Raffaella Origa

Onset of cardiac iron loading in pediatric patients with thalassemia major.

We reviewed cardiac T2* assessments from 77 thalassemia major patients between the ages of 2.5 and 18 years to study optimal timing of cardiac iron screening by magnetic resonance imaging. No patient under 9.5 years of age showed detectable cardiac iron in contrast to 36% of patients between the ages of 15–18 years old, corresponding to an odds-ratio of 1.28 (28%) per year. All patients with cardiac iron had received at least 35 grams of transfusional iron. Liver iron and ferritin failed to predict cardiac iron loading. Initiation of cardiac magnetic resonance imaging assessment should be determined according to age and transfusional burden rather than indices of iron overload. When appropriate chelation therapy has been administered since birth, cardiac magnetic resonance imaging can be postponed until 8 years of age when anesthesia is not required. Patients with suboptimal chelation, increased transfusional requirements, or who have initiated transfusions later in life should be tested sooner.

Pregnancy and β-thalassemia: an Italian multicenter experience

Background Recent advances in the management of thalassemia have significantly improved life expectancy and quality of life of patients with this hemoglobinopathy, with a consequent increase in their reproductive potential and desire to have children. Design and Methods We describe the methods of conception and delivery, as well as the course and outcome of pregnancy including transfusions, iron overload and chelation in 46 women with thalassemia major (58 pregnancies) and in 11 women with thalassemia intermedia (17 pregnancies). Conception was achieved after gonadotrophin-induced ovulation in 33 of the women with thalassemia major and spontaneously in all of those with thalassemia intermedia. Results Among the women with thalassemia major, 91% of the pregnancies resulted in successful delivery of 45 singleton live-born neonates, five sets of twins and one set of triplets. No secondary complications of iron overload developed or worsened during pregnancy. When considering only the singleton pregnancies, the proportion of babies with intrauterine growth retardation did not differ from that reported in the general Italian population. The high prevalence of pre-term births (32.7%) was mostly related to multiple pregnancies and precautionary reasons. Pregnancy was safe in most women with thalassemia major or intermedia. However, women with thalassemia intermedia who had never previously been transfused or who had received only minimal transfusion therapy were at risk of severe alloimmune anemia if blood transfusions were required during pregnancy. Conclusions Provided that a multidisciplinary team is available, pregnancy is possible, safe and usually has a favorable outcome in patients with thalassemia. In women with hypogonadotropic hypogonadism, gonadal function is usually intact and fertility is usually retrievable.

No evidence of cardiac iron in 20 never- or minimally-transfused patients with thalassemia intermedia

Iron loading in non-transfused thalassemia intermedia (TI) patients is mainly due to an increased intestinal absorption secondary to chronic anemia and varies from 2 to 5 grams per year.[1][1] In thalassemia major (TM) iron derived from red blood cell breakdown accumulates first in the

Effect of Food, Type of Food, and Time of Food Intake on Deferasirox Bioavailability: Recommendations for an Optimal Deferasirox Administration Regimen

Deferasirox (ICL670) is representative of a new class of tridentate iron chelators, formulated as tablets for dispersion. Deferasirox has exhibited high potency and a clinically manageable safety profile in preclinical models and in an extensive clinical program. The effect of food and time of food intake on the pharmacokinetics of deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of deferasirox (20 mg/kg) was assessed following administration either before a high‐fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of deferasirox when consumed concomitantly. In contrast, this is not the case when deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption.

Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia

Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non‐transfusion‐dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade® in non‐transfusion‐dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron‐overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).

Clinical and molecular analysis of haemoglobin H disease in Sardinia: haematological, obstetric and cardiac aspects in patients with different genotypes

In this study, 251 Sardinian patients (187 adults and 64 children) with haemoglobin (Hb) H disease were evaluated. Two‐hundred and sixteen patients (86%) had the deletional type (‐ ‐/‐α) and 36 (14%) patients had the non‐deletional type (‐ ‐/αNDα). A clear genotype–phenotype correlation was found, with the non‐deletional type more severe than the deletional type. Diagnosis of Hb H disease was incidental in about 60% of cases. Aplastic crises due to B19 parvovirus infection were found in five patients (2·1%), while 23 patients (9·6%) experienced one or more haemolytic crises. Nineteen patients with Hb H received sporadic red blood cell transfusions and three patients were repeatedly transfused. Forty‐seven of 61 married women (77%) had 82 pregnancies. In children, mean serum ferritin was 87 ±92 μg/l and in adults, was 192 ± 180 μg/l in females and 363 ± 303 μg/l in males. For the 98 male patients, a significant correlation was found between ferritin values and age (r2 = 0·33, P < 0·0001). In the Sardinian population, Hb H disease needs regular monitoring for early detection and treatment of possible complications, such as worsening of anaemia that may require red cell transfusion, cholelithiasis and iron overload.

Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload

Deferasirox (DFX) monotherapy is effective for reducing myocardial and liver iron concentrations (LIC), although some patients may require intensive chelation for a limited duration. HYPERION, an open-label single-arm prospective phase 2 study, evaluated combination DFX-deferoxamine (DFO) in patients with severe transfusional myocardial siderosis (myocardial [m] T2* 5-<10 ms; left ventricular ejection fraction [LVEF] ≥56%) followed by optional switch to DFX monotherapy when achieving mT2* >10 ms. Mean dose was 30.5 mg/kg per day DFX and 36.3 mg/kg per day DFO on a 5-day regimen. Geometric mean mT2* ratios (Gmeanmonth12/24/Gmeanbaseline) were 1.09 and 1.30, respectively, increasing from 7.2 ms at baseline (n = 60) to 7.7 ms at 12 (n = 52) and 9.5 ms at 24 months (n = 36). Patients (17 of 60; 28.3%) achieved mT2* ≥10 ms and ≥10% increase from baseline at month 24; 15 switched to monotherapy during the study based on favorable mT2*. LIC decreased substantially from a baseline of 33.4 to 12.8 mg Fe/g dry weight at month 24 (-52%). LVEF remained stable with no new arrhythmias/cardiac failure. Five patients discontinued with mT2* <5 ms and 1 died (suspected central nervous system infection). Safety was consistent with established monotherapies. Results show clinically meaningful improvements in mT2* in about one-third of patients remaining on treatment at month 24, alongside rapid decreases in LIC in this heavily iron-overloaded, difficult-to-treat population. Combination therapy may be useful when rapid LIC reduction is required, regardless of myocardial iron overload. This trial was registered at www.clinicaltrials.gov as #NCT01254227.

Deferasirox: pharmacokinetics and clinical experience

Introduction: Iron overload is an inevitable consequence of transfusion therapy for a variety of underlying anemias. Iron overload, without effective chelation, will lead to significant morbidity and mortality. Deferasirox (Exjade®) is an oral tridentate iron chelator used for reducing iron overload. Areas covered: In addition to the pharmacokinetic and pharmacodynamic profile of deferasirox, this review examines the efficacy and safety data from pivotal studies with deferasirox in iron-overloaded patients with various anemias, including thalassemia, sickle cell disease and myelodysplastic syndromes. A qualitative literature search for deferasirox was performed using PubMed and recent key congress publications (EHA and ASH); key search terms were deferasirox, pharmacokinetic, pharmacodynamic, efficacy and safety. Expert opinion: Based on the current available data, deferasirox treatment is effective with a clinically manageable safety profile although appropriate dosing according to the severity of iron burden and iron intake, together with the careful monitoring of laboratory parameters and adverse events, is recommended. However, despite advances made in the treatment of iron overload, some patients still do not respond adequately to iron chelators, and increased awareness, understanding and further research are still needed.

A genetic score for the prediction of beta-thalassemia severity.

Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.−158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We characterized 54 genetic variants at these five loci robustly associated with the amelioration of beta-thalassemia phenotype, to build a predictive score of severity using a representative cohort of 890 β-thalassemic patients. Using Cox proportional hazard analysis on a training set, we assessed the effect of these loci on the age at which patient started regular transfusions, built a Thalassemia Severity Score, and validated it on a testing set. Discriminatory power of the model was high (C-index=0.705; R2=0.343) and the validation conducted on the testing set confirmed its predictive accuracy with transfusion-free survival probability (P<0.001) and with transfusion dependency status (Area Under the Receiver Operating Characteristic Curve=0.774; P<0.001). Finally, an automatized on-line calculation of the score was made available at http://tss.unica.it. Besides the accurate assessment of genetic predictors effect, the present results could be helpful in the management of patients, both as a predictive score for screening and a standardized scale of severity to overcome the major-intermedia dichotomy and support clinical decisions.

Cholelithiasis in thalassemia major

Objectives:  Aim of this study was to evaluate prevalence and characteristics of cholelithiasis in a large population of patients with thalassemia major (TM).