Cardiac iron load and function in transfused patients treated with deferasirox (the MILE study).

OBJECTIVES: To assess the effect of iron chelation therapy with deferasirox on cardiac iron and function in patients with transfusion-dependent thalassemia major, sickle cell disease (SCD), and myelodysplastic syndromes (MDS). METHODS: This phase IV, single-arm, open-label study over 53 wk evaluated the change in cardiac and liver iron load with deferasirox (up to 40 mg/kg/d), measured by magnetic resonance imaging (MRI). RESULTS: Cardiac iron load (myocardial T2*) significantly improved (P = 0.002) overall (n = 46; n = 36 thalassemia major, n = 4 SCD, n = 6 MDS). Results were significant for patients with normal and moderate baseline cardiac iron (P = 0.017 and P = 0.015, respectively), but not in the five patients with severe cardiac iron load. Liver iron concentration (LIC) significantly decreased overall [mean LIC 10.4 to 8.2 mg Fe/g dry tissue (dw); P = 0.024], particularly in those with baseline LIC >7 mg Fe/g dw (19.9 to 15.6 mg Fe/g dw; P = 0.002). Furthermore, myocardial T2* significantly increased in patients with LIC <7 mg Fe/g dw, but not in those with a higher LIC. Safety was consistent with previous reports. CONCLUSIONS: Once-daily deferasirox over 1 yr significantly increased myocardial T2* and reduced LIC. This confirms that single-agent deferasirox is effective in the management of cardiac iron, especially for patients with myocardial T2* >10 ms (Clinicaltrials.gov identifier: NCT00673608).

High rates of potentially infectious exposures between immunocompromised patients and their companion animals: an unmet need for education.

A cross-sectional survey of 265 adult patients with haematological malignancy, haemoglobinopathy or human immunodeficiency virus was performed to determine the potential risk of infection from animal exposures. One hundred and thirty-seven (52%) owned an animal; the majority were dogs (74%) and cats (39%), but 14% owned birds and 3% reptiles. Eighty percent engaged in behaviour with their animals that potentially put them at risk of zoonotic infections. The most frequent behaviours were picking up animal faeces 72 (52%), cleaning animal areas 69 (50%) and allowing animals to sleep in the same bed 51 (37%). Twenty-eight percent allowed the animal to lick their face. Of all patients, 80 (30%) had been bitten or scratched by an animal. Only 16% of those who owned pets could recall receiving education regarding safe behaviours around animals. These immunocompromised patients are at risk of infection through exposure to pets. Our study highlights the need for increased education of patients regarding how to remain safe around their pets.

Urolithiasis is prevalent and associated with reduced bone mineral density in ß-thalassaemia major.

Asymptomatic urolithiasis is common and of mixed composition in patients with ß-thalassaemia major. Twenty-seven subjects were imaged using dual-energy computer tomography to determine the presence and composition of urolithiasis. The prevalence of urolithiasis was 59% and affected patients generally had multiple stones, often with more than one component: struvite (33%), calcium oxalate (31%) and cystine (22%). Hypercalciuria was present in 78% of subjects and calcium-containing urolithiasis was associated with reduced femoral neck Z scores.

Benign Cardiac Effects of Hemoglobin H Disease.

BACKGROUND/AIMS: Hemoglobin H (HbH) disease is associated with iron overload, but whether this results in serious cardiac or vascular sequelae is unresolved. METHODS: We identified 39 adult subjects (age 42 ± 12 years, 13 men) with HbH disease who had undergone echocardiography, 27 of whom had also undergone cardiac and liver magnetic resonance assessment of iron loading using T2*-weighted imaging. RESULTS: None of the subjects had a history of heart failure or arrhythmias. There were 13/39 subjects with a ferritin level within the sex-based normal range and only 4/39 had ferritin >1,000 ng/ml. Left ventricular (LV) and left atrial dilatation was common, but LV ejection fraction was normal (≥55%) in all subjects. Age was positively correlated with log ferritin in the 27 nontransfused subjects (r = 0.43) and was inversely correlated with the transmitral E wave and E/A ratio (r = -0.69 and r = -0.79, respectively), but no relation of log ferritin with E or E/A was evident. The peak tricuspid regurgitation velocity was normal in 24/29 subjects for whom this was obtained, and it was no more than mildly elevated in the other 5. None of the tested subjects had an abnormal cardiac T2* reading, but half had evidence of liver iron loading. CONCLUSION: No myocardial iron loading or serious cardiac or vascular sequelae were identified in this cohort with HbH disease.

Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with ß-thalassemia major: a longitudinal study.

ß-Thalassemia major causes ineffective erythropoiesis and chronic anemia and is associated with iron overload due to both transfused iron and increased iron absorption, the latter mediated by suppression of the iron-regulatory hormone hepcidin. We sought to determine whether, in ß-thalassemia major, transfusion-mediated inhibition of erythropoiesis dynamically affects hepcidin. We recruited 31 chronically transfused patients with ß-thalassemia major and collected samples immediately before and 4 to 8 days after transfusion. Pretransfusion hepcidin was positively correlated with hemoglobin and ferritin and inversely with erythropoiesis. The hepcidin-ferritin ratio indicated hepcidin was relatively suppressed given the degree of iron loading. Posttransfusion, hemoglobin and hepcidin increased, and erythropoietin and growth differentiation factor-15 decreased. By multiple regression, pre- and posttransfusion hepcidin concentrations were both associated positively with hemoglobin, inversely with erythropoiesis, and positively with ferritin. Although men and women had similar pretransfusion hemoglobin, men had significantly increased erythropoiesis and lower hepcidin, received a lower transfusion volume per liter blood volume, and experienced a smaller posttransfusion reduction in erythropoiesis and hepcidin rise. Age of blood was not associated with posttransfusion hemoglobin or ferritin change. Hepcidin levels in patients with ß-thalassemia major dynamically reflect competing influences from erythropoiesis, anemia, and iron overload. Measurement of these indices could assist clinical monitoring.

Rapid microwave-assisted chemical cleavage - mass spectrometric method for the identification of hemoglobin variants in blood.

A sensitive, rapid analytical method has been developed for the characterization of human hemoglobin disorders with very small volumes (<1 µL) of blood. As an alternative to conventional enzymatic digestion, a site-specific chemical cleavage method has been established using 0.05% formic acid under microwave-irradiation conditions for short time intervals, for example, less than 10 min. Peptide analysis was performed by MALDI TOF MS and capillary liquid chromatographic ESI MS/MS. The cleavage of the hemoglobin chains with formic acid occurred at either side or at both sides (C- and N-terminal) of aspartic acid residues, but preferentially N-terminally. The method has been applied to blood samples from hemoglobin S carrier heterozygotes and hemoglobin S thalassaemia compound heterozygotes with a reduced expression level of hemoglobin S. Both MALDI TOF MS and ESI MS/MS analysis allowed the identification of the hemoglobin S "signature" peptide. This alternative method of sample preparation is compatible with MS techniques and is expected to significantly contribute to the further development of rapid, robust, reproducible and sensitive analytical methods in proteomics and biomedical diagnostics where protein variant characterization is a crucial factor for biomarker discovery and disease identification.

Cardiac and hepatic siderosis in myelodysplastic syndrome, thalassemia and diverse causes of transfusion-dependent anemia: the TIMES study.

The significant morbidity and mortality associated with iron overload can be reduced by effective iron chelation. Magnetic resonance imaging (MRI) provides accurate and reproducible iron load assessment. The aim of this epidemiological study was to assess the prevalence and severity of cardiac and hepatic siderosis by MRI and to evaluate the impact of MRI on clinical management in patients with transfusion-dependent anemia and non-transfusion-dependent thalassemia (NTDT). We enrolled 243 patients with myelodysplastic syndromes (MDS), thalassemia major (TM), NTDT or other chronic anemia. Overall, 10% and 48% had cardiac and hepatic siderosis, respectively. Mean liver iron concentration (LIC) was above target range in all groups; mean myocardial T2∗ was normal. Hepatic siderosis was more prevalent than myocardial siderosis in patients with MDS, occurring in 54.4% and 4.4% of patients, respectively. As also observed in patients with NTDT or other anemia, hepatic siderosis was present in a large proportion of MDS patients who were chelation naïve (57.7%), as well as in patients receiving iron chelation therapy (ICT) (52.4%), despite a lower transfusion load compared with TM. Correlation between LIC and serum ferritin was observed across diseases; however, not all patients requiring ICT could be identified with serum ferritin alone, as serum ferritin underestimated LIC in 4.4% and overestimated LIC in 7.5% of patients. Exploratory analyses showed serum ferritin thresholds for liver siderosis detected by MRI at approximately 300 ng/mL higher in MDS than in TM. Most patients reported low-medium adherence to ICT; MRI assessment led to change in ICT in 46% of evaluable patients, including 52% of MDS patients. Accurate organ iron monitoring by MRI facilitated appropriate initiation of chelation, dose optimization and clinical decision making. Trial registration: ClinicalTrials.gov: NCT01736540.

Complex phenotypes in the haemoglobinopathies: recommendations on screening and DNA testing.

This document considers a number of scenarios involving complex haemoglobinopathies and provides 28 recommendations at both the clinical and laboratory levels on how these should be managed.

Imaging manifestations of acquired elastopathy resembling pseudoxanthoma elasticum in patients with beta thalassaemia major and sickle cell disease.

Development of an acquired systemic elastopathy resembling pseudoxanthoma elasticum in patients with chronic haemoglobinopathies such as beta thalassaemia major and sickle cell disease is well documented. There is paucity of any comprehensive literature on the radiological manifestations of this entity. This pictorial review aims to describe and illustrate the multi system and multi modality imaging findings of this condition.

Deferasirox at therapeutic doses is associated with dose-dependent hypercalciuria.

Deferasirox is an oral iron chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies. Whilst initial long-term studies established the renal safety of deferasirox, there are now increasing reports of hypercalciuria and renal tubular dysfunction. In addition, urolithiasis with rapid loss of bone density in patients with ß thalassemia major has been reported. We conducted a cross-sectional cohort study enrolling 152 adult patients comprising of ß thalassemia major (81.5%), sickle cell disease (8%), thalassemia intermedia (2%), HbH disease (6.5%) and E/ß thalassemia (2%). Cases were matched with normal control subjects on age, gender and serum creatinine. Iron chelator use was documented and urine calcium to creatinine ratios measured. At the time of analysis, 88.8% of patients were receiving deferasirox and 11.2% were on deferoxamine. Hypercalciuria was present in 91.9% of subjects on deferasirox in a positive dose-dependent relationship. This was not seen with subjects receiving deferoxamine. At a mean dose of 30.2±8.8mg/kg/day, deferasirox was associated with an almost 4 fold increase in urine calcium to creatinine ratio (UCa/Cr). Hypercalciuria was present at therapeutic doses of deferasirox in a dose-dependent manner and warrants further investigation and vigilance for osteoporosis, urolithiasis and other markers of renal dysfunction.

Thalassemia bone disease: a 19-year longitudinal analysis.

Thalassemia is an inherited disorder of alpha or beta globin chain synthesis leading to ineffective erythropoiesis requiring chronic transfusion therapy in its most severe form. This leads to iron overload, marrow expansion, and hormonal complications, which are implicated in bone deformity and loss of bone mineral density (BMD). In this 19-year retrospective longitudinal study, the relationships between BMD (determined by dual-energy X-ray absorptiometry) and risk factors for osteoporosis in 277 subjects with transfusion-dependent thalassemia were examined. The mean age at first review was 23.2 ± 11.9 years and 43.7% were male. Hypogonadism was present in 28.9%. Fractures were confirmed in 11.6% of subjects and were more frequent in males (16.5%) compared with females (7.7%). Lumbar spine (LS), femoral neck (FN), and total body (TB) Z-scores were derived. Patients with transfusion-dependent thalassemia had a significant longitudinal decline in BMD at the FN and TB. In the linear mixed-model analysis of BMD and risk factors for bone loss, FN Z-score was more significantly associated with risk factors compared with the LS and TB. The rate of decline at the FN was 0.02 Z-score per year and was 3.85-fold greater in males. The decline in FN Z-score over the last 5 years (years 15 to 19) was 2.5-fold that of the previous 7 years (years 8 to 14) and coincided with a change in iron chelator therapy from desferrioxamine to deferasirox. Hemoglobin (Hb) levels positively correlated with higher TB and LS Z-scores. In conclusion, the FN is the preferred site for follow-up of BMD. Male patients with ß-thalassemia experienced a greater loss of BMD and had a higher prevalence of fractures compared with females. Transfusing patients (particularly males) to a higher Hb target may reduce the decline in BMD. Whether deferasirox is implicated in bone loss warrants further study.

Extra-medullary haematopoiesis: a pictorial review of its typical and atypical locations.

Extra-medullary haematopoiesis (EMH) occurs in many haematological disorders and is secondary to insufficient bone marrow function or ineffective erythropoiesis. It usually presents as haematopoietic masses in several typical and atypical body locations. This pictorial review briefly discusses the common EMH locations encountered in clinical practice, including the liver, spleen, lymph nodes and paravertebral regions. Unusual presentation as focal hepatic and splenic masses is also discussed. Some atypical EMH locations are then presented together with their pathophysiology and relevant illustrations. These include EMH in the intra-spinal canal, pre-sacral region, nasopharynx and paranasal sinuses. Intra-spinal EMH can cause cord compression and present with neurological symptoms. In these cases, urgent treatment may be required. Haematopoietic masses in the other atypical locations can present with obstructive symptoms or may be diagnosed incidentally on imaging. EMH in unusual locations need to be monitored with follow-up imaging to ensure their stability. In some circumstances, tissue biopsy is appropriate to confirm the diagnosis and exclude other sinister pathology (e.g. malignancy). Treatment is only required where symptoms are present. Management options include blood transfusion, radiotherapy, hydroxyurea or surgical resection in selected cases.

A case of hypophosphatemic osteomalacia secondary to deferasirox therapy.

Patients with ß-thalassemia major require iron-chelation therapy to avoid the complication of iron overload. Until recently, deferoxamine (DFO) was the major iron chelator used in patients requiring chronic hypertransfusion therapy, but DFO required continuous subcutaneous therapy. The availability of deferasirox (Exjade®), an orally active iron chelator, over the past 4 years represented a necessary alternative for patients requiring chelation therapy. However, there have been increasing reports of proximal renal tubular dysfunction and Fanconi syndrome associated with deferasirox in the literature. We report a case of hypophosphataemic osteomalacia secondary to deferasirox therapy.

Health-Related Quality of Life, Treatment Satisfaction, Adherence and Persistence in ß-Thalassemia and Myelodysplastic Syndrome Patients with Iron Overload Receiving Deferasirox: Results from the EPIC Clinical Trial.

Treatment of iron overload using deferoxamine (DFO) is associated with significant deficits in patients' health-related quality of life (HRQOL) and low treatment satisfaction. The current article presents patient-reported HRQOL, satisfaction, adherence, and persistence data from ß-thalassemia (n = 274) and myelodysplastic syndrome (MDS) patients (n = 168) patients participating in the Evaluation of Patients' Iron Chelation with Exjade (EPIC) study (NCT00171821); a large-scale 1-year, phase IIIb study investigating the efficacy and safety of the once-daily oral iron chelator, deferasirox. HRQOL and satisfaction, adherence, and persistence to iron chelation therapy (ICT) data were collected at baseline and end of study using the Medical Outcomes Short-Form 36-item Health Survey (SF-36v2) and the Satisfaction with ICT Questionnaire (SICT). Compared to age-matched norms, ß-thalassemia and MDS patients reported lower SF-36 domain scores at baseline. Low levels of treatment satisfaction, adherence, and persistence were also observed. HRQOL improved following treatment with deferasirox, particularly among ß-thalassemia patients. Furthermore, patients reported high levels of satisfaction with deferasirox at end of study and greater ICT adherence, and persistence. Findings suggest deferasirox improves HRQOL, treatment satisfaction, adherence, and persistence with ICT in ß-thalassemia and MDS patients. Improving such outcomes is an important long-term goal for patients with iron overload.

Clinical efficacy and safety evaluation of tailoring iron chelation practice in thalassaemia patients from Asia-Pacific: a subanalysis of the EPIC study of deferasirox.

Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients' Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects.

Hyperhaemolysis in sickle cell disease--an unusual and potentially life-threatening complication.

As sickle cell disease is increasing in Australia, paediatricians and other health care providers need to be aware of the broad range of complications that can occur in this condition. Although the complications of splenic sequestration and chest crises are well recognised, the infrequent but equally dramatic complication of hyperhaemolysis is less well appreciated. Here, we report a case of hyperhaemolysis in a Victorian paediatric patient.