Mean Liver Iron Concentration Research Articles

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.

The Impact of Iron Overload in Patients with Acute Leukemia and Myelodysplastic Syndrome on Hepatic and Endocrine functions.

Patients with hematologic malignancies undergoing chemotherapy and requiring blood transfusion usually have an elevated serum ferritin. These findings have led to the suggestion that iron overload is common and may have deleterious effects in these patients. However, the relationship between serum ferritin and parenchymal iron overload in such patients is unknown. Therefore, we measured the liver iron content (LIC) by the FerriScan® method and investigated the liver function and some endocrine tests in 27 patients with acute leukemia (AL) or myelodysplastic syndromes (MDS). Using FerriScan® method, the normal mean LIC levels are: 4.3±2.9 mg Fe/g dry weight (d.w.). In our patients, the mean serum ferritin level was 1965±2428 ng/mL. In our patients, the mean total iron in the blood received by them was 7177±5009 mg. In 6 out of 27 patients LIC was >7 mg Fe/g d.w. and in 11/27 serum ferritin was >1000 ng/ml. Measuring fasting blood glucose revealed 3/27 with diabetes mellitus and 4/27 with impaired fasting glucose (IFG). All patients had normal serum concentrations of calcium, parathormone (PTH), free thyroxine (FT4) and thyrotropin (TSH). Four patients had elevated serum alanine transferase (ALT). LIC was correlated significantly with ferritin level (r=0.5666; P<0.001) and the cumulative amount of iron in the transfused blood (r=0.523; P<0.001). LIC was correlated significantly with ALT (r=0.277; P = 0.04) and fasting blood glucose (FBG) was correlated significantly with the amount of iron transfused (r=0.52, p<0.01) and ALT level (r=0.44; P<0.01). The age of patients did not correlate with LIC, FBG or ALT. In conclusions, these results contribute to our understanding of the prevalence of dysglycemia and hepatic dysfunction in relation to parenchymal iron overload in patients with hematologic malignancies undergoing chemotherapy and requiring blood transfusions. (www.actabiomedica.it)

Progression of liver fibrosis can be controlled by adequate chelation in transfusion-dependent thalassemia (TDT).

A substantial proportion of patients with transfusion-dependent beta-thalassemia major suffer from chronic liver disease. Iron overload resulting from repeated transfusions and HCV infection has been implicated in the development of liver fibrosis. Hepatic siderosis and fibrosis were assessed in 99 transfusion-dependent thalassemia (TDT) patients using transient elastography (TE) and liver iron concentration (LIC) assessed by T2*MRI at baseline and after 4years. Data were analyzed retrospectively. At baseline, the overall mean liver stiffness measurement (LSM) was 7.4±3.2kPa and the mean LIC was 4.81±3.82mg/gdw (n=99). Data available at 4±1.5years showed a significant reduction in LSM (6.6±3.2kPa, p 0.017) and hepatic siderosis measured by LIC (3.65±3.45mg/gdw, p 0.001). This result was confirmed when considering patients with iron overload at the time of the first measurement (n=41) and subjects treated with a stable dose of deferasirox over the entire period of observation (n=39). A reduction of LSM, yet not statistically significant, was achieved in patients on combined deferoxamine + deferiprone, while the group on deferoxamine (n=11) remained stable over time. HCV-RNA positivity was found in 33 patients at T0, 20 of which were treated during the observation period. Patients who underwent anti-HCV therapy showed a more evident reduction in LSM (9±3 vs 7±3.1kPa, p 0.016). Adequate chelation therapy is mandatory in order to prevent liver disease progression in TDT. Patients could benefit from regular non-invasive assessment of liver fibrosis by TE to indirectly monitor treatment adequacy and therapeutic compliance.

Pregnancy in patients with thalassemia major: a cohort study and conclusions for an adequate care management approach.

An improvement in quality of life and survival occurred among thalassemia major (TM) patients: pregnancy in such patients has become a reality. Safe pregnancy and delivery require efforts to ensure the best outcomes. Between 2007 and 2016, 30 TM patients had 37 pregnancies. We analyzed the hematological parameters before, during, and after pregnancies and in 19 patients a cardiovascular magnetic resonance (CMR) T2* was performed. The mean age at first pregnancy was 30±4years; the current mean age is 35±5years. Twenty-four patients (80%) had a single pregnancy, five patients (17%) had two pregnancies, and one patient (3%) became pregnant three times. Seventeen pregnancies (46%) were spontaneous, 20 (64%) needed gonadotrophin-induced ovulation and/or reproductive technologies. All pregnancies resulted in live births. Seven were twin pregnancies (19%). The mean gestational hemoglobin was 9.2±0.5g/dl, lower than pre- and postpregnancy (9.8±1g/dl, p=ns and 9.6±1g/dl, p=0.02, respectively). Median ferritin levels increased progressively (1071, range 409-5724ng/ml, before pregnancy vs 2231, range 836-6918ng/ml, after pregnancy, p<0.0001). CMR before pregnancy showed a normal cardiac T2* (mean 35.34±8.90ms) and a mean liver iron concentration (LIC) of 3.37±2.11mg/g dry weight (dw). After pregnancy, the mean cardiac T2* was 31.06±13.26ms and the mean LIC was significantly increased (9.06±5.75mg/gdw, p=0.0001). Pregnancy is possible and safe in thalassemia major. During pregnancy, iron accumulates, especially in the liver; a prompt resumption of chelation after delivery is mandatory.

Bone quality in beta-thalassemia intermedia: relationships with bone quantity and endocrine and hematologic variables.

We report the first evaluation of bone quality in 70 thalassemia intermedia (TI) patients (37 males, 33 females, age 41±12years). Thirty-three patients (47%) had been transfused, 34 (49%) had been splenectomized, 39 (56%) were on iron chelation therapy, and 11 (16%) were on hydroxyurea. Mean hemoglobin was 9.2±1.5g/dl, median ferritin 537ng/dl (range 14-4893), and mean liver iron concentration 7.6±6.4mg Fe/g dw. Fifteen patients (21%) had endocrinopathies, and 29 (41%) had vitamin D deficiency. Bone quantity (bone mineral density, BMD) and bone quality (trabecular bone score, TBS) were evaluated by densitometry. In 53/70 patients (76%), osteopathy was found (osteoporosis in 26/53, osteopenia in 27/53). BMD values were higher in the never-transfused patients and in the not-chelated group. A highly significant correlation was found between splenectomy and BMD at all the sites, with lower values in the splenectomized patients. TBS values were significantly lower in TI patients than in 65 non-thalassemic controls (1.22 vs 1.36, p<0.01), mainly in those splenectomized and in the transfused and chelated groups (p<0.01). TBS did not correlate with liver iron concentration values. Our data disclose the major role of non-invasive bone quality evaluation in TI patients, especially those with the worst health state, to obtain a comprehensive assessment of fracture risk. Splenectomy seems to play a major part in bone complications.

Liver Iron Concentration in Patients Referred to a Secondary Hospital for Hyperferritinemia: Analysis of the Different Groups According to HFE Mutations and the Transferrin Saturation Index

Background: Olynyk et al. studied the liver iron concentration (LIC) by MRI of 52 consecutive patients of northern European origin who were referred to a tertiary hospital for hyperferritinemia (HF). They described three groups according to HFE mutations and the transferrin saturation index (TSI) (group A: no predisposing mutations (PM) for hereditary hemochromatosis (HH) and TSI > 45 %, group B: PM for HH and TSI > 45 %; group C: no PM for HH and normal TSI). In the Basque country, HH predisposing mutations differ, with prevalence of the H63D/H63D mutation. Objectives: To study the importance of HFE mutations and the TSI in determining LIC of HF patients attending the outpatient clinic at a secondary hospital. Methods: Prospective study of 132 consecutive patients with HF. In 120 HFE study was available. In 79 LIC was obtained by MRI. In 71 patients values of HFE mutations, TSI, and LIC by MRI were available. Results: Mean age: 55.68 ± 14.26 (23 - 83), 55 men and 16 women. The mean LIC in men was 35.66 ± 36.85; women 38.81 ± 29.75. The mean LIC in group A: 38.80 ± 45.18 (5 - 210), group B: 48.96 ± 37.51 (15 - 160), group C: 28.12 ± 18.85 (5 - 75). We compared the LIC mean values of the 3 groups with no significant differences. Conclusions: LIC values are similar in different groups of patients referred to a secondary hospital for HF, despite variable predisposition to HH.

Luspatercept Increases Hemoglobin, Decreases Transfusion Burden and Improves Iron Overload in Adults with Beta-Thalassemia

▪Background.Luspatercept (ACE-536) is a modified activin receptor type IIB fusion protein that promotes late-stage erythroid differentiation. In beta-thalassemia, imbalanced production of alpha and beta globin chains in erythroid precursors causes ineffective erythropoiesis (IE) leading to anemia and dysregulated iron homeostasis. In a mouse model of beta-thalassemia, luspatercept corrected the effects of ineffective erythropoiesis and in a phase 1 clinical study with healthy volunteers, was well tolerated and increased hemoglobin (Suragani R, Nat Med, 2014; Suragani R, Blood, 2014; Attie K, Am J Hematol, 2014).Aims.This is an ongoing, phase 2, multicenter, open-label, dose-finding study followed by a long-term extension study to evaluate the effects of luspatercept in patients (pts) with either transfusion-dependent (TD) or non-transfusion dependent (NTD) beta-thalassemia with the following key endpoints: erythroid response (including Hgb increase) and patient-reported quality-of-life (QoL) measures in NTD patients, and reductions in RBC transfusion burden in TD patients.Methods.Inclusion criteria included age ≥ 18 yr and either TD (defined as ≥ 4 RBC units transfused in the 8 weeks prior to first dose, confirmed over 6 months) or NTD (defined as < 4 RBC units transfused in the 8 weeks prior to first dose with baseline Hgb < 10.0 g/dL). Luspatercept was administered subcutaneously every 3 weeks for up to 5 doses over 12 weeks with an 8 week follow-up (20 weeks total). Six cohorts (n=35) were treated at dose levels from 0.2-1.25 mg/kg. Pts in the expansion cohort (n=29) and all pts who rolled over to the extension study (n=51) were treated at ≥ 0.8 mg/kg with escalation up to 1.25 mg/kg.Results. A total of 30 TD pts enrolled in the base study and, of those, 24 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 38 yr (range 22-55 yr), 67% had prior splenectomy. At baseline, median transfusion burden was 8 units/12 weeks (range 4-15 units) and mean (SD) liver iron concentration (LIC) was 5.1 (5.3) mg/g dw. A total of 20/24 (83%) and 16/24 (67%) TD pts achieved a ≥ 33% and ≥ 50% decrease in transfusion burden over any 12-week period compared to baseline, respectively. Duration of response ranged from 12 to 48+ weeks.A total of 34 NTD pts enrolled in the base study and, of those, 27 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 37 yr (range 23-62 yr); 67% had prior splenectomy. At baseline, median Hgb was 8.7 g/dL (range 7.6-9.8 g/dL) and mean (SD) LIC was 4.9 (3.4) mg/g dw. A total of 21/27 (78%) and 15/27 (56%) NTD pts achieved ≥ 1.0 g/dL and ≥ 1.5 g/dL increases, respectively, in mean Hgb over any 12-week period compared to baseline. Duration of response ranged from 16 to 72+ weeks, with no trend for lower Hgb response over time. Increases in mean hemoglobin over a 12-week period correlated with increases in a pt-reported QoL questionnaire, FACIT-F (r=0.67, p=0.001). 3/5 (60%) pts with baseline LIC ≥ 5 mg/g dw had a decrease in LIC ≥ 2 mg/g dw after at least 6 months of treatment; 8/9 (89%) patients with baseline LIC < 5 mg/g dw maintained LIC < 5 mg/g dw.Luspatercept was generally well tolerated, with no related SAEs. AEs were mostly mild-moderate. The most frequent related AEs (≥ 10% in base + extension studies) in TD pts were bone pain, myalgia, arthralgia, headache, asthenia, and musculoskeletal pain. The most frequent related AEs (≥ 10% in base + extension studies) in NTD pts were bone pain, headache, musculoskeletal pain, and arthralgia.Conclusions: Luspatercept treatment in pts with beta-thalassemia had a favorable safety profile. Efficacy was clinically relevant in both NTD pts (increased Hgb levels, decreased LIC, and improved quality of life) and TD pts (decreased RBC transfusions). A Phase 3, double-blind, placebo-controlled study of luspatercept in regularly transfused adults with beta-thalassemia is ongoing (NCT02604433). DisclosuresZhang:Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Leneus:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership.

The Safety and Efficacy of Deferasirox for the Transplant Patients with Iron Overload

Introduction: Iron overload in patients who received hematopoietic cell transplantation (HCT) is one of the major clinical issues. Although deferasirox is well known to be an iron chelating agent, its safety for the patients who received HCT is unknown. Then, we designed a multicenter prospective study (phase 1) to evaluate the safety and efficacy of deferasirox in patients with iron overload after HCT.Methods: The eligibility criteria includes the duration at least 6 month after HCT, serum ferritin more than 1,000 ng/ml, red blood cell (RBC) transfusions more than 20 units, disease remission, normal renal function, performance status of 0 or 1, and the unfit of phlebotomy. The exclusion criteria were history of iron chelating therapy after HCT, presence of moderate or severe chronic graft-versus-host disease (GVHD), uncontrollable complications, and the history of hepatitis B or C virus infection. A registration target was set at 20 patients including 5 ineligibles. Safety of deferasirox was assessed by the dose escalation methods in the individual. After the registration, deferasirox was started at a dose of 5 mg/kg for four weeks. Then, the dose was increased to 7.5 mg/kg and 10 mg/kg. The patient attended every two weeks for the safety evaluation. Cessation criteria were any grade 2 to 4 of adverse event or early disease relapse. Namely, 4 weeks medication within grade 1 of adverse events was defined as tolerable and successful medication for the identical dose. Primary endpoint was the maximum tolerate dose of deferasirox and defined from the dose in which 50 to 80% of the eligible patients were tolerable.Results: A total of 16 patients were enrolled to the study from March 2013 to January 2016. One case was excluded out of analysis due to the early relapse and 15 were eligible. Median age was 42 years old (range: 22-68). Disease included acute myeloid leukemia (n=6), acute lymphoblastic leukemia (n=2), aplastic anemia (n=2), non-Hodgkin's lymphoma (n=2), and others (n=3). Median duration from HCT to deferasirox administration was 9 months (range: 6-84). Median amount of RBC transfusions was 54 units (range: 20-156). Median value of serum ferritin was 1,537 ng/ml (range: 1,027-7,655). Regarding to the dose escalation test, 9 cases succeeded in taking from the initial 5mg/kg to the final 10mg/kg and 6 resulted in withdrawal during the treatment: abnormality of clinical test in 5 mg/kg (n=3), late relapse in 7.5 mg/kg (n=1), self-cessation and gastrointestinal event in 10 mg/kg (n=2). Achievement rates of successful medication were 80% in 5 mg/kg (12 of 15), 73% in 7.5 mg/kg (11 of 15), and 60% in10 mg/kg (9 of 15), respectively. Among 10 evaluable cases, mean value of ferritin decreased from 1,605 ng/ml at pre-treatment to 1,303 ng/ml at post-treatment. The change of other markers were as follows: hemoglobin from 12.0 g/dl to 12.6 g/dl, aspartate aminotransferase (AST) from 24.9 IU/L to 28.3 IU/L, alanine aminotransferase (ALT) from 25.8 IU/L to 28.4 IU/L, creatinine (Cr) from 0.80 mg/dl to 1.05 mg/dl. Liver iron content (LIC) was examined only in 3 cases and the mean LIC was did not change before and after the treatment at 200 μmol/g. Main of grade 1 of adverse events were elevation of clinical test including Cr (60%), AST (40%), ALT (40%), and alkaline phosphatase (33%), diarrhea (27%), abdominal pain (20%), skin rash (20%), constipation (20%), nausea (13%). None of the patients developed the exacerbation of GVHD.Conclusion: This dose escalating method of deferasirox treatment for transplant patients may be feasible. Ten mg/kg of deferasirox may be maximum tolerated dose when given after HCT. The efficacy of iron chelation would be inadequate due to the low dose and short term of deferasirox. Validation of phase 2 study is warrant. DisclosuresMorita:Bristol-Myers Squibb: Speakers Bureau. Kanda:Otsuka Pharmaceutical: Honoraria, Research Funding. Okamoto:Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Teijin Pharma Limited: Research Funding; Astellas Pharma Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

Progression of Liver Fibrosis Can be Controlled Under Adequate Chelation in Transfusion-Dependent Thalassemia (TDT).

BACKGROUND. A substantial proportion of patients with transfusion-dependent beta-thalassemia major suffer from chronic liver disease. Iron overload resulting from repeated transfusions and HCV infection have been implicated in the development of liver fibrosis. The objective of iron chelation is to avoid the complications of siderosis, such as hepatocellular injury. As a matter of fact, adequate chelation therapy is mandatory in order to prevent liver disease progression. In the last few years the availability of different chelating agents (coupled with anti-HCV therapy) allowed control of liver disease due to secondary iron overload. Transient elastography (TE, Fibroscan®) is a non-invasive and rapid diagnostic tool that enables accurate prediction of hepatic fibrosis by measuring liver stiffness (LSM). Patients with TDT could benefit from regular non-invasive assessment of liver fibrosis as an indirect indicator of treatment adequacy and therapeutic compliance.AIM. We investigated the efficacy of adequate iron chelation to prevent the progression of liver fibrosis in TDT patients over a time period of approximately 4 years.MATERIALS AND METHODS. We analysed data in a retrospective cohort study over a 4±1.5-year time period. Ninety-nine patients with beta-thalassemia major (41 M, 58 F, aged 36±6 years), followed at Rare Disease Center, Ca’ Granda Hospital in Milan, were enrolled in the study. All patients received regular transfusions every 2-4 weeks. Chelation therapy was registered using deferasirox (DFX), deferoxamine (DFO), deferiprone (DFP) or a combination of the three. All the participants underwent TE and T2-weighted magnetic resonance imaging (T2*MRI) twice (at baseline,T0 and after approximately 4 years, T1). Liver iron concentration (LIC) was assessed by T2*MRI using the appropriate formula at T0 and T1. LSM was measured according to the following cut-off: <5.0 kPa no fibrosis (F0), 5.1-7.9 kPa mild fibrosis (F1), >7.9 kPa moderate fibrosis (F2), >10.3 advanced fibrosis (F3), >11.9 kPa cirrhosis (F4). We divided our cohort into groups depending on the administered chelating agent and the presence of iron overload defined by a LIC > 4.23 mg Fe/g dry weight (corresponding to a T2* value > 6.3 ms).RESULTS. At baseline the mean pre-transfusion Hb levels was 9.74 ± 1.17 g/dL, the mean iron intake 0.33 ± 0.07 mg Fe/kg/d and median serum ferritin 669.5 ng/ml (range 113-5912). HCV-RNA positivity was found in 33 patients (33%) at T0: 20 patients were treated for hepatitis C during the observation period. The overall mean LSM was 7.4±3.2 kPa, the mean hepatic T2* was 9.92±7.01 ms and the mean LIC was 4.81±3.82 mg/g dw (n=99). Data available at 4±1.5 years showed a significant reduction in liver stiffness (6.6±3.2 kPa, p 0.017), iron overload measured by hepatic T2* (12.84±7.28 ms, p < 0.001) and LIC (3.65±3.45 mg/g dw, p 0.001). This result was confirmed when considering patients with iron overload at the time of the first measurment (n=41). The number of patients with moderate to advanced fibrosis (LSM ≥ F2) decreased, yet not significantly (30% vs 19%, p 0.07). Subjects treated with a stable dose of DFX over the entire period of observation (n=39) showed a reduction of LSM (6.9±2.3 vs 6.06±2.4, p 0.04) and a concomitant improvement of hepatic T2* and LIC values (respectively 11.02±6.57 vs 15.04±6.42 and 3.84±2.81 vs 2.49±1.89, p < 0.001). In this group we observed a substantial decrease in the number of patients with LIC > 4.23 mg Fe/g dw (33% vs 13%, p 0.01). A reduction of LSM, yet not statistically significant due to the limited size of the cohort, was achieved in patients on combined DFO+DFP at T0 and T1 (n=6, 8.6±5.5 vs 7.3±3.8). The group of patients on DFO (n=11) remained stable over time. Patients who underwent anti-HCV therapy showed an even more evident reduction in LSM (9±3 vs 7±3.1, p 0.016).CONCLUSION. These data support evidence on the efficacy of adequate iron chelation therapy and, if necessary, anti-HCV treatment in decreasing or at least controlling the progression of liver fibrosis measured by TE in transfusion-dependent BTM patients. Therapeutic compliance and tailoring of drugs is essential to prevent hepatic injury resulting from siderosis. Moreover, proper chelation and treatment of HCV infection act sinergistically to limit progression of liver disease in TDT patients with active hepatitis C, so that development of cirrhosis could be either prevented or greatly delayed. DisclosuresCappellini:Novartis: Membership on an entity's Board of Directors or advisory committees; 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.

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.

Safety, tolerability, and outcomes of regular automated red cell exchange transfusion in the management of sickle cell disease

We report here our experience with regular automated red cell exchange transfusion for the management of chronic complications of sickle cell disease in 50 patients in our institution from June 2011 to December 2014. The mean sickle hemoglobin level was 44% and 8.5% pre- and post-transfusion, respectively. Platelets were reduced by a mean 70% during the procedure with a count of less than 50 × 109 /l in 6% of cases. The alloimmunization rate was 0.065/100 units of red cells with no hemolytic reactions. Patients with no iron overload at baseline showed no evidence of iron accumulation with a mean liver iron concentration of 1.6 mg/g dry tissue and 1.9 mg/g dry tissue at baseline and 36 months, respectively. All six patients with pre-existing iron overload and on chelation therapy, showed a gradual reduction of their liver iron concentration and two patients could discontinue chelation during the follow-up period. Seventy percentage of patients who were on the programme for recurrent painful crises showed a sustained reduction in the number of emergency hospital attendances; the mean number of days in hospital for emergency treatment was 103 in the year prior to commencing ARCET and reduced to 62 (40%) after the first 12 months, 51 (50%) after 24 months, and 35 days (66%) after 36 months. J. Clin. Apheresis 31:545-550, 2016. © 2015 Wiley Periodicals, Inc.

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.

Different Thresholds of Serum Ferritin Levels for Prediction of Liver Iron Concentration in Hemoglobinopathies

▪Introduction. This was a cross-sectional study of patients with hemoglobinopathies attending 13 Italian centers participating in the LICNET (Liver Iron Cutino Network) network promoted from Piera Cutino partnership and instituted by our center (Campus of Haematology Franco e Piera Cutino-A.O.O.R. Villa Sofia Cervello, Italy) on February 2013. LICNET is addressed to the diagnostics of iron overload in liver by R2 MRI (Ferriscan®) in patients with hemoglobinopathies. Ferriscan is a rapid scan method now available (10 minutes). This tool is crucial to have accurate and reliable measures for iron body burden control in hemoglobinopathies.Methods. Data included patients with β-thalassemia major (TM) (regularly transfused) (TX), β-thalassemia intermedia (TI) (both TX and non-transfused) (non-TX), and sickle cell disease (SCD) (both TX and non-TX). The main aim of the study was to evaluate how serum ferritin levels (SFLs) predict liver iron concentration (LIC) in different hemoglobinopathies, and to have valuable information about prognosis and response to therapy. In particular, to identify SFLs that best predict LIC thresholds of clinical significance (7 and 15 mg Fe/g dw) by identifying levels with highest sum of sensitivity and specificity was used the receiver operating characteristic (ROC) curve analysis.Results. A total of 363 patients were evaluated in this analysis, with a mean age of 35.6 ± 13.0 years (range: 6-76) and including 160 (44.1%) males. The underlying diagnosis were β-TM (n=204, 56.2), β-TI (n=102, 28.1%), and SCD (n=57, 15.7%). Among β-TI patients, 60 (58.8%) were on transfusion therapy. Similarly, in patients with SCD 34 (59.6%) were on transfusion therapy. The mean LIC in the study population was 7.8 ± 9.6 mg Fe/g dw and the median was 4.0 mg Fe/g dw.Across underlying diseases, LIC distribution was as follows: β-TM (mean: 9.0 ± 10.7, median: 4.9 mg Fe/g dw), TX β-TI (mean: 7.1 ± 7.3, median: 5.0 mg Fe/g dw), non-TX β-TI (mean: 5.1 ± 6.0, median: 3.2 mg Fe/g dw), TX SCD (mean: 8.5 ± 11.0, median: 4.5 mg Fe/g dw), and non-TX SCD (mean: 3.1 ± 1.9, median: 2.4 mg Fe/ g dw). It was apparent that TX patients irrespective of underlying diagnosis have a comparable proportion of patients with high LIC risk categories (>7 mg Fe/g dw) (p=0.627).Among chelated patients, LIC distribution was as follows: Deferoxamine (DFO) (mean: 7.3 ± 8.5, median: 4.7 mg Fe/g dw), Deferiprone (DFP) (mean: 11.6 ± 11.4, median: 8.4 mg Fe/g dw), Deferasirox (DFX) (mean: 7.8 ± 10.3, median: 3.2 mg Fe/g dw), DFO+DFP (mean: 8.2 ± 10.6, median: 4.5 mg/ Fe g dw), and other combinations (mean: 6.5 ± 4.0, median: 5.1 mg Fe/ g dw), with a statistically significant difference noted between groups (p =0.009) with the highest median among chelated patients noted in DFP treated patients and lowest median noted in DFX treated patients.For underlying disease groups, ROC curve analysis showed that SFLs that best predict LIC thresholds of 7 and 15 mg Fe/g dw varied, although patients with β-TI showed lowest SFLs to predict these thresholds especially non-TX patients (Fig. 1, Fig.2).Discussion. This study suggest as high values of LIC are present even in patients with TI or SCD, confirming that gastro-intestinal iron absorption is one of the main mechanism for secondary iron overloading. Moreover, close to 20% of patients with non-TX β-TI continue to have high LIC thresholds, while none of non-TX patients with SCD have LIC values > 7 mg Fe/g dw. The evidence that SFLs of 900 ng/mL are related in β-TI with LIC > 15 mg Fe/g dw (Fig. 2) suggests as chelation treatment could be reconsidered earlier in this cohort of patients. Finally, these findings suggest as LIC is predicted by different SFLs according to the different types of hemoglobinopathy. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Vitamin D Insufficiency and Liver Iron Concentration in Transfusion Dependent Hemoglobinopathies in British Columbia

Patients with thalassemia major (TM) and other chronically transfused hereditary anemias are at increased risk of complications including endocrinopathies and bone disease due to iron overload. Vitamin D is important for bone health. Vitamin D deficiency is common in patients with transfusional iron overload, and the mechanism remains unclear. The first step in vitamin D metabolism, hydroxylation, occurs in the liver and liver iron overload may interfere with this step. This study investigates an association between degree of liver iron overload and vitamin D levels in patients with transfusion dependent hemoglobinopathies. Patients with TM, hemoglobin Eβ TM (Eβ TM), and congenital dyserythropiotc anemia (CDA) attending the Inherited Bleeding and Red Blood Cell Disorder Program in British Columbia (IBRBCD BC), Canada were identified. Included patients had an assessment of liver iron concentration (LIC) by MRI and endocrinology assessment including 25 hydroxy vitamin D level. Thirty patients were identified. The mean LIC was 5.13 mg/g dry weight (DW). Vitamin D deficiency/insufficiency was identified in 19 (63.3%). Eleven (36.7%) patients had an LIC ≥5 mg/gDW, 8 of whom had a vitamin D level 5 mg/gDW and vitamin D level <60nmol/L (P= 0.027) and there was a significant inverse correlation between LIC and vitamin D (R=-0.33). These results indicate an association between increased LIC and vitamin D insufficiency/deficiency, suggesting that liver iron overload may indeed affect vitamin D metabolism. Prospective trials are needed to confirm these results.

A 5-year follow-up in deferasirox treatment: improvement of cardiac and hepatic iron overload and amelioration in cardiac function in thalassemia major patients.

Deferasirox (DFX) is an oral iron chelator with established efficacy and safety. We evaluated by T2* cardiovascular magnetic resonance (CMR) the efficacy of DFX in preventing and removing cardiac and liver iron load and cardiac volume changes, along 5years in adult thalassemia major (TM) patients. Twenty-three TM patients (9 males/14 women, mean age 36 ± 4years) were included in this study. Repeated CMR was performed to assess myocardial and liver iron load(baseline t0, after 2.5 years t1, after 5 years t2). Myocardial T2* values changed progressively and increased significantly between t0 and t2 (t0: 27.15 ± 9.58 vs t2: 36.64 ± 6.68, p = 0.0001). At baseline evaluation, a cardiac T2* value <20ms was detected in six patients (26%): they showed an improvement of cardiac T2* values between t0 and t1, with normal T2* levels reached in all patients at t2. In the overall population, a significant reduction of both end-diastolic and end-systolic left ventricular volumes (EDV, ESV) were detected between t0 and t2 (EDV, t0: 132 ± 31ml vs t2: 124 ± 22ml, p = 0.033; ESV, t0: 48 ± 14ml vs t2: 41 ± 10ml, p = 0.0007). A significant reduction in liver iron concentration (LIC) was detected at t1 (5.36 ± 3.58mg/g dw at baseline vs 3.35 ± 2.68mg/g dw at t1, p = 0.004). In patients with cardiac iron overload at baseline (n.6), mean cardiac T2* values doubled at t2, and mean LIC value is reduced of 29%. After 5years of treatment, DFX continually and significantly reduced myocardial and liver iron overload, and it prevented further iron deposition.

Dietary Intake Insufficient to Support Nutritional Adequacy in Patients with Thalassemia

Many patients with beta-thalassemia major have depressed circulating levels of essential micronutrients. These nutritional deficiencies may be caused by an elevated requirement for these nutrients, increased excretion and/or because of inadequate dietary intake. However, the relationship between dietary intake and circulating levels of key nutrients has not been explored. Therefore, the aim of this prospective, cross-sectional study was to quantitate intake using gold standard dietary assessment techniques, as well as to assess circulating levels of key micronutrients in the fasted state in a contemporary sample of subjects with transfusion-dependent thalassemia (age >5 years). Dietary intake was determined with the Block© 2005 3-day semi-quantitative food frequency questionnaire (NutritionQuest, Berkeley, CA) completed within 3 months of a pre-transfusion blood sample. Dietary intake (mg/day) was calculated relative to the Institute of Medicine recommendations for age and gender. Intake was then compared to circulating levels of vitamin C, 25-OH vitamin D, alpha & gamma-tocopherol, zinc, copper and selenium. The usage of nutritional supplements was documented. All results were analyzed using STATA (v 9.3, College Station, TX). Forty-one patients (20 male, mean age 28.3 ± 10.7 years) with an average BMI of 22.1 ± 5.2 kg/cm2 and pre-transfusion hemoglobin of 10.9 ± 1.5 g/dL were enrolled. The mean liver iron concentration (LIC) measured by Ferritometer was 13.5 ± 11.3 mg/g dry liver-weight. As has been observed previously, 14 to 30% of patients had low circulating levels of Zn, Cu, 25-OHD, vitamin C and alpha-tocopherol. No deficiencies were observed for selenium. Patients consumed on average 1555 ± 835 kcal/d (80% of estimated energy requirement) and 1.3 ± 0.9 g/kg protein. Average dietary intake was inadequate (less than estimated average requirement) for Ca, Zn, Cu, and vitamins C, D, and E. Among patients with low circulating micronutrient levels, 86% of those with low serum zinc also had low dietary zinc intake; similarly, 88% of those with low circulating copper also had low copper intake. Significant inverse correlations were observed between LIC and blood concentrations of the antioxidants vitamin C (r = -0.62), alpha-tocopherol (r = -0.37) and zinc (r = -0.35). The relationship between iron overload and vitamin C was further explored in a retrospective sample of 49 patients where simultaneous values of both measures were available (228 samples). Vitamin C level progressively decreased with increasing iron burden. The mean vitamin C level was 0.57 ± 0.47 mg/dL with LIC >15 mg/g compared with 1.06 ± 0.45 mg/dL when LIC was <7 mg/g (P <0.001). Serum ferritin levels were not associated with vitamin C deficiency (plasma concentration <0.4 mg/dL) at mild to moderate degrees of liver iron overload. However, with extreme iron overload (LIC >25 mg/g), ferritin levels were significantly greater in the presence of vitamin C deficiency (6545 ± 2597 ng/mL versus 4720 ± 1915 ng/mL, p=0.045). These data suggest that iron overload negatively influences blood levels of several micronutrients. Moreover, dietary intake is insufficient to support circulating levels of nutrients in optimally transfused thalassemia patients. Nutritional adequacy is essential for optimal health, and vitamin C status can impact chelation efficiency. Future research should consider nutritional supplementation and health outcomes in patients with transfusion-dependent thalassemia. DisclosuresNo relevant conflicts of interest to declare.

A 5-Years Follow-up in Deferasirox Treatment: Improvement of Cardiac and Hepatic Iron Overload and Amelioration in Cardiac Function in Thalassemia Major Patients

Introduction. During the last 10 years the cardiac deaths in adult thalassemia major (TM) patients are significantly reduced because of the availability of new oral iron chelators and the introduction of T2* cardiovascular magnetic resonance (CMR), which allows to evaluate the cardiac iron load. Deferasirox (DFX) is an oral iron chelator with established efficacy and safety. Based on myocardial T2* values, the risk of cardiac heart failure can be estimated prompting to intensify chelation therapy, if necessary. We would evaluate by T2* CMR the efficacy of DFX in preventing and removing cardiac and hepatic iron load and cardiac volume changes, along 5 years in adult TM patients.Methods. Twenty-three TM patients (9 males/14 women, mean age 36 ± 4 yrs) were included in this study. They repeated CMR to assess myocardial and liver iron load. Cardiac and hepatic iron load was assessed measuring myocardial T2* at 3 different time-points: basal value (t0), after a period of 2.5 years ± 6 months (t1) and after a period of five years (t2). During the follow-up period two patients became pregnant and they stopped chelation therapy with deferasirox for the duration of the pregnancy: they restarted oral iron chelation therapy with DFX after the delivery without any adverse event. Six patients underwent treatment with interferon and ribavirin to treat their hepatitis C: the dose of DFX was modulated based on increased iron intake during the treatment period.Results. Overall, the mean iron intake was 0.34±0.10 mg/Kg/day and the pre-transfusional mean hemoglobin (Hb) was 9.7±0.5 g/dl. The median ferritin value was 575 ng/ml (range 252-2530 ng/ml). The mean dosage of deferasirox at the beginning of the observation period was 24.4 ± 5.3 mg/kg/day; the mean dose of DFX along the 5-years follow-up was 25.3 ± 1.2 mg/kg/day. An initial reduction of mean ferritin levels was observed in the first 2.5 years of observation reaching a statistical significance only after 5 years (1055±563 ng/ml at baseline vs 960±568 ng/ml at t1 vs 751±627 ng/ml at t2, p=0.009 between t1 and t2). Myocardial T2* values changed progressively and increased significantly between t0 and t2 (t0: 27.15 ± 9.58 vs t2: 36.64 ± 6.68, p=0.0001). At baseline evaluation, a cardiac T2* value < 20 ms was detected in 6 patients (26 %): they showed an improvement of cardiac T2* values between t0 and t1, with normal T2* levels reached in all patients at t2. In the overall population a significant reduction of both end-diastolic and end-systolic left ventricular volumes (EDV, ESV) were detected between t0 and t2 (EDV, t0: 132±31 ml vs t2: 124±22 ml, p=0.033; ESV, t0: 48±14 ml vs t2: 41±10 ml, p=0.0007) (Table 1). A significant reduction in Liver Iron Concentration (LIC) was detected at t1 (5.36±3.58 mg/g dw at baseline vs 3.35±2.68 mg/g dw at t1, p=0.004). In patients with cardiac iron overload at baseline (n.6), mean cardiac T2* values doubled at t2 and mean LIC value is reduced of 29 %.Conclusions. Wecan conclude that DFX, at a personalized dose, progressively and significantly reduces myocardial and liver iron overload and it prevented the iron deposition along 5-years of continuous treatment.Table 1Left ventricular ejection fraction and cardiac volumes during the period of follow-up.Overall patientsPatients with baseline T2* 10–20 mst0t2P-valuet0t2P-valueLVEF(%, mean ± SD)64 ± 666 ± 6ns61 ± 763 ± 6NsEDV(ml, mean ± SD)(nv: 52-141 ml)132 ± 31124 ± 220,033139 ± 33121 ± 220.03ESV(ml, mean ± SD)(nv: 13-51 ml)48 ± 1441 ± 100,000754 ± 1444 ± 100.02 LVEFLeft Ventricular Ejection Fraction; EDV: End-Diastolic left ventricular Volume; nv: normal value; ESV End-Systolic left ventricular Volume; SD: Standard Deviation; ns: not significative. DisclosuresCappellini:Novartis, Shire, Cellgene, Sanofi: Advisory board Other.

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.

Hepatocellular carcinoma in thalassaemia: an update of the Italian Registry.

The risk of developing hepatocellular carcinoma (HCC) in patients with thalassaemia is increased by transfusion-transmitted infections and haemosiderosis. All Italian Thalassaemia Centres use an ad hoc form to report all diagnoses of HCC to the Italian Registry. Since our last report, in 2002, up to December 2012, 62 new cases were identified, 52% of whom were affected by thalassaemia major (TM) and 45% by thalassaemia intermedia (TI). Two had sickle-thalassaemia (ST). The incidence of the tumour is increasing, possibly because of the longer survival of patients and consequent longer exposure to the noxious effects of the hepatotropic viruses and iron. Three patients were hepatitis B surface antigen-positive, 36 patients showed evidence of past infection with hepatitis B virus (HBV). Fifty-four patients had antibodies against hepatitis C virus (HCV), 43 of whom were HCV RNA positive. Only 4 had no evidence of exposure either to HCV or HBV. The mean liver iron concentration was 8 mg/g dry weight. Therapy included chemoembolization, thermoablation with radiofrequency and surgical excision. Three patients underwent liver transplant, 21 received palliative therapy. As of December 2012, 41 patients had died. The average survival time from HCC detection to death was 11·5 months (1·4-107·2 months). Ultrasonography is recommended every 6 months to enable early diagnosis of HCC, which is crucial to decrease mortality.