.Discussion & Conclusion The study provides the clinical features and the prevalence of morbidities in Hb H disease in Taiwan. Surprisingly, the prevalence of thromboembolic event and pulmonary hypertension are overlooked in our routine Hb H disease care. We need to schedule close and careful clinical follow up of Hb H patients as they get older, they get some morbidities or they are non-deletional genotype. DisclosuresNo relevant conflicts of interest to declare.

Implications of Low Zinc and Copper Levels As Well As Altered Iron Trafficking Proteins on Oxidant Stress in Patients with Transfusion Dependant Thalassemia

Introduction:Patients with transfusion dependent thalassemia (TDT) have a genetic anemia that causes incomplete erythropoiesis and iron overload. Plasma zinc deficiency is also seen in roughly 25% of patients with TDT. Iron overload is thought to be related to a number of secondary complications in TDT including cardiomyopathy and diabetes. However, in TDT the effects of altered Zn status are not as well characterized and the effects of low copper (Cu) are even less well known. One possible cause of these complications is oxidative damage to tissues. This oxidative stress can be caused by labile plasma iron (LPI), a component of the non-transferrin bound iron pool, which is often seen in individuals suffering from iron overload. LPI is both redox-active and chelatable and is the likely culprit distributing iron to extra-hepatic tissues. Through reactive Fenton chemistry, LPI, can also cause lipid peroxidation releasing malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which are damage-associated molecular patterns and markers of oxidative tissue damage that activate the immune system to induce inflammation. Incomplete erythropoiesis as well as transfusional iron overload are responsible for an increase in the amount of poorly handled, redox active LPI in TDT. Thus, we hypothesized that changes in the levels of key iron trafficking proteins (such as soluble transferrin receptor (sTfR) or hemopexin) would affect oxidative stress levels in TDT. We also hypothesized that metal dyshomeostasis, such as a functional Zn or Cu deficiency would affect oxidative stress.Aims: The purpose of this pilot project is to 1) Determine the state of circulating levels of oxidative stress markers and iron trafficking proteins in TDT patients and 2) Explore the relationship between the markers and proteins measured in (1)and the Zn and Cu status of TDT patients.Methods:39 subjects with informed consent were enrolled (29 patients with TDT and 10 controls). Liver iron concentration (LIC) was measured by a superconducting quantum interference device (SQUID™). LPI was measured using dihydrorhodamine 123. Both MDA and MDA + 4-HNE were measured using N-methyl-2-phenylindole. The iron trafficking proteins sTfR, transferrin, haptoglobin and hemopexin were measured by immunoassay isolation followed by multiplex multiple reaction monitoring mass spectrometry. Zn and Cu were assessed by inductively coupled plasma atomic emission spectroscopy. Fructosamine was measured by quantitative spectrophotometry.Results: Patients with TDT had elevated LIC levels of 2681 ± 2424 ug iron/g wet weight. Plasma levels of the iron trafficking proteins, transferrin, hemopexin and haptoglobin were all decreased in TDT patients (P<0.001) with a corresponding increase in soluble transferrin receptor (StfR) and the LPI (P<0.001). Serum Zn was significantly reduced in TDT patients (p = 0.028) and urinary Zn was significantly elevated (p =0.024). Serum Cu was also significantly reduced in TDT patients (p =0.026). Reduced Zn levels in TDT patients correlated with elevated MDA levels (p = 0.0195, R = -0.382) as were serum Cu levels (p = 0.0158, R = -0.394). Reduced levels of plasma iron trafficking proteins (haptoglobin, hemopexin, and transferrin) were correlated with elevated levels of MDA and LPI (all p-values < 0.05). Plasma MDA was also correlated with fructosamine levels (p < 0.001, R= 0.57).Conclusion: Metal dyshomeostasis involving Zn and Cu may be important contributors to oxidative stress and iron injury in TDT. We confirm previous findings in TDT of elevated levels of LPI as well as the oxidative stress markers MDA and 4-HNE. We expand previous findings of reduced transferrin levels in TDT to show a similar reduction in both haptoglobin and hemopexin. StfR levels were elevated in TDT patients, possibly due to a strong erythropoietic drive. Both reduced haptoglobin and hemopexin as well as decreased Zn and Cu levels and increased Zn excretion appear to be present in TDT. These preliminary findings suggest that low levels of Zn, Cu, haptoglobin and hemopexin may be related to increased oxidative stress and LPI in TDT, which could be important contributors to secondary complications of TDT. DisclosuresWalter:Apopharma: Research Funding.

Real-life experience with liver iron concentration R2 MRI measurement in patients with hemoglobinopathies: baseline data from LICNET.

Real-life data on the use of R2 MRI for the assessment of liver iron concentration (LIC) remain limited. We conducted a cross-sectional analysis on 363 patients (mean age 35.6 yr, 44.1% men) with hemoglobinopathies (204 β-thalassemia major [TM], 102 β-thalassemia intermedia [TI], and 57 sickle cell disease [SCD]) that were evaluated with R2 MRI as part of LICNET, an MRI network of 13 Italian treatment centers. The mean LIC was 7.8 mg/g (median: 4.0), with high LIC (>7 mg/g) noted in both transfused (TM, TI 37%; SCD 38%) and non-transfused (TI 20%) patients. Ferritin levels correlated with LIC in both transfused (TM, TI, SCD) and non-transfused (TI) patients (P < 0.001), although lower values predicted high LIC in non-transfused patients (1900 vs. 650 ng/mL in TM vs. non-transfused TI). A correlation between LIC and ALT levels was only noted in HCV-negative patients (rs = 0.316, P < 0.001). The proportion of patients with high LIC was significantly different between iron chelators used (P = 0.023), with the lowest proportion in deferasirox (30%) and highest in deferiprone (53%)-treated patients. High LIC values persist in subgroups of patients with hemoglobinopathy, warranting closer monitoring and management optimization, even for non-transfused patients with relatively low ferritin levels.

Association of Liver Iron Concentration Levels with Myocardial T2* Responses in Transfusion-Dependent Thalassemia Major Patients Treated with Deferasirox and Deferoxamine- Extension of Cordelia Study

Background: Beta thalassemia major patients (pts) are at an increased risk of heart failure, due to the deposition of iron in the heart causing myocardial siderosis. Intensive long-term iron chelation therapy (ICT) is required to obtain a normal myocardial T2* (mT2* >20 ms). Previously published studies suggested that cardiac iron removal lags changes in liver iron, and liver iron concentration (LIC) may affect the rate of removal of cardiac iron (Porter et al, ASH 2013). The objective of these analyses was to evaluate the association of the severity of LIC levels with the change in mT2* responses in pts with myocardial siderosis when treated with deferasirox (DFX) and deferoxamine (DFO) for up to 24 months (mo) in the CORDELIA study. Due to the very low pt numbers in the DFO arm, the results for these pts are not presented here. Methods: The study design, inclusion, and exclusion criteria have been reported previously (Pennell et al, Am J Hematol. 2015). Pts were categorized into LIC Results: Of 197 pts, 160 (81.2%) completed 12 mo of treatment and 146 (74.1%) entered into the extension study whereas 103 pts continued on initially assigned treatment. Pts completing 24 mo of treatment included 65 (87.8%) of 74 pts (mean age 20.1±6.9 years, 59.5% male) on DFX and the results for these pts are presented as follows. Average actual doses (mg/kg/d) were 26.7±8.9, 31.5±7.4, 38.0±2.9 for LIC The LIC levels for pts categorized by LIC For pts with BL LIC The mT2* responses for pts categorized according to visit specific LIC levels (LIC Discussion: Overall, DFX treatment resulted in a substantial decrease in LIC and improved mT2*. These results suggest a greater difference in mT2* improvement and CIC reduction in pts who achieved lower LIC during treatment with DFX. This divergence was progressive with time, being maximal at Mo 24. Thus, a therapeutic response in LIC with DFX may be associated with a greater likelihood of improving mT2*. Pts with high LIC ≥15 may require an effective long-term treatment with higher doses of ICT to have an improvement in mT2*, suggesting that cardiac iron removal is likely to be slow in heavily iron overloaded pts. These results are consistent with the previous report which showed a significant decrease in LIC and increased mT2* responses at Mo 36 in pts who attained lower end-of-year LIC levels when treated with DFX (Porter et al, ASH 2013) and highlight the potential value of monitoring the liver and cardiac responses during ICT. To further understand the kinetics between liver and cardiac iron removal, prospective investigation is warranted. Disclosures Pennell:Novartis: Consultancy, Research Funding; Apotex: Consultancy, Research Funding. Porter:Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. Piga:Acceleron: Research Funding; Cerus: Research Funding; Apopharma: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene Corporation: Honoraria. Han:Novartis: Employment. Vorog:Novartis: Employment. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau.