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.

'Phenoconversion' in adult patients with ß-thalassemia.

Rate and risk factors for phenoconversion from non-transfusion-dependent ß-thalassemia (NTDT) to transfusion-dependent ß-thalassemia (TDT) during a 10-year follow up of adult patients in Italy.

Health-Related Quality-of-Life Profile of Pediatric Patients with ß Thalassemia after Hematopoietic Stem Cell Transplantation.

Matched hematopoietic stem cell transplantation (HSCT) is a feasible and curative treatment in pediatric patients with beta thalassemia major (ß-TM). However, little data are available regarding patients and their parents' health-related quality of life (HRQoL) after the procedure. As such, we investigated the HRQoL of pediatric patients with ß-TM after HSCT compared to that of patients treated with blood transfusions and iron chelation. The health-related quality of life of 43 ß-TM pediatric patients and 43 parents were evaluated using the Pediatric Quality of Life Inventory (PedsQL). A total of 25 patients underwent HSCT: 15 from a sibling and 10 from an HLA-matched donor. The median follow-up time from HSCT was 5 years (range 1-13 years). The mean ages at the survey were 10.1 years (range 5-15) and 9.6 years (range 5-15) for transfused and transplanted patients, respectively. A significant reduction in HRQoL was reported in the group of transfused patients compared with that of patients transplanted in the following PedsQL domains: children's and parents' physical functions, Δ = -15.4, p = 0.009 and Δ = -11.3, p = 0.002, respectively; children's and parents' emotional functioning, Δ = -15.2, p = 0.026 and Δ = -15.2, p = 0.045, respectively; child's and parents' school functioning, Δ = -25, p = 0.005 and Δ = -22.5, p = 0.011, respectively; total child and parents scores, Δ = -14.5, p = 0.004 and Δ = -13.2, p = 0.005, respectively. The results of a multivariable analysis showed that the HSCT procedure was significantly associated with a higher total child PedsQL score (adjusted mean difference = 15.3, p = 0.001) and a higher total parent PedsQL score (adjusted mean difference = 14.1, p = 0.006). We found no significant difference in the HRQoL measured after sibling or unrelated human leukocyte antigen (HLA)-matched HSCT. Finally, a significant positive correlation across all the PedsQL domains was found between the scores reported by the children and those reported by their parents. In conclusion, our study shows that HSCT in pediatric patients with ß-TM is associated with a good overall HRQoL profile. This information further supports physicians when counseling patients and their parents before the HSCT procedure.

Long-Term Health-Related Quality of Life and Clinical Outcomes in Patients with ß-Thalassemia after Splenectomy.

Few data are available on the efficacy and safety of splenectomy in patients with transfusion-dependent Beta-Thalassemia Major (ß-TM) and on its impact on a patient's health-related quality of life (HRQoL). We examined the long-term HRQoL of adult patients with ß-TM in comparison with those treated with medical therapy by using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). We also evaluated the safety and efficacy of splenectomy. Overall, 114 patients with a median age of 41 years (range 18-62) were enrolled in this cross-sectional study. Twenty-nine patients underwent splenectomy (25.4%) at a median age of 12 years (range 1-32). The median follow-up after splenectomy was 42 years (range 6-55). No statistically significant differences were observed in any of the scales of the SF-36 between splenectomized and not-splenectomized patients. The majority of surgical procedures (96.6%) were approached with open splenectomy. Post-splenectomy complications were reported in eight patients (27.5%): four overwhelming infections, three with pulmonary hypertension, and one with thrombosis. A significantly higher prevalence of cardiovascular comorbidities (58.6 vs. 21.2%, p < 0.001) and diabetes (17.2 vs. 3.5%, p = 0.013) was observed in splenectomized patients. These patients, however, required fewer red blood cell units per month, with only 27.6% of them transfusing more than 1 unit per month, compared with 72.9% of the not-splenectomized group. Overall, our data suggest that physicians should carefully consider splenectomy as a possible treatment option in patients with ß-TM.

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.

First and Second Level Haemoglobinopathies Diagnosis: Best Practices of the Italian Society of Thalassemia and Haemoglobinopathies (SITE).

The purpose of this best practice paper is to review the current recommendations for the identification and prenatal diagnosis of hemoglobinopathies. METHODS: The management committee of SITE selected and gathered a multidisciplinary team in order to formulate recommendations based on the available scientific evidence integrated with the opinions of experts, with the purpose of supporting clinicians. RESULTS: We provide recommendations for first level tests (complete blood count, hemoglobin separation and iron balance), second level tests (molecular diagnosis) and prenatal diagnosis. Five Italian experts in hemoglobinopathies were consulted regarding the orientation of prenatal diagnosis, and for each indication, the degree of agreement among the experts has been specified. CONCLUSIONS: Best practice recommendations are the final outcome of this translational research and allow transfer to daily clinical practice.

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.

Thalassaemia is paradoxically associated with a reduced risk of in-hospital complications and mortality in COVID-19: Data from an international registry.

Although numerous patient-specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalassaemic syndromes in COVID-19 patients remains poorly understood. We studied the outcomes of 137 COVID-19 patients with a history of transfusion-dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all-cause mortality. The presence of thalassaemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models.

Delta-globin gene expression improves sickle cell disease in a humanised mouse model.

Sickle cell disease (SCD) is a widespread genetic disease associated with severe disability and multi-organ damage, resulting in a reduced life expectancy. None of the existing clinical treatments provide a solution for all patients. Gene therapy and fetal haemoglobin (HbF) reactivation through genetic approaches have obtained promising, but early, results in patients. Furthermore, the search for active molecules to increase HbF is still ongoing. The delta-globin gene produces the delta-globin of haemoglobin A2 (HbA2). Although expressed at a low level, HbA2 is fully functional and could be a valid anti-sickling agent in SCD. To evaluate the therapeutic potential of a strategy aimed to over-express the delta-globin gene in vivo, we crossed transgenic mice carrying a single copy of the delta-globin gene, genetically modified to be expressed at a higher level (activated), with a humanised mouse model of SCD. The activated delta-globin gene gives rise to a consistent production of HbA2, effectively improving the SCD phenotype. For the first time in vivo, these results demonstrate the therapeutic potential of delta-globin, which could lead to novel approaches to the cure of SCD.

Changing patterns of thalassaemia in Italy: a WebThal perspective.

BACKGROUND: Migration has impacted the spread of thalassaemia which is gradually becoming a global health problem. Italy, with an approximate estimation of 7,000 patients, does not have an accurate national record for haemoglobinopathies. This cross-sectional evaluation includes data for approximately 50% of beta-thalassaemia patients in Italy to provide an overview of the burden of thalassaemia syndromes. MATERIALS AND METHODS: The analysis included data on epidemiology, transfusions and clinical parameters from 3,986 thalassaemia patients treated at 36 centres in Italy who were alive on 31st December 2017. The study used WebThal, a computerised clinical record that is completely free-of-charge and that does not have any mandatory fields to be filled. RESULTS: For patients with thalassaemia major, 68% were aged ≥35 years and 11% were aged ≤18 years. Patients with thalassaemia intermedia were slightly older. Transfusion data, reported in a subgroup of 1,162 patients, showed 9% had pre-transfusion haemoglobin <9 g/dL, 63% had levels between ≥9 and <10 g/dL, and 28% had levels ≥10 g/dL. These 1,162 patients underwent 22,272 transfusion days during 2017, with a mean of 19 transfusion days/year/patient (range 1-54 days). Severity of iron overload was reported in 756 patients; many had moderate or mild liver iron load (74% had liver iron <7.5 mg/g dry weight). In the same cohort, 85% of patients had no signs of cardiac iron load (MRT2* >20 ms), and only 3% showed signs of high-risk heart condition (T2* <10 ms). Most patients had normal alanine amino transferase levels due to treatment with the new anti-hepatitis C virus (HCV) drugs. DISCUSSION: This study provides an overview of the current health status of patients with thalassaemia in Italy. Moreover, these data support the need for a national comprehensive thalassaemia registry.