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.

Successful treatment with MEK-inhibitor in a patient with NRAS-related cutaneous skeletal hypophosphatemia syndrome.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is caused by somatic mosaic NRAS variants and characterized by melanocytic/sebaceous naevi, eye, and brain malformations, and FGF23-mediated hypophosphatemic rickets. The MEK inhibitor Trametinib, acting on the RAS/MAPK pathway, is a candidate for CSHS therapy. A 4-year-old boy with seborrheic nevus, eye choristoma, multiple hamartomas, brain malformation, pleural lymphangioma and chylothorax developed severe hypophosphatemic rickets unresponsive to phosphate supplementation. The c.182A > G;p.(Gln61Arg) somatic NRAS variant found in DNA from nevus biopsy allowed diagnosing CSHS. We administered Trametinib for 15 months investigating the transcriptional effects at different time points by whole blood RNA-seq. Treatment resulted in prompt normalization of phosphatemia and phosphaturia, catch-up growth, chylothorax regression, improvement of bone mineral density, reduction of epidermal nevus and hamartomas. Global RNA sequencing on peripheral blood mononucleate cells showed transcriptional changes under MEK inhibition consisting in a strong sustained downregulation of signatures related to RAS/MAPK, PI3 kinase, WNT and YAP/TAZ pathways, reverting previously defined transcriptomic signatures. CSHS was effectively treated with a MEK inhibitor with almost complete recovery of rickets and partial regression of the phenotype. We identified "core" genes modulated by MEK inhibition potentially serving as surrogate markers of Trametinib action.

Myocardial longitudinal strain as the first herald of cardiac impairment in very early iron overload state: an echocardiography and biosusceptometry study on beta-thalassemia patients.

BACKGROUND: Heart diseases due to iron overload are still the main cause of mortality in patients affected by beta-thalassemia. Detection of cardiac iron overload in pre-clinical stage allows tailoring of chelation therapy and follow-up strategies. Echocardiographic longitudinal strain analysis may be a useful tool for early detection of cardiac functional impairment iron-related. METHODS: We examined 58 patients with beta-thalassemia on regular blood transfusion and iron chelation, without overt cardiac disease who had recent Biosusceptometry SQUID to quantify liver iron concentration and cardiac assessment by CMR T2*. RESULTS: Average global longitudinal strain (GLS) was able to identify abnormal (<20 ms) cardiac T2* values with 96% specificity and negative predictive value of 92% (AUC 0.84, P=0.01). Apical 4-ch GLS may help identify early longitudinal impairment associated with severe liver iron overload with 96% specificity and negative predictive value of 92% (AUC 0.84, P=0.02). Patients with severe liver iron overload had lower average Global Longitudinal Strain values compared to other patients (P-value =0.005). CONCLUSION: GLS was a sensitive marker to detect both myocardial and liver iron overload in a population that is still free from cardiac symptoms. Thus, strain echocardiography may be a useful tool for early detection of iron overload in Beta-thalassemia.

Pharmacological and clinical evaluation of deferasirox formulations for treatment tailoring.

Deferasirox (DFX) is the newest among three different chelators available to treat iron overload in iron-loading anaemias, firstly released as Dispersible Tablets (DT) and more recently replaced by Film-Coated Tablets (FCT). In this retrospective observational study, pharmacokinetics, pharmacodynamics, and safety features of DFX treatment were analyzed in 74 patients that took both formulations subsequently under clinical practice conditions. Bioavailability of DFX FCT compared to DT resulted higher than expected [Cmax: 99.5 (FCT) and 69.7 (DT) µMol/L; AUC: 1278 (FCT) and 846 (DT), P < 0.0001]. DFX FCT was also superior in scalability among doses. After one year of treatment for each formulation, no differences were observed between the treatments in the overall iron overload levels; however, DFX FCT but not DT showed a significant dose-response correlation [Spearman r (dose-serum ferritin variation): - 0.54, P < 0.0001]. Despite being administered at different dosages, the long-term safety profile was not different between formulations: a significant increase in renal impairment risk was observed for both treatments and it was reversible under strict monitoring (P < 0.002). Altogether, these data constitute a comprehensive comparison of DFX formulations in thalassaemia and other iron-loading anaemias, confirming the effectiveness and safety characteristics of DFX and its applicability for treatment tailoring.

The Influence of Cardiovascular Risk Factors and Hypogonadism on Cardiac Outcomes in an Aging Population of Beta-Thalassemia Patients.

Beta-thalassemia major (ß-TM) is a hereditary genetic disease worsened by many comorbidities due to transfusion-related iron despite chelation therapy. Since there has recently been an increase in life expectancy of patients to up to 50 years old, which influences the prevalence of these diseases and the time span for traditional cardiovascular risk factors to play their role, this study aims to evaluate their distribution and prevalence in a population of thalassemia major patients and their relationship with observed cardiovascular events and potential modifying factors. One hundred and fifty-nine ß-TM patients with at least 15 years of follow-up were included in this study. The mean age was 40.9 ± 8.4 years; 28% had diabetes mellitus and 62% had hypogonadism. The cardiovascular risk assessed using algorithms (CUORE and Pooled Cohort Risk Equation-PCRE) was low, but 3.8% of patients had at least one episode of heart failure, 35.9% showed early signs of heart failure, 22% received a diagnosis of diastolic dysfunction, and 21.4% showed supraventricular arrhythmias. Hypogonadism was shown to be related to the occurrence of cardiovascular events. The chronic accumulation of iron in the heart and the specific metabolic profile, mainly observed in patients with hypogonadism, allows us to define ß-TM as a condition with a high level of cardiovascular risk from many points of view (iron-related myopathy, atherosclerosis and arrhythmias), which requires better stratification tools and a specific follow-up program.