Differential effects of iron chelators on iron burden and long-term morbidity and mortality outcomes in a large cohort of transfusion-dependent ß-thalassemia patients who remained on the same monotherapy over 10 years.

We conducted a retrospective cohort study on 663 transfusion-dependent ß-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload.

Revisiting iron overload status and change thresholds as predictors of mortality in transfusion-dependent ß-thalassemia: a 10-year cohort study.

Data on iron overload status and change thresholds that can predict mortality in patients with transfusion-dependent ß-thalassemia (TDT) are limited. This was a retrospective cohort study of 912 TDT patients followed for up to 10 years at treatment centers in Italy (median age 32 years, 51.6% female). The crude mortality rate was 2.9%. Following best-predictive threshold identification through receiver operating characteristic curve analyses, data from multivariate Cox-regression models showed that patients with Period Average Serum Ferritin (SF) > 2145 vs ≤ 2145 ng/mL were 7.1-fold (P < 0.001) or with Absolute Change SF > 1330 vs ≤ 1330 ng/mL increase were 21.5-fold (P < 0.001) more likely to die from any cause. Patients with Period Average Liver Iron Concentration (LIC) > 8 vs ≤ 8 mg/g were 20.2-fold (P < 0.001) or with Absolute Change LIC > 1.4 vs ≤ 1.4 mg/g increase were 27.6-fold (P < 0.001) more likely to die from any cause. Patients with Index (first) cardiac T2* (cT2*) < 27 vs ≥ 27 ms were 8.6-fold (P < 0.001) more likely to die from any cause. Similarly, results at varying thresholds were identified for death from cardiovascular disease. These findings should support decisions on iron chelation therapy by establishing treatment targets, including safe iron levels and clinically meaningful changes over time.

Management of the Sickle Cell Trait: An Opinion by Expert Panel Members.

The number of individuals with the sickle cell trait exceeds 300 million worldwide, making sickle cell disease one of the most common monogenetic diseases globally. Because of the high frequency of sickle cell disease, reproductive counseling is of crucial importance. In addition, unlike other carrier states, Sickle Cell Trait (SCT) seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and complications during pregnancy and surgery. This expert panel believes that increasing knowledge about these clinical manifestations and their prevention and management can be a useful tool for all healthcare providers involved in this issue.

Overall and complication-free survival in a large cohort of patients with ß-thalassemia major followed over 50 years.

We report data on survival and complications for a longitudinal cohort of 709 transfusion-dependent ß-thalassemia major patients (51.1% males) born between 1970 and 1997 and followed through 2020 at seven major centers in Italy. Overall survival probability at 30 years was 83.6% (95%CI: 78.5-89.1) in the oldest birth cohort (1970-1974) compared with 93.3% (95%CI: 88.6-98.3) in the youngest birth cohort (1985-1997) (p = 0.073). Females showed better survival than males (p = 0.022). There were a total of 93 deaths at a median age of 23.2 years with the most frequent disease-related causes being heart disease (n = 53), bone marrow transplant (BMT) complication (n = 10), infection (n = 8), liver disease (n = 4), cancer (n = 3), thromboembolism (n = 2) and severe anemia (n = 1). There was a steady decline in the number of deaths due to heart disease from the year 2000 onwards and no death from BMT was observed after the year 2010. A progressive decrease in the median age of BMT was observed in younger birth cohorts (p < 0.001). A total of 480 (67.7%) patients developed ≥1 complication. Patients in younger birth cohorts demonstrated better complication-free survival (p < 0.001) which was comparable between sexes (p = 0.230). Independent risk factors for death in multivariate analysis included heart disease (HR: 4.63, 95%CI: 1.78-12.1, p = 0.002), serum ferritin >1000 ng/mL (HR: 15.5, 95%CI: 3.52-68.2, p < 0.001), male sex (HR: 2.75, 95%CI: 0.89-8.45, p = 0.078), and splenectomy (HR: 6.97, 95%CI: 0.90-54.0, p < 0.063). Survival in patients with ß-thalassemia major continues to improve with adequate access to care, best practice sharing, continued research, and collaboration between centers.

Incidence of cancer and related deaths in hemoglobinopathies: A follow-up of 4631 patients between 1970 and 2021.

BACKGROUND: The correlation between thalassemia and malignancies other than hepatocellular carcinoma (HCC) and the possible relationship between other hemoglobinopathies and tumor risk have been poorly evaluated. METHODS: Eight Italian specialized centers evaluated the incidence of malignant neoplasms in hemoglobinopathies as well as their sites and features. The study cohort included 4631 patients followed between 1970 and 2021 (transfusion-dependent ß-thalassemia, 55.6%; non-transfusion-dependent thalassemia, 17.7%; sickle cell disease, 17.6%; hemoglobin H disease, 8.3%). RESULTS: A total of 197 diagnoses of cancer were reported (incidence rate, 442 cases per 100,000 person-years). The liver was the most frequent site of tumors in both sexes, with a higher incidence (190 cases per 100,000 person-years) in comparison with the general population found in all types of hemoglobinopathies (except hemoglobin H disease). In recent years, tumors have become the second cause of death in patients with transfusion-dependent thalassemia. A lower risk of breast and prostate cancer was observed in the whole group of patients with hemoglobinopathies. The first cancer diagnoses dated back to the 1980s, and the incidence rate sharply increased after the 2000s. However, although the incidence rate of cancers of all sites but the liver continued to show an increasing trend, the incidence of HCC showed stability. CONCLUSIONS: These findings provide novel insights into the relationship between cancer and hemoglobinopathies and suggest that the overall risk is not increased in these patients. HCC has been confirmed as the most frequent tumor, but advances in chelation and the drugs that have led to the eradication of hepatitis C may explain the recent steadiness in the number of diagnoses that is reported here.

Long-Term Neuroradiological and Clinical Evaluation of NBIA Patients Treated with a Deferiprone Based Iron-Chelation Therapy.

Neurodegeneration with brain iron accumulation (NBIA) comprises various rare clinical entities with brain iron overload as a common feature. Magnetic resonance imaging (MRI) allows diagnosis of this condition, and genetic molecular testing can confirm the diagnosis to better understand the intracellular damage mechanism involved. NBIA groups disorders include: pantothenate kinase-associated neurodegeneration (PKAN), mutations in the gene encoding pantothenate kinase 2 (PANK2); neuroferritinopathy, mutations in the calcium-independent phospholipase A2 gene (PLA2G6); aceruloplasminemia; and other subtypes with no specific clinical or MRI specific patterns identified. There is no causal therapy, and only symptom treatments are available for this condition. Promising strategies include the use of deferiprone (DFP), an orally administered bidentate iron chelator with the ability to pass through the blood-brain barrier. This is a prospective study analysis with a mean follow-up time of 5.5 ± 2.3 years (min-max: 2.4-9.6 years) to define DFP (15 mg/kg bid)'s efficacy and safety in the continuous treatment of 10 NBIA patients through clinical and neuroradiological evaluation. Our results show the progressive decrease in the cerebral accumulation of iron evaluated by MRI and a substantial stability of the overall clinical neurological picture without a significant correlation between clinical and radiological findings. Complete ferrochelation throughout the day appears to be of fundamental importance considering that oxidative damage is generated, above, all by non-transferrin-bound iron (NTBI); thus, we hypothesize that a (TID) administration regimen of DFP might better apply its chelating properties over 24 h with the aim to also obtain clinical improvement beyond the neuroradiological improvement.

Safety and Efficacy of the New Combination Iron Chelation Regimens in Patients with Transfusion-Dependent Thalassemia and Severe Iron Overload.

The aim of this study is the evaluation of the safety and the efficacy of long-term combination therapy deferasirox plus desferrioxamine and deferasirox plus deferiprone in a large group of transfusion-dependent thalassemia patients with high values of serum ferritin and/or magnetic resonance, indicative of severe liver and cardiac iron accumulation. Sixteen adults with transfusion-dependent thalassemia were treated simultaneously with deferasirox plus desferrioxamine, while another 42 patients (seven children) were treated with deferasirox plus deferiprone. The hepatic and cardiac iron overload was assessed prior to treatment and then annually with magnetic resonance imaging, and the serum ferritin was measured monthly. Adverse events were checked at each transfusion visit. The safety of both the combinations was consistent with established monotherapies. Both treatments were able to decrease the serum ferritin and liver iron concentration over time, depending on the level of compliance with therapy. Cardiac iron measured as R2* did not significantly change in patients treated with deferasirox plus desferrioxamine. Most patients with MRI indicative of myocardial siderosis at the beginning of treatment reached normal values of cardiac iron at the last determination if treated with deferasirox plus desferrioxamine. The greatest limitation of these therapies was low patient adherence to the two drugs, which is not surprising considering that the need for an intensive chelation is generally linked to previous issues of compliance.

Comparison between different software programs and post-processing techniques for the MRI quantification of liver iron concentration in thalassemia patients.

PURPOSE: In magnetic resonance imaging (MRI) relaxometry, various software programs are available to perform R2* measurements and to estimate the liver iron concentration (LIC). The main objective of our study was to compare R2* LIC values, obtained with three different software programs based on specific decay models and calibration curves, with LIC estimates provided by R2-relaxometry (FerriScan). METHODS: This retrospective study included 15 patients with 15 baseline MRIs and 34 serial examinations. R2* LIC estimates were calculated using the FuncTool, CMRtools/Thalassemia Tools and Quanta Hematology programs. Longitudinal LIC changes (ΔLIC) were calculated using the subset of 34 serial MRIs. RESULTS: After Bland-Altman analysis on baseline data, Quanta Hematology, which employs the monoexponential-plus-constant fit, produced the lowest mean difference [0.01 ± 0.14 log(mg/gdw)] with the closest limits of agreement. In the longitudinal setting, Quanta Hematology again gave the lowest mean difference between R2 and R2* LIC (0.1 ± 2.6 mg/gdw). Using FerriScan as reference, the value of concordant directional ΔLIC changes was the same for all programs (27/34, 85.7 %). CONCLUSIONS: R2* LICs are higher than R2 LICs at iron levels <7 mg/gdw, while R2 LIC averages higher than R2* LIC with increasing iron load. The monoexponential-plus-constant model provided the best agreement with R2 LIC estimates.

Characterization of ferromagnetic or conductive properties of metallic foreign objects embedded within the human body with magnetic iron detector (MID): Screening patients for MRI.

PURPOSE: A preliminary assessment of the MRI-compatibility of metallic object possibly embedded within the patient is required before conducting the MRI examination. The Magnetic Iron Detector (MID) is a highly sensitive susceptometer that uses a weak magnetic field to measure iron overload in the liver. MID might be used to perform a screening procedure for MRI by determining the ferromagnetic/conductive properties of embedded metallic objects. METHODS: The study was composed by: (i) definition of MID sensitivity threshold; (ii) application of MID in a procedure to characterize the ferromagnetic/conductive properties of metallic foreign objects in 958 patients scheduled for MID examination. RESULTS: The detection threshold for ferromagnetic objects was found to be the equivalent of a piece of wire of length 2 mm and gauge 0.8 mm(2) and, representing purely conductive objects, an aluminum sheet of area 2 × 2 cm(2) . Of 958 patients, 165 had foreign bodies of unknown nature. MID was able to detect those with ferromagnetic and/or conducting properties based on fluctuations in the magnetic and eddy current signals versus control. CONCLUSION: The high sensitivity of MID makes it suitable for assessing the ferromagnetic/conductive properties of metallic foreign objects embedded within the body of patients scheduled for MRI.