Adlette Inati

Levels of non-transferrin-bound iron as an index of iron overload in patients with thalassaemia intermedia.

Non‐transferrin‐bound iron (NTBI) was evaluated as an index of iron overload in a cross‐sectional randomised study in 74 non‐transfused patients with thalassaemia intermedia (TI). Mean NTBI (2·92 ± 3·43 μmol/l), serum ferritin (1023 ± 780 ng/ml) and liver iron concentration (LIC; 9·0 ± 7·4 mg Fe/g dry weight) were increased above reference‐range levels. Significant positive correlations occurred between mean NTBI and LIC (Pearson correlation 0·36; P = 0·002) and serum ferritin (Pearson correlation 0·421; P < 0·0001); with higher levels observed in splenectomised patients. NTBI assessment has potential as a simple reliable approach to determining iron status in TI.

Efficacy and tolerability of peginterferon alpha-2a with or without ribavirin in thalassaemia major patients with chronic hepatitis C virus infection

Thalassaemia patients with genotype 1 or 4 chronic hepatitis C virus (HCV) infection were randomised to receive peginterferon alpha‐2a 180 mg/week ribavirin for 48 weeks. Primary efficacy variable was sustained viral response (SVR) at 72 weeks. Thirty‐two patients were evaluated; 20 enrolled. Baseline characteristics were comparable. SVR occurred in four of 12 and five of eight patients in the monotherapy and combination groups (30% and 62·5%; P = 0·19), respectively. Undetectable RNA at 12 weeks and age <18 years were associated with improved SVR (P < 0·05). Transfusion requirements rose by 34% in the combination arm (P = 0·08). Peginterferon/ribavirin was effective in thalassaemics with HCV and moderate iron overload.

Asymptomatic brain magnetic resonance imaging abnormalities in splenectomized adults with thalassemia intermedia

Summary.  Background: A high incidence of thrombotic events in thalassemia intermedia (TI) patients led to the identification of a hypercoagulable state. Brain involvement has not been widely studied in TI, although limited reports confirm a low incidence of overt stroke and high incidence of silent brain infarcts. Patients/methods: This was a prospective study conducted on 30 adult, splenectomized TI patients. Patients were screened for absence of neurological signs or symptoms, and stroke‐related risk factors. Patient charts were reviewed for demographics, duration since splenectomy, and any history of transfusion therapy. Blood samples were obtained for complete blood counts and serum ferritin. Direct determination of liver iron concentration (LIC) was performed by R2 magnetic resonance imaging (MRI). Brain MRI was performed on all patients, looking for ischemic lesions and/or atrophy. Results: The mean age of patients was 32.1 ± 11 years (range, 18–54 years), with a male to female ratio of 13:17. Eighteen patients (60%) had evidence of one or more white matter lesions (WMLs) on brain MRI, all involving the subcortical white matter. Fourteen patients had evidence of multiple WMLs, with a mean of 5 ± 10 lesions (range, 2 to > 40 lesions). The vast majority of patients (94%) had small (< 0.5 cm) to medium (0.5–1.5 cm) WMLs, with only one patient showing evidence of a large (> 1.5 cm) WML. Eleven patients (37%) had mild cerebral atrophy. On multivariate analysis only age and transfusion history were independently and significantly associated with the occurrence of zero, single or multiple WMLs. Conclusion: WMLs and brain atrophy are a common finding in adult, splenectomized, TI patients. Increasing age and transfusion naivety are associated with a higher incidence and multiplicity of lesions.

Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations

The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans.

Comparison between deferoxamine and deferiprone (L1) in iron‐loaded thalassemia patients

Abstract: Introduction: Iron‐chelating therapy with deferoxamine in patients with thalassemia major has dramatically improved the prognosis of this disease. However, the limitations of this treatment have stimulated the design of alternative orally active iron chelators. Objective: To compare the effectiveness and safety of, and compliance with, oral deferiprone (L1), and deferoxamine, in thalassemia major patients. Methods: All patients were followed up in one center in Lebanon. Sixteen patients were on L1 (75 mg/kg/d), and 40 patients on subcutaneous deferoxamine (20–50 mg/kg/d). Serum ferritin level, urinary iron excretion (UIE) and side effects were monitored over a two year period. Results: Patients on L1 had an initial serum ferritin concentration of 3663±566 µg/l (mean±SEM), that dropped to 2599±314 at 6 months (p<0.02; paired t‐test), and stabilised at that level over the 24 months follow up. Patients on deferoxamine had an initial mean serum ferritin concentration of 3480±417 (NS compared to the L1 group), which dropped gradually to 3143±417 (p<0.05) and 2819±292 (p<0.02) at 6 and 24 months, respectively. The most common adverse reactions associated with L1 were arthralgia and nausea, but they did not necessitate stopping the drug. Conclusion: L1 had comparable efficacy as deferoxamine with minimal side effects and better compliance. Provided long term side effects are not encountered, L1 seems to be a valuable alternative iron chelator for patients unable or unwilling to use deferoxamine effectively.

Iron Overload: Consequences, Assessment, and Monitoring

In patients suffering from transfusion-dependent anemia, excess iron secondary to regular transfusions cannot be physiologically excreted. This leads to a state of chronic iron overload with iron accumulating in the liver, heart, and endocrine organs, and ultimately results in significant morbidity and mortality. Historically, iron overload was assessed through measurement of serum ferritin or direct determination of liver iron concentration (LIC) by means of biopsy. Although both correlate well with iron overload severity, several limitations pertinent to both are of concern. This has led to the identification of novel noninvasive iron assessment measures, namely magnetic resonance imaging (MRI) R2 and T2*. Moreover, investigations of other potential indices like nontransferrin-bound iron (NTBI) and labile plasma iron (LPI) are yielding promising results. Optimal iron overload assessment and monitoring is a key element in the development of improved strategies of iron chelation therapy that can be tailored to meet the patients specific needs.

Relation Between Iron-Overload Indices, Cardiac Echo-Doppler, and Biochemical Markers in Thalassemia Intermedia

Cardiovascular impairment is a major cause of morbidity and mortality in patients with thalassemia intermedia. In this study, echocardiographic assessment of left heart condition was performed in patients with thalassemia intermedia, and its relation to hematologic variables--amino terminal pro-brain natriuretic peptide (NT-proBNP), ferritin, hemoglobin--and liver iron concentration (LIC) was investigated. Echocardiographic assessment was performed using pulse-wave Doppler and tissue Doppler imaging. Data from 74 patients with thalassemia intermedia--35 men, 39 women, mean age 26.5 years (8 to 63)--were randomly selected and evaluated. Blood samples were collected for NT-proBNP levels in a random subgroup of 19 patients. Mean baseline values were hemoglobin 8.4 g/dl (4.9 to 13.1), serum ferritin 902.6 ng/ml (15 to 4,140), LIC 9.0 mg Fe/g (0.5 to 32.1), and NT-proBNP 113.5 pg/ml (16.4 to 371). Correlation between LIC and pulmonary artery systolic pressure was significant, suggesting that iron loading in the liver is indicative of cardiovascular sequelae. NT-proBNP was significantly correlated with the ratio of the left ventricular early rapid filling wave to early diastolic velocity at the mitral annulus (r = 0.50, p = 0.04) and hemoglobin (r = -0.49, p = 0.03), but not with other characteristics assessed. In conclusion, this study has highlighted the importance of using tissue Doppler imaging rather than pulse-wave Doppler to characterize left ventricular diastolic dysfunction in patients with thalassemia intermedia. Demonstration of the correlation of LIC and pulmonary artery systolic pressure independent of left ventricular filling pressures supports our hypothesis that left ventricular diastolic dysfunction does not contribute to the increased pulmonary artery systolic pressure in patients with thalassemia intermedia.

A double‐blind, placebo‐controlled phase II study of the efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer, in sickle cell disease

This placebo‐controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2‐dimethylbutyrate (HQK‐1001), a fetal globin gene‐inducing short‐chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12–55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/β0 thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK‐1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1–1.6%) with HQK‐1001 and 0.2% (95% CI: −0.7–1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK‐1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK‐1001 and 1.7 with placebo. The most common adverse events in the HQK‐1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK‐1001 at this dose and schedule are not recommended in SCD. Intermittent HQK‐1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation. Am. J. Hematol. 89:709–713, 2014.

Absence of cardiac siderosis by MRI T2* despite transfusion burden, hepatic and serum iron overload in Lebanese patients with sickle cell disease

Background:  The use of magnetic resonance imaging (MRI) to detect organ‐specific iron overload is becoming increasingly common. Although hepatic iron overload has been recognized in patients with sickle cell disease (SCD), cardiac iron deposition has only been examined in a few reports.

Safety and Effectiveness of 100 mg/kg/day Deferiprone in Patients with Thalassemia Major: A Two-Year Study

Deferiprone at a dose of 75 mg/kg/day is not sufficiently effective to maintain iron stores at a level which has been considered safe in all patients with iron overload. Our main aim was to determine the safety of long-term therapy with high-dose (100 mg/kg/day) deferiprone. A secondary aim was to determine the efficacy of this high dose. Twelve thalassemia major patients received deferiprone at a dose of100 mg/kg/day over 2 years. Transient aspartate aminotransferase increase (8 patients), gastrointestinal discomfort (3 patients) and arthralgia (2 patients) were the most commonly reported side effects. None of the patients discontinued therapy. The mean serum ferritin level fell from 3,901 ± 3,618 to 1,790 ± 2,205 µg/l after 2 years (p < 0.05). Five of the 12 patients continued to receive deferiprone for an additional 3 years. No new side effects were encountered. The mean serum ferritin level in this subgroup was initially 2,510 ± 332 µg/l and dropped to 1,511 ± 664 µg/l after 5 years (p < 0.05). Liver iron levels at the end of the 2-year study ranged from 1.0 to 30.9 mg/g dry weight, 3 of the patients having levels above 15 mg/g.