Adequate Chelation Therapy Research Articles

Pubertal Development in Girls with Beta Thalassaemia and Assessment of the Adequacy of Chelation Therapy: A Quasi-experimental Study

Introduction: Beta thalassaemia is the most prevalent hereditary autosomal disorder, significantly impacting endocrine function during pubertal development. The pathology is rooted in the excessive deposition of iron in vital organs. If left untreated, this condition leads to serious morbidity and mortality. Hypogonadism stands as the most common endocrine complication. Aim: To observe pubertal development in girls with thalassaemia and evaluate the adequacy of chelation therapy in such patients by measuring levels of Follicle Stimulating Hormone (FSH), Luteinising Hormone (LH), oestrogen, and serum ferritin. Materials and Methods: A quasi-experimental study was conducted at the Thalassaemia Clinic at the Department of Obstetrics and Gynaecology, Burdwan Medical College, Purba Bardhaman, West Bengal, India involving 300 diagnosed Beta Thalassaemia Major (BTM) (case) patients aged 13 to 17 years over a period of one and a half years (January 2020 to June 2021). The girls in the study groups were sequentially enrolled from the Outpatient Department of the Thalassaemia Clinic after meeting inclusion and exclusion criteria. Demographic data, anthropometric measurements, and Sexual Maturity Rating (SMR) were recorded. Hormonal assays of serum FSH, LH, oestrogen, and serum ferritin levels were conducted. Thalassaemic girls with serum ferritin levels exceeding 500 ng/mL received chelation therapy. Serum ferritin levels were measured at two-month intervals for up to six months, with reassessment of serum FSH, LH, oestrogen, and ferritin levels at the end of the six-month period. Statistical analysis was conducted using Statistical Package for Social Sciences (SPSS) version 27.0, Microsoft excel spreadsheet, and Epi Info 7. Results: A total of 190 (63.3%) of the thalassaemic girls were aged 13 to 15 years, with a mean Body Mass Index (BMI) of 22.5000±2.6100 kg/m2 , and 74 of them (38.94%) experienced menarche in this age group. Out of 300 cases, 269 thalassaemic girls (89.6%) received chelation therapy, and 89 cases (33.09%) reached menarche after chelation therapy. A significant (p<0.0001) increase in mean LH and FSH levels was observed after chelation therapy. The mean ferritin level decreased from 3168.85 ng/mL to 2227.24 ng/mL following chelation therapy. Conclusion: Pubertal development failure is common in beta thalassaemic girls. Intervention in the form of adequate chelation therapy in girls with high serum ferritin levels yielded favourable outcomes, as evident from serum gonadotropin and oestrogen levels.

Hypermanganesemia with Dystonia Type 2: A Rare Entity. (P12-11.001)

<h3>Objective:</h3> NA <h3>Background:</h3> Hypermanganesemia with dystonia type 2 is an established, rare autosomal recessive partially reversible neurodegenerative condition characterised by mutations in the SLC39A14 gene. Manganese deposition in such cases has a special predilection for the basal ganglia structures leading to dystonia and parkinsonian features. We report such a case of hypermanganesemia in a 1 year old child presenting with extrapyramidal features. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 1 year old female child presented with regression of developmental milestones for the past 2 months, losing the ability to stand or even sit without support—skills that she had previously acquired at an appropriate time. This was associated with dystonic posturing of her neck and limbs for the last 1 month. Cognitive skills were normal as per her age without any history of convulsions or other systemic features. Her birth and family history were unremarkable. Her neurological examination was remarkable only for generalised dystonia of her limbs, neck and trunk. Magnetic resonance imaging was suggestive of paramagnetic substance deposition in bilateral basal ganglia and dentate nucleus. Normal routine blood parameters were followed by extensive investigations to rule out Wilson’s disease, NBIA and other autoimmune pathologies. Her blood manganese levels were significantly elevated and her genetic sequencing revealed compound heterozygous mutations of the SLC39A14 gene at exons 7 and 8. She was started on chelation therapy with Penicillamine and oral iron. Dystonia resolved significantly by the end of 6 months of therapy with marked improvement in her motor developmental milestones. <h3>Conclusions:</h3> Hypermanganesemia with dystonia type 2 (HMNDYT2) is a rare genetic disorder characterised by neuronal manganese deposition without other systemic features. This case highlights the importance of recognising this potentially rare treatable condition and with adequate chelation therapy at the right time, near total restoration of motor symptomatology is possible. <b>Disclosure:</b> Dr. Bhattacharya has nothing to disclose. Dr. Chintha has nothing to disclose. Dr. Biswas has nothing to disclose. Dr. Das has nothing to disclose. Dr. Chakraborty has nothing to disclose. Dr. Mukherjee has nothing to disclose.

Wilson’s disease: a review of clinical guidelines, literature and a case report

Wilson’s disease (hepatocerebral dystrophy) is a rare hereditary disease that is caused by impaired copper metabolism affecting many organs, but mainly the liver and nervous system. Interest in the problem does not subside, because diagnosis and management of patients presents certain difficulties. The article highlights the literature data, clinical recommendations when discussing their own clinical observation of two patients (brother and sister) in whom the disease was diagnosed in childhood. Presented are clinical data, dynamics of laboratory parameters during 15 years of follow-up against the background of adequate chelation therapy with D-penicylamine and zinc sulfate, as well as during interruption of treatment. The necessity of adherence to a lifelong regimen of therapy is emphasized, since it is this tactic that demonstrates effectiveness in improving the prognosis of the disease.

Ferritin Levels Do Not Reflect the Severity of Iron Overload in Diamond Blackfan Anemia

▪Introduction: Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterized by hypoplastic anemia, congenital malformations and an increased risk to develop malignancies.Until now, treatment of DBA consists of red blood cell (RBC) transfusions, glucocorticoids (GC) and allogeneic hematopoietic stem cell transplantation in a selection of patients. Whereas RBC transfusions are the main cause of IO, elevated iron parameters have also been reported in non-transfusion-dependent DBA patients. Here we investigated the incidence and severity of IO in a well-described cohort of transfusion-dependent and non-transfusion-dependent DBA patients in order to gain more insight in the regulation of iron metabolism in DBA, and to provide clinical guiding to improve the diagnosis and management of IO in DBA.Methods: In this retrospective, observational study we have included twenty-nine pediatric and adult DBA patients for whom at least one serum ferritin level and/or MRI result was available. Ten patients (34%) were classified as transfusion-dependent (TD) (ten or more transfusions during the twelve months prior to evaluation). Non-transfusion-dependent (NTD) patients (66%) were treated with either GC, incidental transfusions or received no treatment. Transfusion burden (transfusion history) was assessed via medical records. Serum ferritin levels ≥250 ng/mL in males and ≥150 ng/mL in females were considered to be elevated. Results of MRI were expressed as liver iron content (LIC) and as cardiac T2* in milliseconds (ms). LIC ≥3 mg/g indicates significant hepatic IO, and LIC ≥7 mg/g is associated with clinical morbidity. Cardiac T2* ≤20 ms indicates significant cardiac IO.Results: In 15/29 (52%) MRI analysis of IO was performed. Hepatic IO (LIC >3 mg/g) was present in 9/29 (31%) of DBA patients, of which 8/9 (89%) had moderate to severe IO (LIC>7mg/g), despite the fact that all but one were treated with chelation therapy. Overall serum ferritin levels and LIC correlated significantly (r=0.7907, p<0.001), and all TD patients with LIC ≥7 mg/g had serum ferritin levels ³400 ng/mL, however, none of the patients had a serum ferritin >1000 ng/mL (Figure 1A). Interestingly, in the NTD group, hepatic IO was present in 2/7 patients (29%), who both only had mildly elevated serum ferritin levels (263 ng/mL and 277 ng/mL) and were not treated with iron chelation therapy. Based on total transfusion burden since birth, patients were classified in distinct groups: nine patients who received ³10 transfusions during life (9/10) were diagnosed with hepatic IO, whilst none of the patients who received <10 transfusions were diagnosed with hepatic IO. Both mean serum ferritin levels and mean LIC values were significantly higher in patients with ³10 transfusions compared to all with <10 transfusions (Figure 1B-C).Discussion: We demonstrate that IO is common in DBA yet can be easily overlooked in NTD patients that were treated with transfusions in the past. While serum ferritin levels significantly correlated with LIC values, this parameter cannot be used exclusively to screen for IO or titrate iron chelation therapy. We conclude that in clinical practice, biochemical parameters in combination with transfusion history justify a low-threshold to perform an MRI-based evaluation of IO, and to start adequate chelation therapy. [Display omitted] DisclosuresVan Beers: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Research Funding; RR Mechatronics: Research Funding. Wijk: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Axcella health: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Relationship between serum ferritin and endocrinopathies in thalassemic children: A hospital-based study

Background: Thalassemia syndromes are a heterogeneous group of Mendelian disorders characterized by lack of/decreased synthesis of either ?/? globin chains of hemoglobin. It results in ineffective erythropoiesis and lysis of mature red blood cells in the spleen. Thalassemic patients require multiple blood transfusions which led to iron overload. Objective: This study evaluated endocrinopathies in thalassemic patients of age 5–18 years and relationship with serum ferritin level. Materials and Methods: This is a hospital-based cross-sectional study on 70 transfusion dependent thalassemic children of 5–18 years attending the department of pediatrics, of a tertiary care hospital in Assam. Their height, sexual maturity rating, serum ferritin, calcium, alkaline phosphatase, phosphate, thyroid stimulating hormone, random blood sugar, and fasting blood sugar were recorded. The data were analyzed statistically and p &lt;0.05 was considered to be statistically significant. Results: The study population (70) consisted of 40 males and 30 females. In this study, 91.67% (22 of 24 cases) had delayed puberty, 50% (35 of 70) were stunted, 37.14% (26 of 70 cases) were hypocalcemic, 31.43% (22 of 70) had hypothyroidism, and 2.85% (2 of 70) were diabetic. The mean serum ferritin level was 2845±859.40 ng/ml in delayed puberty while it was 2027.50±21.92 ng/ml (p&gt;0.05) in thalassemic children with normal puberty. The mean serum ferritin in stunted thalassemic children was 2909.86±820.93 ng/ml and it was 1421.43±283.41 ng/ml (p&lt;0.001) in normal height thalassemics. The mean serum ferritin in hypothyroid thalassemics is 2806.59±929.57ng/ml and is 1885.75±846.89 ng/ml (p&lt;0.001) in euthyroid cases. The mean serum ferritin in diabetic thalassemics was 2772.50±1092.48 ng/ml and it was 2147.16±965.63 ng/ml (p&gt;0.05) in nondiabetic thalassemics. Conclusion: Growth retardation and endocrinal complications significantly occur in transfusion-dependent thalassemic children. Adequate chelation therapy helps in controlling serum ferritin levels thereby enabling chronically transfused thalassemic children to grow normally without early endocrinal complications.

Establishment of a thalassaemia major quality improvement collaborative in Pakistan

ObjectivesThe aim of this study was to establish multidisciplinary care for patients with transfusion-dependent thalassaemia (TDT) by creating a TDT quality improvement (QI) collaborative in a resource-constrained setting. This study...

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.

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.

Pattern of Growth Retardation and Sexual Maturation in Children having Beta Thalassaemia

Introduction: Thalassaemia is a group of genetic disorders of blood, characterized by decreased synthesis of one of two types of poly peptide chain (α or ß) that form a normal adult human haemoglobin molecule (Hb A- α2 ß2). This results in decreased filling of red cell with haemoglobin and anaemia. Retardation of growth and delayed sexual maturation can occur as a complication of thalassaemia. The objectives of this study were to study the pattern of growth failure and sexual maturity rate (SMR) in children with β-thalassaemia major, and to compare it with controls.Material and Methods: In this case-control study conducted simultaneously at two centres at Bebe Nanki Mother And Child Care Centre, Amritsar and Sri Guru Ram Das Charitable hospital, Amritsar, the growth parameters (height,weight and sexual maturation ) and serum ferritin levels of a total of 114 patients aged 8-16 years (64 males and 50 females) with β-thalassaemia major were compared with those of 100 healthy controls of the same age and gender.Results: Underweight was observed in 89(78.1%) of patient group and 9(9%) of control group. Short stature was observed in 64(56.1%) patients and 7(7%) of the control group. The mean age of menarche for female thalassaemia patients was 12.11±2.1 years and for control females was 11.42±1.11years, The SMR were delayed in 108(95%) of patients and in 6 (6%) of controls. The level of serum ferritin was found to be significantly associated with delayed SMR in thalassaemia patients.Conclusion: Growth failure and delayed SMR significantly occur in thalassaemia patients, when compared to the controls. Adequate chelation therapy can help in controlling serum ferritin levels and thereby facilitating normal physical growth and sexual development in chronically transfused thalassaemia patients.J Nepal Paediatr Soc 2016;36(1):56-60

Misleading Gastrointestinal Symptoms: The Ongoing Story of Chronic Lead Intoxication.

Inorganic lead intoxication has emerged as an important and challenging clinical problem owing to increased awareness of lead and enhanced surveillance of exposed individuals. However, recognition may not be very difficult when there is an obvious history of exposure. Our interest began a few years ago when we could trace an outbreak, following a patient who was admitted with colickly abdominal pain, convulsions, and coma. After that, 16 more cases were identified and characterized. All patients recovered completely after adequate chelation therapy. Although the clinical picture of lead intoxication is pleomorphic, the increased awareness of gastroenterologists in this subject may possibly bring chronically complaining difficult patients to an earlier, unexpected, and fairly treatable disease.

Management of beta-thalassemia-associated osteoporosis.

Beta-Thalassemia-associated osteoporosis is a multifactorial and complex condition. Different acquired and genetic factors are involved in its pathogenesis. These factors produce an imbalance in bone remodeling by inhibiting osteoblast activity and increasing osteoclast function, leading to bone loss and increased fracture risk. The management of patients presenting with thalassemia-associated osteoporosis should consist of the implementation of general measures and the prescription of a specific pharmacological agent, with the aim of reducing fracture risk and preventing disability and deterioration of quality of life. General measures include control of anemia, adequate chelation therapy, healthy nutrition and lifestyle, regular exercise, adequate management of comorbid conditions, hormone replacement therapy in patients with hypogonadism, and vitamin D supplementation/therapy. Among the pharmacological agents currently available for the management of osteoporosis in postmenopausal women and men, bisphosphonates have been shown to improve bone mineral density, to reduce bone turnover, and to decrease bone/back pain in patients with thalassemia-associated osteoporosis, with a good profile of safety and tolerability. On the other hand, there are limited experiences with other pharmacological agents (e.g., denosumab or teriparatide). The complexity of this condition presents diagnostic and therapeutic challenges and underscores the importance of a comprehensive and multidisciplinary approach.

Current possibilities of chelation therapy

Iron overload is one of the major problems in patients with hereditary and acquired anemias whose treatment uses regular packed red blood cell transfusions. The paper analyzes in detail all currently used iron store-estimating methods, such as a calculation method; determination of serum ferritin levels; measurement of liver iron concentration by both determining directly iron content in a biopsy specimen and indirectly by T2*-weighted magnetic resonance imaging (MRI (T2*)), estimation of myocardial iron by MRI (T2*). According to the current concept, the patients receiving regular packed red blood cell replacement transfusions need adequate chelation therapy, the goal of which is to reduce toxic iron in the cell and the extracellular space and total body iron stores, which can prevent irreversible organ and tissue damage, increase survival, and improve quality of life in patients. The paper gives an algorithm for chelation therapy (to choose a chelating agent for its primary use, to modify therapy in relation to a treatment goal, and to discontinue chelation therapy). Intensive chelation therapy as continuous intravenous deferoxamine infusion or combined therapy (simultaneous or successive use of 2 different iron chelating agents) is recommended in case of severe iron overload. This literature review analyzes in detail the dosing regimen and possible combinations of different iron chelating agents, as well as criteria for evaluating their efficiency and safety.

The Effects of Deferasirox on Iron in Pituitary, Pancreas and Thyroid Glands: An Observational Case-Control Study

In the absence of adequate chelation therapy, cardiomyopathy caused by iron overload is the leading cause of death in patients with β-thalassemia major (BTM). Additionally, more than half of the adult patients with BTM suffer from hypogonadism (HG), osteoporosis, diabetes mellitus (DM) or hypothyroidism. The use of iron chelators is the mainstay of treatment in patients with BTM to ameliorate these complications. In this study, we aimed to compare the chelation effects of deferasirox (DFX) and other iron chelators on iron in heart, liver, in addition to pituitary, pancreas and thyroid glands.The study included a total of 37 patients with BTM, who were on the same iron chelator for at least 1 year of duration and above 7 years of age. All of the patients were on iron chelation therapies with either monotherapy with DFX (n=29), desferrioxamine (n=4), deferiprone (n=1) or combination therapy of desferrioxamine and deferiprone (n=3). The mean dose of DFX was 30.8 ± 6.3 mg/kg/day (20-40), the mean dose of desferrioxamine 43.1 ± 5.3 mg/kg/day (39-50) and mean dose of deferiprone was 73.26 ± 9.45 mg/kg/day (70-90). All of the patients were compliant to chelation treatment.Cardiac T2*, hepatic T2*, thyroid T2 and R2, pituitary T2 and R2, pancreas T2* and R2* MRI were ordered twice to the patients in order to measure the accumulation of iron. The median time interval between the two MRI was 6 months (range 6-11 months). The effect of DFX (n=29) on iron measurements in different organs were compared to the effects of other chelators group (OCG) (n=8).The mean age of patients participating in the study was 20.8 ± 6.3 years (7.1-36.8). Of the study group, 7.1% of the patients had DM, 8.1% had hypothyroidism and 13.5% had HG at enrollment. According to our previous study for the cut-off value determinations for iron accumulation in BTM with comparison to healthy controls (data unpublished), all of the patients in both groups were found to have pituitary iron accumulation at initial MRI. The changes in iron measures in various organs were summarized in Table 1, indicating a decrease in cardiac, pituitary and pancreas iron loading in both drug groups in follow-up MRI’s (p>0.05). On the other hand δ Liver T2* was negative direction indicating a decrease in hepatic iron loading in DFX group, wheras positive in OCG indicating an increase in follow-up, although insignificant (Table 1, p=0.9). In both groups iron loading in thyroid was found to increase in follow-up and there was no difference between drug groups (Table 1).In conclusion, DFX is as effective as other drugs in chelation of iron from cardiac, hepatic, pituitary, pancreas and thyroid. The increase in iron in thyroid gland during follow-up in both groups may indicate that iron chelation may not be as efficient in thyroid as it is in other organs. Although, all patients had pituitary iron accumulation, only 13.5% were found to have HG, indicating that patients become symptomatic only occur after a threshold of accumulation was achieved. Our study is initiative for the measurements of iron accumulation with MRI in thyroid.Table 1δT2* and δR2 change values between first and second MRI assessmentsChelation typeMean±SDMedianRangepδ Liver T2 * a (ms)Deferasirox-0.06-8.5-7.200.90Other chelators0.79-0.98-4.40δ Cardiac T2 * b (ms)Deferasirox-3.83±9.50.88Other chelators-3.2±8.82δ Pituitary T2 b (ms)Deferasirox-0.7±11.30.09Other chelators-1.4±6.4δ Pituitary R2a (Hz)Deferasirox0.10-6,20-3,100.25Other chelators0.20-4,60-1,30δ Thyroid R2 a (Hz)Deferasirox-1.4-6,1-12,70.06Other chelators-0.1-3,80-8,1δ Thyroid T2 a (ms)Deferasirox4.8-59,8-14,60.08Other chelators0.4-20,6-20,1δ Pancreas T2* b (ms)Deferasirox-7.46±21.60.99Other chelators-7.52±9.63δ Pancreas R2 * b (Hz)Deferasirox9.24±45.230.11Other chelators56.4±73.3 SDStandard Deviation; aNon-parametric variable, median values were provided; bParametric variables, mean±SD were provided. DisclosuresNo relevant conflicts of interest to declare.

Effect of long-term transfusion therapy on the glycometabolic status and pancreatic beta cell function in patients with beta Thalassemia major

Background:Diabetes mellitus is a major complication of iron overload in patients with beta thalassemia major.Design:This is a descriptive study conducted in a Tertiary Care Teaching Hospital to analyze beta cell function and insulin resistance, and their relation to iron overload status in beta thalassemia major. Fasting glucose, two-hour post load glucose, fasting insulin, alanine amino transaminase (ALT), and ferritin were used as outcome measures. The homeostatic model assessment (HOMA model) was used to calculate the beta cell function and insulin resistance index.Results:Of the 30 cases, 20% had impaired fasting glucose, 3.3% had impaired glucose tolerance, and none had diabetes. Fasting glucose was not significant between the cases and controls (P = 0.113). Fasting insulin (P = 0.001), ferritin (P = 0.001), and ALT (P = 0.001) levels were significantly high in the cases. Insulin resistance index was significantly higher in the cases (P = 0.001) as also the beta cell function (P = 0.001). With increase in age and the number of units transfused there is a decline in beta cell function, fasting insulin, and insulin resistance after attaining the maximum level. This suggests that initial insulin resistance is followed by insulin depletion due to loss of beta cell function, leading to diabetes mellitus.Conclusion:Impaired glucose tolerance (IGT) and insulin resistance precede the onset of insulin-dependent diabetes and adequate chelation therapy is essential for delaying the onset or for prevention of diabetes.

Significant Suppression of the Colony Forming Capacity of Erythroid Progenitors by Iron Overload in Patients with MDS and Sequential Anlyses of BFU-E Under Chelation Therapy.

Abstract 3826Poster Board III-762 IntroductionThe majority of patients with MDS depend on regular blood cell (RBC) transfusions during the course of their disease. Patients with lower-risk MDS are at particularly high risk of developing iron overload because of their longer median survival. Transfusional iron overload is known to be associated with increased morbidity mainly due to cardiac and/or hepatic damage. As a result an excess mortality rate in polytransfused pts. has been demonstrated. A negative prognostic impact of transfusion need is a proven independent marker for a bad prognosis. Jensen et al. (1996) demonstrated that an adequate chelation therapy could improve the transfusion need of pts. with MDS significantly (Br J Haematol 1996, 94, 288-299). This observation was supported by recent findings of another group (Messa, Acta Haematol, 2008, 120, 70-4) with improvement of transfusion need under adequate chelation therapy. Thus iron overload might not only be harmful to hepatocytes and cardiomyocytes but also to bone marrow progenitor cells. Their function is intrinsically impaired by MDS itself and might be further affected by a “second hit” in the form of toxic iron overload which might additionally impair their colony forming capacity. Patients and methodsWe performed colony assays from the peripheral blood from 52 pts. with MDS (RA/RARS: n=18, RCMD/RS: 12, RAEB-I/II: 13, 5q-syndrome: 3, MDS-U: 2, CMML: 1, and others: 2; age: 39 – 86 yrs. (median: 68 yrs.); cytogenetics: normal: 26, 5q-: 6, -7/7q-: 2, complex: 4, others: 4) with (serum ferritin ≥250 μg/L, range: 273 – 6267 μg/L, median: 664 μg/L) and without iron overload (range: 11 – 213 μg/L). Only pts. without hepatic and/or active infectious diseases, without chemotherapy/epigenetic therapy during the last 6 months and without cytokine and/or corticoid therapy during the last 3 months before performance of colony assays were considered. BFU-E and CFU-GM were analysed by the same person (U.S.) after 12 – 16 days in cultures from peripheral blood, performed as described (Leuk Res, 2001; 25(11):955-9) in 14 (BFU-E)/ 12 (CFU-GM) pts. with normal ferritin-values (normal range: 20-250 μg/L) in comparison to 38/32 pts. with ferritin values surmounting 250 μg/L. Pts. with diffuse growth or cluster formation (leukemic growth) were excluded. Statistical evaluation was performed with SAS 9.1 software using Wilcoxon-Mann-Whitney tests. The results were regarded as significant if the p-value was under 5%. Both patient subgroups were balanced according to cytogenetics, age and MDS WHO-subtype. ResultsIn the patients subgroup with normal ferritin (n=14) the numbers of BFU-E ranged between 0 and 76 (std.dev. 19.63) with a median of 3.5 and a mean of 10.7, the numbers of CFU-GM ranged between 0.5 and 38.5 (std.dev. 13.23), with a median of 6.75 and a mean of 13.2. In the patients with elevated serum ferritin (n=38) the numbers of BFU-E ranged between 0 and 250 (std.dev.40.47) with a median of 0.5 and a mean of 8.86, the numbers of CFU-GM ranged between 0 and 120 (std.dev. 29.62) with a median of 3.0 and a mean of 18.94). Statistical comparison of the numbers of BFU-E and CFU-GM between patients with normal and elevated serum ferritin yielded a highly significant difference (p=0.001348) for BFU-E and no difference for CFU-GM (p=0.570296). ConclusionsOur data provide further evidence that in MDS iron overload significantly impairs bone marrow function by suppression of the burst forming activity of erythroid progenitors. If this iron is removed by adequate chelation burst forming activity might be partially restored. Myeloid progenitors do not seem to be affected by iron overload. PerspectiveTo address the question whether chelation therapy could improve erythropoiesis we performed 4 colony assays at minimum as follow up in 32pts the analysis of which is under way. In this group 8 pts. showed a normal ferritin while 26 pts. had an elevated ferritin (> 250 μg/L). Of these, pts. 10 were treated with chelation therapy. Furthermore, 9 pts. were monitored by magnetic resonance imaging (MRT). The results of these examinations will be related to the other parameters evaluated in this study and presented in detail. Disclosures:Haase:Novartis Oncology, Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Treatment with Deferasirox Effectively Decreases Iron Burden in Patients with Sickle Cell Disease and Thalassemia Intermedia.

Abstract 1517Poster Board I-540Iron overload was not thought to be an important issue in sickle cell disease (SCD) in the past because of the short life-span of SCD patients. However, the increase in longevity during the recent years has been associated with clinical evidence of iron overload in some SCD patients due to accumulation of transfusional iron, increased absorption associated with intensive erythropoiesis and iron deposition as a result of continuous hemolysis. Therefore, iron overload may play an important role in the severity of SCD and iron chelation has a definite indication in several SCD cases. Thalassemia intermedia (TI) encompasses a wide clinical spectrum of beta-thalassemia phenotypes. Iron overload is alsofrequently present in TI patients as a result of increased intestinal iron absorption secondary to chronic anemia and to sporadic blood transfusion therapy, which may be administered intermittently when hemoglobin (Hb) levels fall <7 g/dL. Thus, a variable rate of iron loading, reaching toxic levels in some patients, was seen in a series of intermittently transfused TI patients who need adequate chelation therapy. Deferasirox (Exjade®) is a once-daily orally administered iron chelator approved for the treatment of transfusional iron overload in patients with transfusion-dependent anemia. Here, we report on the efficacy and safety of deferasirox in iron-overloaded patients with SCD and TI. We evaluated 18 adult patients with SCD (8M/10F; mean age 41.3 ± 8.5 years) and 11 with TI (5M/6F; mean age 41.2 ± 6.5 years) who had serum ferritin levels >1000 ng/mL and who were sporadically transfused with <20 units of red blood cells before starting deferasirox treatment for up to 12 months. Twenty-four patients (15 with SCD and 9 with TI) and 5 (3 with SCD and 2 with TI) patients were initially treated with deferasirox at 10 and 20 mg/kg/day, respectively, based on the number of blood transfusions received before the initiation of treatment. After 3 months, dose adjustments (increases) were allowed in increments of 5 mg/kg/day every 3 months as required to reduce markers of iron overload. Total iron burden was monitored by measuring serum ferritin levels before and monthly after starting deferasirox, while liver iron concentration and cardiac iron burden were measured by magnetic resonance imaging (MRI) T2 and T2* parameters at baseline and 12 months after deferasirox treatment. Left ventricular ejection fraction (LVEF) by MRI, and 24-hour proteinurea (Prot 24h) before and after treatment, were also measured. Hb levels, serum creatinine, cystatin-C (a sensitive marker of renal impairment), alanine (ALT) and aspartate aminotransferase (AST) were measured before and every month during deferasirox treatment. Serum ferritin level was significantly reduced after 12 months of deferasirox treatment in both SCD (mean±SD: from 1993±997 ng/ml to 1106±1016 ng/ml, p<0.001) and TI patients (from 2030±1040 ng/ml to 1165±684 ng/ml, p=0.02). Similarly baseline liver T2 and T2* significantly increased following 12 months of therapy in SCD (from 21.1±5.7 ms to 27.4±8.0 ms, p=0.001 and from 4.1±3.8 ms to 6.0±3.4 ms, p=0.013, for T2 and T2* respectively) and TI patients (from 20.1±4.1 ms to 23.7±6.2 ms, p=0.01 and from 3.4±3.0 ms to 4.4±3.0 ms, p=0.02, for T2 and T2* respectively). Mean cardiac T2* and LVEF were normal at baseline and did not significantly change after 12 months of treatment in SCD and TI patients. There were also no significant changes in mean serum creatinine, Hb or Prot 24h levels after 12 months of deferasirox treatment, while mean ALT and AST levels significantly decreased over 12 months in both groups of patients (p<0.02 and p<0.04 for SCD and TI, respectively). In terms of cystatin-C, there was a significant increase after 12 months of treatment in SCD patients (from 0.97±0.32 mg/l to 1.12±0.4 mg/l, p<0.001) but not in TI patients, in whom the increase was of borderline significance (from 0.98±0.23 mg/l to 1.13±0.27 mg/l, p=0.094). These data indicate that, over 12 months, deferasirox significantly reduced liver iron burden and serum ferritin levels in these iron-overloaded patients with SCD and TI. The decreases in ALT and AST are suggestive of an improvement in liver function, while there must be some caution for renal impairment, mainly in SCD. This study indicates that deferasirox provides effective iron chelation therapy in these patients without any significant adverse effects. DisclosuresNo relevant conflicts of interest to declare.

Evidence for a Suppression of the Colony Forming Capacity of Erythroid Progenitors by Iron Overload in Patients with MDS

Introduction: In MDS transfusional iron overload is known to be related to increased morbidity mainly due to cardiac and/or hepatic damage. As a consequence an excess mortality rate in polytransfused pts. has been demonstrated. A negative prognostic impact of transfusion need has been proven as an independent marker of bad prognosis. In 1996 Jensen et al. demonstrated that an adequate chelation therapy could improve the transfusion need of pts. with MDS significantly (Br J Haematol 1996, 94, 288–299). This observation and personal communications of several more cases with improvement of transfusion need under adequate chelation therapy implies that iron overload might not only be harmful to hepatocytes and cardiomyocytes but also to bone marrow progenitor cells. Their function is intrinsically impaired by MDS itself and thus might be further affected by a “second hit” in the form of toxic iron overload which might further impair their colony forming capacity.Patients and methods: For this purpose we performed colony assays from the peripheral blood from 42 pts. with MDS (RA/RARS: n=14, RCMD/RS: 12, RAEB-I/II:10, 5q-syndrome: 3, MDS-U: 2, CMML: 1; age: 39 – 86 yrs. (median: 69 yrs.); cytogenetics: normal: 26, 5q-: 6, −7: 2, complex: 4, others: 4) with (serum ferritin ≥250 μg/L, range: 273 – 6267 μg/L) and without iron overload (range: 23 – 213 μg/L). Only pts. without hepatic and/or active infectious diseases, without chemotherapy/epigenetic therapy during the last 6 months and without cytokine and/or corticoid therapy during the last 3 months before performance of colony assays were considered. BFU-E and CFU-GM were analysed by the same person (U.S.) after 12 – 16 days in cultures from peripheral blood, performed as described (Vehmeyer K et al., Leuk Res , 2001; 25(11):955–9) in 11(BFU-E)/9 (CFU-GM) pts. with normal ferritin-values (normal range: 20–250 μg/L) in comparison to 31/26 pts. with ferritin values surmounting 250 μg/L. Pts. with diffuse growth or cluster formation (leukemic growth) were excluded. Statistical evaluation was performed with SAS 9.1 software using Wilcoxon-Mann-Whitney tests. The results were regarded as significant if the p-value was smaller than 5%. Both patients subgroups were balanced according to cytogenetics, age and MDS WHO-subtype.Results: In the patients subgroup with normal ferritin (n=11) the numbers of BFU-E ranged between 0 and 76 (std.dev. 21.96) with a median of 3.5 and a mean of 10.1, the numbers of CFU-GM ranged between 0.5 and 38.5 (std.dev. 13.99), with a median of 5.5 and a mean of 11.1. In the patients with elevated serum ferritin (n=31) the numbers of BFU-E ranged between 0 and 27 (std.dev.5.32) with a median of 0.5 and a mean of 2.35, the numbers of CFU-GM ranged between 0 and 120 (std.dev. 30.18) with a median of 3.0 and a mean of 19.33). Statistical comparison of the numbers of BFU-E and CFU-GM between patients with normal and elevated serum ferritin yielded a highly significant difference (p=0.003845) for BFU-E and no difference for CFU-GM (p=0.939728).Conclusions: Our data for the first time provide evidence that in MDS iron overload significantly impairs bone marrow function by suppression of the burst forming activity of erythroid progenitors. If this iron is removed by adequate chelation burst forming activity might be partially restored. Myeloid progenitors do not seem to be affected by iron overload.

Early detection of cardiac iron deposition in patients with thallassemia, what is the best strategy?

b-Thallassemia is an inherited disorder of haemoglobin synthesis, resulting in chronic haemolytic anemia. Adequate blood transfusions and continuous chelation therapy are the milestones of treatment. In adults, the major haemoglobin is haemoglobin A, a tetramer consisting of one pair of a chains and one pair of b chains. Normally the ratio of a to b chains is one. In patients with thallassemia production of b chains is diminished. The excess a chains are unstable and incapable of forming soluble teramers. These chains precipitate in the cell, leading to a variety of clinical manifestations [1]. Thallassemias arise from over 100 mutations, that affect every step for production of normal haemoglobin. The frequency for genetic abnormalities associated with b-thallassemia approaches 0.1 in South Mediterranean areas in Europe. Both sexes are equally affected [2]. The bthallassemia syndromes are remarkable for their heterogeneity and clinical expression of the genetic abnormality [3]. Patients with a b-thallassemia mutation on each chromosome usually exhibit some degree of a-globin inclusion body formation, with consequent anemia, hemolysis and varying degrees of ineffective erythropoiesis [1]. The clinical syndrome associated with this genetic disorder is called thallassemia major. Patients, who are heterozygotes for b-thallassemia are mostly asymptomatic. This, because the erythrocyte is able to catabolize some of the excess unpaired a-globulin chains [1]. The syndrome is usually described as thallassemia minor or thallassemia intermediate. In patients with b-thallassemia major cardiac abnormalities occur frequently next to disorders of the liver and spleen, skeletal abnormalities and kidney and endocrine abnormalities [4]. Heart failure and rhythm disturbances are the main cause of death in adults with thallassemia major. In a recently published multicenter study 5% of patients aged 16–24 years and 23% of patients older than 25 years had heart disease requiring medication [5]. In another study congestive heart failure was observed in 5.4% of patients with thallassemia intermedia. Eight percent of these patients had a history of acute pericarditis [4]. The most prominent finding in patients with thallassemia major is left ventricular dysfunction, which is mainly due to severe anemia and iron overload because of the regular blood transfusions required to avoid hypoxia [6]. The estimation of iron stores in the heart would be very helpful in order to evaluate the efficacy of chelation therapy and determine the cardiac risk. Although the iron storage proteins like hemosiderin and ferritin are mostly intracellular, serum ferritin is highly correlated with the amount of iron deposition L. H. B. Baur (&) Department of Cardiology, Atrium Medical Centre Parkstad, University of Maastricht, Maastricht, The Netherlands e-mail: lbr01@atriummc.nl

Liver disease in chelated transfusion-dependent thalassemics: the role of iron overload and chronic hepatitis C

Iron overload and hepatitis virus C infection cause liver fibrosis in thalassemics. In a monocentric retrospective analysis of liver disease in a cohort of 191 transfusion-dependent thalassemics, in 126 patients who had undergone liver biopsy (mean age 17.2 years; 58 hepatitis virus C-RNA positive and 68 hepatitis virus C-RNA negative) the liver iron concentration (median 2.4 mg/gr dry liver weight) was closely related to serum ferritin levels (R = 0.58; p<0.0001). Male gender (OR 4.12) and serum hepatitis virus C-RNA positivity (OR 11.04) were independent risk factors for advanced liver fibrosis. The majority of hepatitis virus C-RNA negative patients with low iron load did not develop liver fibrosis, while hepatitis virus C-RNA positive patients infected with genotype 1 or 4 and iron overload more frequently developed advanced fibrosis. Hepatitis virus C infection is the main risk factor for liver fibrosis in transfusion-dependent thalassemics. Adequate chelation therapy usually prevents the development of liver fibrosis in thalassemics free of hepatitis virus C-infection and reduces the risk of developing severe fibrosis in thalassemics with chronic hepatitis C.

Osteopenia Is Commonly Present in Prepubertal Children with Severe Hb E/βthalassemia Despite Adequate Transfusion and Iron Chelation Therapy.

Objectives: Previous studies showed that low bone mineral density (BMD) is highly prevalent in Hb E/βthalassemia, who received occasional transfusion. Concerning the clinical heterogeneity of this syndrome, we determine whether adequate transfusion and chelation therapy in severe cases with Hb E/β0 thalassemia could ameliorate this complication.Methods: 50 pre-pubertal patients, age from 8–13, were recruited after informed consent. 26 were classified as severe group using Thalassemia International Federation (TIF) criteria, while 24 were mild. In severe patients, each received transfusion every 3 weeks (12–15 ml/kg) to keep their pre-transfusion Hb at 10 g/dL and they received iron chelation either by deferioxamine (20–40 mg/kg/d) or deferaxirox (25–30 mg/kg/d). Demographic data and history of chelation therapy were recorded. Serum free T4, TSH, PTH, cortisol, 25-OH Vit D, osteocalcin, alkaline phosphatase, serum ferritin (SF), Ca and P were determined. We measured the BMD of lumbar spines (L2-L4) and total body using DEXA (Lunar, Prodigy) and adjusted for height-age (HA) and bone age (BA). WHO criteria for BMD was Z-score −1 to −2.5 = osteopenia and < −2.5 = osteoporosis.Results: They were compound heterozygotes of Hb E with either codon 41/41 (50.6%), codon 17 (19%), IVS2#654 (14%), IVS1#1 (4%), IVS1#5 (3%) and codon 71/72 (2%) mutations. In severe group, 15 cases had poor compliance for chelation therapy (group A) (average SF; 6027 ± 2564 ng/ml) while 11 cases had good compliance (group B) (average SF; 2374.3 ± 189 ng/ml) and the ferritin level in mild group (group C) were 197 ± 89.4 ng/ml. There were no statistical significances among these three groups regarding baseline Hb, age and sex-distribution, weight, height and their corrected Z-scores for the standard of Thai children. Only the onset of anemia was significant lower in group C (5.4 ±1.8 yrs) compared to 2.12 ± 1.35 and 2.24 ± 2 yrs in group A and B respectively. All had normal free T4, TSH, PTH, Ca and P. As expected, 7 cases (78%) of group A with marked iron overload had osteopenia while one (7%) had osteoporosis. A strong invert correlation between BMD and serum ferritin in this group was observed. To our surprise, 6 out of 11 (54%) in group B and 14 out of 24 (58%) in group C also had osteopenia. However, there was no correlation between BMD and baseline Hb, ferritin and other clinical parameters in the group B and C.Conclusion: Low BMD in thalassemia might be resulted from ineffective erythropoiesis, bone marrow expansion and iron deposition in the bone marrow. In severe Hb E/βthalassemia, despite adequate transfusion, osteopenia and osteoporosis remain highly prevalent especially when iron overload is a co-factor. However, detecting this complication in a “so-call' milder group was surprising since this group of patients was less anemia and rarely required blood transfusion. These suggest that several factors beside anemia and bone marrow expansion might play roles on developing this complication. Moreover, the current standard transfusion and chelation protocol might not be preventable our patients from bone complications and they were at a greater risk of fracture in adulthood. It will be of interest to investigate whether calcium and Vit D supplement with or without osteoclast inhibitors could prevent osteopenia in this highly common hereditary anemia.