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Emerging Therapies and Strategies in Thalassemia: Toward a New Era...
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Emerging Therapies and Strategies in Thalassemia: Toward a New Era in Management

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 16470

Special Issue Editors

Dr. Paolo Ricchi

E-Mail Website
Guest Editor
Center for Rare Red Blood Cell Diseases, AORN A. Cardarelli, Naples, Italy
Interests: thalassemias; hemoglobinopathies; iron chelation therapy; cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Gian Luca Forni

E-Mail Website
Guest Editor
Center for Congenital Anemias and Iron Dysmetabolism, Galliera Hospital, Genoa, Italy
Interests: thalassemias; haemoglobinopathies; congenital anemias; iron overload; hemochromatosis

Special Issue Information

Dear Colleagues,

Until a few years ago, HSCT was the only cure able to modify natural history of thalassaemia syndromes; nevertheless, survival and quality of life in patients with thalassaemia have been significantly improved with standard therapies comprising red blood cells transfusion and iron chelation, which represent a longstanding approach. On the other hand, aging and increase in life expectancy is disclosing a complex scenario of multiple disease-related morbidities, including osteoporosis, endocrine disorders, liver disease, renal dysfunction, and cancer. Therefore, new strategies are needed to achieve further control in disease burden. Looking at pathophysiological mechanisms of beta-thalassaemia, new drugs able to ameliorate globin synthesis reducing ineffective erythropoiesis, chain imbalance and iron overload, have been tested for a few years now. Furthermore, considering standard treatments, there is still the need to provide more strength of scientific evidence with long-term prospective observations or, if possible, with randomized trials. Similarly, to correctly manage the wide spectrum of thalassemia syndromes, biomarkers able to assess preventive and curative treatments in selected populations at increased risk of developing complications and to correctly evaluate interventional procedures in a homogeneous population are also needed.

This Special Issue on “Emerging Therapies and Strategies in Thalassaemia: Toward a New Era in management” aims to update researchers and clinicians by going over the main points that could represent a remarkable therapeutic advance or improvement in the management made recently in the field of thalassaemia syndromes.

Dr. Paolo Ricchi
Dr. Gian Luca Forni
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HSCT
  • Gene therapy
  • New drugs
  • Iron chelation
  • Aging
  • Long-term observation
  • Biomarkers
  • New strategies

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Published Papers (7 papers)

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Editorial

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2 pages, 176 KiB  
Editorial
Special Issue: “Emerging Therapies and Strategies in Thalassemia: Toward a New Era in Management”
by Paolo Ricchi and Gian Luca Forni
J. Clin. Med. 2022, 11(17), 5175; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11175175 - 01 Sep 2022
Viewed by 788
Abstract
This Special Issue on “Emerging Therapies and Strategies in Thalassemia: Toward a New Era in management” aims to update researchers and clinicians regarding the field of thalassemia syndromes [...] Full article
(This article belongs to the Special Issue Emerging Therapies and Strategies in Thalassemia: Toward a New Era in Management)

Research

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11 pages, 728 KiB  
Article
Safety and Efficacy of the New Combination Iron Chelation Regimens in Patients with Transfusion-Dependent Thalassemia and Severe Iron Overload
by Raffaella Origa, Monia Cinus, Maria Paola Pilia, Barbara Gianesin, Antonietta Zappu, Valeria Orecchia, Maria Grazia Clemente, Carla Pitturru, Anna Rita Denotti, Francesco Corongiu, Simona Piras and Susanna Barella
J. Clin. Med. 2022, 11(7), 2010; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11072010 - 03 Apr 2022
Cited by 8 | Viewed by 2476
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Emerging Therapies and Strategies in Thalassemia: Toward a New Era in Management)
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12 pages, 853 KiB  
Article
Setting for “Normal” Serum Ferritin Levels in Patients with Transfusion-Dependent Thalassemia: Our Current Strategy
by Anna Spasiano, Antonella Meloni, Silvia Costantini, Emilio Quaia, Filippo Cademartiri, Patrizia Cinque, Alessia Pepe and Paolo Ricchi
J. Clin. Med. 2021, 10(24), 5985; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10245985 - 20 Dec 2021
Cited by 7 | Viewed by 1969
Abstract
This cross-sectional study aimed to establish the association between serum ferritin levels and organ iron overload (IO) and overall morbidity in transfusion-dependent thalassemia (TDT) patients. One hundred and three TDT patients (40.03 ± 9.15 years; 57.3% females) with serum ferritin < 2500 ng/mL [...] Read more.
This cross-sectional study aimed to establish the association between serum ferritin levels and organ iron overload (IO) and overall morbidity in transfusion-dependent thalassemia (TDT) patients. One hundred and three TDT patients (40.03 ± 9.15 years; 57.3% females) with serum ferritin < 2500 ng/mL were included. IO was assessed by T2* magnetic resonance imaging. Three groups were identified based on mean serum ferritin levels: <500 ng/mL (group 0; N = 32), 500–1000 ng/mL (group 1; N = 43), and 1000–2500 ng/mL (group 2; N = 28). All demographic and biochemical parameters were comparable among the three groups, with the exception of the triglycerides being significantly lower in group 0 than in group 2. No difference was found in the frequency of hepatic, endocrine, and cardiac complications. Hepatic IO was significantly less frequent in group 0 versus both groups 1 and 2. No patient with a serum ferritin level < 500 ng/mL had significant myocardial IO and alterations in the main hematological parameters. No difference in the distribution of the different chelation regimens was found. Serum ferritin < 500 ng/mL appears to be achievable and safe for several TDT patients. This target is associated with the absence of significant cardiac iron and significantly lower hepatic IO and triglycerides that are well-demonstrated markers for cardiac and liver complications. Full article
(This article belongs to the Special Issue Emerging Therapies and Strategies in Thalassemia: Toward a New Era in Management)
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15 pages, 1090 KiB  
Article
The Link of Pancreatic Iron with Glucose Metabolism and Cardiac Iron in Thalassemia Intermedia: A Large, Multicenter Observational Study
by Antonella Meloni, Laura Pistoia, Maria Rita Gamberini, Paolo Ricchi, Valerio Cecinati, Francesco Sorrentino, Liana Cuccia, Massimo Allò, Riccardo Righi, Priscilla Fina, Ada Riva, Stefania Renne, Giuseppe Peritore, Stefano Dalmiani, Vincenzo Positano, Emilio Quaia, Filippo Cademartiri and Alessia Pepe
J. Clin. Med. 2021, 10(23), 5561; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10235561 - 26 Nov 2021
Cited by 12 | Viewed by 1850
Abstract
In thalassemia major, pancreatic iron was demonstrated as a powerful predictor not only for the alterations of glucose metabolism but also for cardiac iron, fibrosis, and complications, supporting a profound link between pancreatic iron and heart disease. We determined for the first time [...] Read more.
In thalassemia major, pancreatic iron was demonstrated as a powerful predictor not only for the alterations of glucose metabolism but also for cardiac iron, fibrosis, and complications, supporting a profound link between pancreatic iron and heart disease. We determined for the first time the prevalence of pancreatic iron overload (IO) in thalassemia intermedia (TI) and systematically explored the link between pancreas T2* values and glucose metabolism and cardiac outcomes. We considered 221 beta-TI patients (53.2% females, 42.95 ± 13.74 years) consecutively enrolled in the Extension–Myocardial Iron Overload in Thalassemia project. Magnetic Resonance Imaging was used to quantify IO (T2* technique) and biventricular function and to detect replacement myocardial fibrosis. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Pancreatic IO was more frequent in regularly transfused (N = 145) than in nontransfused patients (67.6% vs. 31.6%; p < 0.0001). In the regular transfused group, splenectomy and hepatitis C virus infection were both associated with high pancreatic siderosis. Patients with normal glucose metabolism showed significantly higher global pancreas T2* values than patients with altered OGTT. A pancreas T2* < 17.9 ms predicted an abnormal OGTT. A normal pancreas T2* value showed a 100% negative predictive value for cardiac iron. Pancreas T2* values were not associated to biventricular function, replacement myocardial fibrosis, or cardiac complications. Our findings suggest that in the presence of pancreatic IO, it would be prudent to initiate or intensify iron chelation therapy to prospectively prevent both disturbances of glucose metabolism and cardiac iron accumulation. Full article
(This article belongs to the Special Issue Emerging Therapies and Strategies in Thalassemia: Toward a New Era in Management)
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Review

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12 pages, 1004 KiB  
Review
Does Hepcidin Tuning Have a Role among Emerging Treatments for Thalassemia?
by Filomena Longo and Antonio Piga
J. Clin. Med. 2022, 11(17), 5119; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11175119 - 30 Aug 2022
Cited by 4 | Viewed by 2705
Abstract
The treatments available for thalassemia are rapidly evolving, with major advances made in gene therapy and the modulation of erythropoiesis. The latter includes the therapeutic potential of hepcidin tuning. In thalassemia, hepcidin is significantly depressed, and any rise in hepcidin function has a [...] Read more.
The treatments available for thalassemia are rapidly evolving, with major advances made in gene therapy and the modulation of erythropoiesis. The latter includes the therapeutic potential of hepcidin tuning. In thalassemia, hepcidin is significantly depressed, and any rise in hepcidin function has a positive effect on both iron metabolism and erythropoiesis. Synthetic hepcidin and hepcidin mimetics have been developed to the stage of clinical trials. However, they have failed to produce an acceptable efficacy/safety profile. It seems difficult to avoid iron over-restricted erythropoiesis when directly using hepcidin as a drug. Indirect approaches, each one with their advantages and disadvantages, are many and in full development. The ideal approach is to target erythroferrone, the main inhibitor of hepcidin expression, the plasma concentrations of which are greatly increased in iron-loading anemias. Potential means of improving hepcidin function in thalassemia also include acting on TMPRSS6, TfR1, TfR2 or ferroportin, the target of hepcidin. Only having a better understanding of the crosslinks between iron metabolism and erythropoiesis will elucidate the best single option. In the meantime, many potential combinations are currently being explored in preclinical studies. Any long-term clinical study on this approach should include the wide monitoring of functions, as the effects of hepcidin and its modulators are not limited to iron metabolism and erythropoiesis. It is likely that some of the aspects of hepcidin tuning described briefly in this review will play a role in the future treatment of thalassemia. Full article
(This article belongs to the Special Issue Emerging Therapies and Strategies in Thalassemia: Toward a New Era in Management)
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14 pages, 303 KiB  
Review
Hearing Loss in Beta-Thalassemia: Systematic Review
by Immacolata Tartaglione, Roberta Carfora, Davide Brotto, Maria Rosaria Barillari, Giuseppe Costa, Silverio Perrotta and Renzo Manara
J. Clin. Med. 2022, 11(1), 102; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11010102 - 25 Dec 2021
Cited by 10 | Viewed by 3283
Abstract
In the last half century, the life expectancy of beta-thalassemia patients has strikingly increased mostly due to regular blood transfusions and chelation treatments. The improved survival, however, has allowed for the emergence of comorbidities, such as hearing loss, with a non-negligible impact on [...] Read more.
In the last half century, the life expectancy of beta-thalassemia patients has strikingly increased mostly due to regular blood transfusions and chelation treatments. The improved survival, however, has allowed for the emergence of comorbidities, such as hearing loss, with a non-negligible impact on the patients’ quality of life. This thorough review analyzes the acquired knowledge regarding hearing impairment in this hereditary hemoglobinopathy, aiming at defining its prevalence, features, course, and possible disease- or treatment-related pathogenic factors. Following PRISMA criteria, we retrieved 60 studies published between 1979 and 2021. Diagnostic tools and criteria, forms of hearing impairment, correlations with beta-thalassemia phenotypes, age and sex, chelation treatment and laboratory findings including iron overload, were carefully searched, analyzed and summarized. In spite of the relatively high number of studies in the last 40 years, our knowledge is rather limited, and large prospective studies with homogeneous diagnostic tools and criteria are required to define all the aforementioned issues. According to the literature, the overall prevalence rate of hearing impairment is 32.3%; age, sex, and laboratory findings do not seem to correlate with hearing deficits, while the weak relationship with clinical phenotype and chelation treatment seems to highlight the presence of further yet to be identified pathogenic factors. Full article
(This article belongs to the Special Issue Emerging Therapies and Strategies in Thalassemia: Toward a New Era in Management)

Other

43 pages, 927 KiB  
Opinion
Good Clinical Practice of the Italian Society of Thalassemia and Haemoglobinopathies (SITE) for the Management of Endocrine Complications in Patients with Haemoglobinopathies
by Maddalena Casale, Marina Itala Baldini, Patrizia Del Monte, Antonia Gigante, Anna Grandone, Raffaella Origa, Maurizio Poggi, Franco Gadda, Rosalba Lai, Monia Marchetti and Gian Luca Forni
J. Clin. Med. 2022, 11(7), 1826; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11071826 - 25 Mar 2022
Cited by 4 | Viewed by 2316
Abstract
Background: The treatment of endocrinopathies in haemoglobinopathies is a continually expanding research area; therefore, recommendations supporting the appropriateness of treatments are a pressing need for the medical community. Methods: The Management Committee of SITE selected and gathered a multidisciplinary and multi-professional team, including [...] Read more.
Background: The treatment of endocrinopathies in haemoglobinopathies is a continually expanding research area; therefore, recommendations supporting the appropriateness of treatments are a pressing need for the medical community. Methods: The Management Committee of SITE selected and gathered a multidisciplinary and multi-professional team, including experts in haemoglobinopathies and experts in endocrinopathies, who have been flanked by experts with methodological and organizational expertise, in order to formulate recommendations based on the available scientific evidence integrated by personal clinical experience. The project followed the systematic approach for the production of clinical practice guidelines according to the methodology suggested by the National Center for Clinical Excellence, Quality and Safety of Care (CNEC). Results: Out of 14 topics, 100 clinical questions were addressed, and 206 recommendations were elaborated on. The strength of recommendations, panel agreement, a short general description of the topic, and the interpretation of evidence were reported. Conclusions: Good Practice Recommendations are the final outcome of translational research and allow one to transfer to the daily clinical practice of endocrine complications in haemoglobinopathies. Full article
(This article belongs to the Special Issue Emerging Therapies and Strategies in Thalassemia: Toward a New Era in Management)
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