Long-term Iron Chelation Therapy Research Articles

Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3–13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1–1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1–1.4, P<0.001) regardless the kind of disease incident, while the number of previous endocrine diseases showed a negative linear effect: the higher the number of diseases at baseline the lower the chance of developing further diseasess (adjusted HR for unit increase 0.5, 95% CI: 0.4–0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients’ risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.

Computer and mobile technology interventions to promote medication adherence and disease management in people with thalassemia.

Thalassemia syndromes are inherited hemoglobin disorders that result when the synthesis of normal hemoglobin is lacking or significantly reduced. For people with thalassemia, long-term red blood cell transfusion remains the mainstay of therapy, which may lead to iron overload causing severe complications and damage in different body organs. Long-term iron chelation therapy is essential for people with thalassemia to minimize the ongoing iron-loading process. In addition, suboptimal adherence can increase adverse events associated with iron overload and result in increased morbidity, mortality, healthcare utilization and cost of care. To identify and assess the effects of computer and mobile technology interventions designed to facilitate medication adherence and disease management in individuals with thalassemia, including:- evaluating the effects of using computer and mobile technology interventions for medication adherence and disease management on health and behavioral outcomes;- identifying and assessing the effects of computer and mobile technology interventions specific to different age groups (children, adolescents and adults) and type of modality (e.g. cell phone, the Internet). We searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL, PsycINFO, ProQuest Dissertations & Theses Global, Psychology and Behavioral Sciences Collection, Web of Science Science & Social Sciences Conference Proceedings Indexes, IEEE Xplore and ongoing trial databases (22 February 2018). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (20 June 2019). We also searched for unpublished work in the abstract book of nine major conferences in the related field. Randomized controlled trials (RCT) and quasi-RCTs comparing single- or multi-component interventions versus no intervention, placebo or standard care, with adherence to iron chelation as the primary outcome were eligible for inclusion. Non-randomized studies of interventions, controlled before-after studies, and interrupted-time-series studies were also eligible for inclusion. Three authors independently assessed study eligibility. If we had included any studies, we would have independently assessed risk of bias and extracted data; we planned to assess the quality of the evidence using GRADE. We did not identify any eligible studies for inclusion in the review. Due to lack of evidence, we cannot comment on the efficacy or effectiveness of computer and mobile technology intervention strategies to promote disease management and adherence to iron chelation therapy in people with thalassemia.We concluded that RCTs are needed to examine a variety of computer and mobile technology intervention strategies that may be useful for promoting disease management and increasing adherence to iron chelation therapy in individuals with thalassemia.

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.

Long-Term Iron Chelation Therapy with Deferiprone in Patients with Thalassemia Major and Low Iron Load

Introduction and Objectives: Iron chelators are effective in reducing iron burden and in improving clinical outcomes in patients with transfusional iron overload. However, limited data are available on their efficacy and safety in transfusion-dependent patients with low iron overload, due mainly to concerns of chelation toxicity observed with deferoxamine (DFO) in patients with serum ferritin (SF) < 1500ug/L. Deferiprone (DFP) has markedly lower affinity for iron (pFe3+ log stability constant = 19.9) than that of deferoxamine (26.6), and may provide a better safety profile in patients with low iron overload. The objective of this study is to evaluate the safety and efficacy of DFP in patients with thalassemia major (TM) and SF <500 ug/L.Methods: A total of 32 patients with TM (15 males) who had achieved SF <500 ug/L while on chelation with combined DFO and DFP (n=30) or on deferasirox (DFX) (n=2) had their chelation switched to DFP monotherapy (75-100mg/kg/day). All patients received 50 mg of oral zinc sulfate once a week for the duration of the study. Iron overload was assessed using SF and MRI T2* of liver and heart within 3 months of switch and then 6-12 monthly thereafter. Renal and liver function tests were performed monthly and trace elements (serum magnesium, copper, zinc and selenium) were also assessed.Results: Patients were followed for a median of 4.5 years (Range: 1-11 years). The median age at time of switch was 22.7 years (Range 11-28). The mean packed red blood cell volume transfused during the study was 197 mL/kg/year (Range: 157-282 mL). There was no significant increase in the SF (Baseline 392 ug/L; Last assessment 418 ug/L; p value 0.55) or the liver iron concentration (Baseline 3.44 mg/g dw; Last assessment 3.1 mg/g dw; p value 0.54) during the follow up. On the contrary, there was a statistically significant improvement in the cardiac T2* (Baseline 30 ms; Last assessment 38 ms; p <0.001). DFP was discontinued in 28% of patients (Ineffective in 3; Agranulocytosis in 1; Pregnancy in 1; Bone marrow transplantation in 2; Deaths in 2). The two deaths were unrelated to the chelation therapy (Decompensated HCV related liver cirrhosis and severe hypoglycaemia in a patient with diabetes mellitus). Two patients had mild asymptomatic hypocalcemia, and one had low copper levels. All three patients normalized their results with no treatment and without stopping DFP. No patient reported gastrointestinal disturbances or arthralgia, and none had elevation of liver enzymes or serum creatinine.Conclusion: Long-term DFP therapy in patients with TM and low iron overload was effective in stabilizing SF and LIC and was associated with improvement in the myocardial iron. The safety profile was consistent with those observed during therapy in patients with more severe iron burden and there were no increase in the unexpected adverse drug reactions. DisclosuresNo relevant conflicts of interest to declare.

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

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

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.

Deferiprone versus deferoxamine in sickle cell disease: results from a 5-year long-term Italian multi-center randomized clinical trial.

Blood transfusion and iron chelation currently represent a supportive therapy to manage anemia, vasculopathy and vaso-occlusion crises in Sickle-Cell-Disease. Here we describe the first 5-year long-term randomized clinical trial comparing Deferiprone versus Deferoxamine in patients with Sickle-Cell-Disease. The results of this study show that Deferiprone has the same effectiveness as Deferoxamine in decreasing body iron burden, measured as repeated measurements of serum ferritin concentrations on the same patient over 5-years and analyzed according to the linear mixed-effects model (LMM) (p=0.822). Both chelators are able to decrease, significantly, serum ferritin concentrations, during 5-years, without any effect on safety (p=0.005). Moreover, although the basal serum ferritin levels were higher in transfused compared with non-transfused group (p=0.031), the changes over time in serum ferritin levels were not statistically significantly different between transfused and non-transfused cohort of patients (p=0.389). Kaplan-Meier curve, during 5-years of study, suggests that Deferiprone does not alter survival in comparison with Deferoxamine (p=0.38). In conclusion, long-term iron chelation therapy with Deferiprone was associated with efficacy and safety similar to that of Deferoxamine. Therefore, in patients with Sickle-Cell-Disease, Deferiprone may represent an effective long-term treatment option.

Study of the effect of iron overload on the function of endocrine glands in male thalassemia patients

Background:Iron overload is an important issue in the state of thalassemic patients due to the harmful effect of high concentration of iron deposited in different tissues in human body including endocrine glands. In the present work, an attempt is carried out to estimate the effect of iron overload in thalassemic patients on the function of endocrine glands through the estimation of their ability to secrete adequate amounts of certain hormones.Materials and Methods:Seventy eight male children with beta-thalassemia, in the age-group of 4–11 years, were enrolled for this research. These children were being treated with frequent transfusions and long-term iron chelation therapy. Thirty age and sex matched children without thalassemia constituted the control group. Ferritin and different hormones were estimated by ELISA technique.Results:The results showed a mild reduction in the function of endocrine glands through the decrease in the level of some hormones. These changes due mainly to the hypoxia and precipitation of iron in certain glands and overlapping with the synthesis or secretion of the hormones.Conclusion:There is a different hormonal disturbances in beta thalassemia patients. Reduction of total body iron store is an important goal of the treatment of thalassemia and measuring the hormones concentration is necessary for the follow up of the thalassemic patients especially during puberty.

Improved survival in thalassemia major patients on switching from desferrioxamine to combined chelation therapy with desferrioxamine and deferiprone

Life expectancy in thalassemia major (TM) is reduced, mainly as a result of deaths from transfusion iron-overload and cardiac dysfunction. Early deaths are preventable by effective long-term iron chelation therapy, but 50% are unable to adhere adequately to standard treatment consisting of sub-

Deferasirox (Exjade®), the Once-Daily Oral Iron Chelator, Demonstrates Safety and Efficacy in Patients with Sickle Cell Disease (SCD): 3.5-Year Follow-up.

Background: Many patients with SCD require chronic transfusion therapy to manage the complications of their disease (eg stroke prevention); as a consequence, secondary iron overload may develop. Controlled data from patients with SCD receiving long-term iron chelation therapy, particularly renal function, are lacking. Cumulative 3.5-year safety and efficacy data are presented for adult and pediatric patients with SCD with transfusional iron overload treated with deferasirox (Exjade®) in a 4-year extension to a 1-year comparative study (109).Methods: Study 109 demonstrated similar dose-dependent liver iron concentration (LIC) reductions with deferasirox and deferoxamine (DFO) in SCD patients with iron overload. Eligible patients entered a 4-year extension phase and received deferasirox only; dose adjustments were based on monthly serum ferritin (SF) levels and safety assessments (adverse events [AEs] and laboratory parameters). Patients with abnormal renal function were excluded.Results: 132 patients (mean age ± SD of 19.1 ± 10.7 years) who were initially randomized in the core study to receive deferasirox are included in this analysis. The median duration of exposure to deferasirox was 37.4 months (3.1 years) at a mean dose of 18.4 ± 6.2 mg/kg/day. Mean iron intake over this period was 0.3 ± 0.1 mg/kg/day. 72 patients (54.5%) continue to receive deferasirox. Reasons for discontinuations include: AEs (n=11), consent withdrawal (n=24), lost to follow-up (n=9), unsatisfactory therapeutic effect (n=4), and other reasons (n=11). There was also one death reported post-liver transplantation, which was not considered by the investigator to be related to the study drug. The most frequent drug-related (investigator-assessed) AEs were nausea (n=20; 15.2%), diarrhea (n=14; 10.6%), vomiting (n=8; 6.1%) and abdominal pain (n=6; 4.5%). Nine patients (6.8%) had two consecutive increases in serum creatinine that were both >33% above baseline and above the upper limit of normal (ULN); however, there were no progressive increases. Five patients (3.8%) had an increase in alanine aminotransferase >10xULN on at least one visit; baseline levels were already >ULN in two patients.Mean daily dose of deferasirox increased from 15.4 ± 6.9 mg/kg/day at month 1 to 22.3 ± 7.3 mg/kg/day at month 42. Overall baseline median SF level was 3439 ng/mL (n=132), which decreased by 651 ng/mL (P=0.0533, Wilcoxon signed rank test; n=49) by month 42 (Figure 1). SF decreases were dose-dependent (data not shown). [Display omitted] Conclusions: Patients with SCD and transfusional iron overload receiving long-term deferasirox demonstrated continued reduction in their body iron burden (according to SF levels), without an exposure-associated increase in AE incidence, or evidence of progressive renal dysfunction.

Changes in MRI-Estimated Cardiac and Hepatic Iron Load in β-Thalassemia Patients Treated with Deferasirox at a Single Institution

Chronic transfusions have dramatically improved the life expectancy of patients with β-thalassemia, but leads to severe iron overload. Long-term iron chelation therapy aims both in the prevention and the reversal of iron load and iron toxicity. The available chelators seem to have different profiles of relative heart and liver iron removal. Data on cardiac efficacy of deferasirox (DFX; Exjade®) are limited. We report results on patients with thalassemia, followed in a single institution, who completed at least 12 months of treatment with deferasirox.Methods: Fifty five patients (22 males, 33 females; mean age: 27±7.1 years, splenectomised: 5 patients, HCV seropositive: 7 patients) were included in the study. The patients were treated with deferasirox at a mean dose of 27.2±5.2 mg/kg/day (range 15–40 mg/kg/day). Sixty-one pairs of MRI assessments of cardiac and hepatic iron overload by using the T2* technique were performed at a mean time interval of 13.7±2.4 months. Cardiac function parameters, mainly ejection function (EF), were also estimated at the same time.Results: Mean, SD and range at the time of the first MRI evaluation showed: ferritin: 2520±1584 ng/mL (371–6953 ng/mL), cardiac T2*: 25.3±10.7 ms (3.8–39.2ms), liver T2*: 4.5±4.6 ms (0.57–21.1ms) and ejection fraction: 66.9±4.8 ms (55.5–75.4%). Follow up assessments showed: ferritin: 2375±1743 ng/mL (39–7245 ng/mL), cardiac T2*: 27,1±11.7 ms (2.7–40.8ms), liver T2*: 6.2±6.2 ms (0.5–26.4ms) and ejection fraction: 66.1±4.8 ms (55.8–75.4%). Changes in liver and cardiac T2* were statistically significant (p=0.0004 and 0.008, respectively). Changes of the cardiac T2* values correlated well with the dose of deferasirox, while changes of liver T2* with ferritin changes (r=−0.284, p=0.032, r=−0. 27 and p=0.046, respectively). A statistical significant improvement (p<0.05) in cardiac and hepatic iron load was observed in the subgroup of 22 patients with severe liver iron load (defined as hepatic T2*<1.9 ms). In 18 patients with moderate/severe cardiac iron load (cardiac T2*<20ms), T2* decreased in 5, remained stable in 2 and improved in 11 patients (mean 10.7±5.5 ms vs. 12.1±7.1, p=0.078).[S1]Conclusions: This observational study shows that treatment with deferasirox improves both hepatic and cardiac iron overload in regularly transfused β-thalassemia patients. Adjustment of the dose is required to enhance iron excretion and achieve better negative iron balance

Delayed Epiphyseal Closure in a Patient With β-Thalassemia Major Complicated by Hypogonadotrophic Hypogonadism

Abstract: A 25-year-old man was referred for a bone scan to assess sacral pain on a background of β-thalassemia major complicated by severe anemia. He required repeated blood transfusions resulting in iron overload, which was treated with long-term iron chelation therapy. This case illustrates the potential skeletal manifestations of thalassemia and its treatment as demonstrated on bone scintigraphy, which include alterations in skeletal development and maturation, particularly delayed epiphyseal closure as well as complications of severe osteoporosis. Although the causes are multifactorial, pituitary iron deposition complicated by hypogonadotrophic hypogonadism should be considered as these patients may benefit from hormone replacement.

Hypogonadism in β-thalassemic adolescents: A characteristic pituitary-gonadal impairment. The ineffectiveness of long-term iron chelation therapy

The pituitary-gonadal function was studied in 18 beta-thalassemic female adolescents, 8 with delayed puberty and 10 with primary amenorrhea,treated with repeated transfusions and long-term iron chelation therapy by subcutaneous infusion. A 100 micrograms gonadotropin-releasing hormone (GnRH) test, a double-bolus GnRH test after estradiol administration in non-responders, a 400 micrograms thyrotropin-releasing hormone (TRH) test and a 'high dose' human menopausal gonadotropin (hMG) test were performed. LH and FSH peak levels were significantly lower in thalassemic patients than in controls, both in the 100 micrograms GnRH test (LH was 4.3 +/- 0.7 mIU/ml vs 40.8 +/- 6.0 mIU/ml and FSH 3.3 +/- 0.5 mIU/ml vs 9.6 +/- 1.1 mIU/ml, respectively) and in the double-bolus GnRH test (LH was 2.3 +/- 0.2 mIU/ml vs 59.0 +/- 4.9 mIU/ml and FSH 1.8 +/- 0.3 mIU/ml vs 14.0 +/- 1.0 mIU/ml). The mean prolactin response to the TRH test was 27.8 +/- 3.2 ng/ml. After the 'high dose' hMG test 12 out of 14 admitted patients showed a poor response, lower than 250 pg/ml. Our data suggest that the hypogonadotropic condition of the thalassemic adolescents is due to pituitary hyporesponsiveness to GnRH and that most of these patients also have an impairment of ovarian function. Both conditions are a consequence of iron deposits in glands. Moreover, there is evidence that pituitary-gonadal function cannot be preserved by long-term iron chelation therapy.