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β-Thalassemia: evolving treatment options beyond transfusion and iron chelation.
Langer, AL, Esrick, EB
Hematology. American Society of Hematology. Education Program. 2021;(1):600-606
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Abstract
After years of reliance on transfusion alone to address anemia and suppress ineffective erythropoiesis in β-thalassemia, many new therapies are now in development. Luspatercept, a transforming growth factor-β inhibitor, has demonstrated efficacy in reducing ineffective erythropoiesis, improving anemia, and possibly reducing iron loading. However, many patients do not respond to luspatercept, so additional therapeutics are needed. Several medications in development aim to induce hemoglobin F (HbF): sirolimus, benserazide, and IMR-687 (a phosphodiesterase 9 inhibitor). Another group of agents seeks to ameliorate ineffective erythropoiesis and improve anemia by targeting abnormal iron metabolism in thalassemia: apotransferrin, VIT-2763 (a ferroportin inhibitor), PTG-300 (a hepcidin mimetic), and an erythroferrone antibody in early development. Mitapivat, a pyruvate kinase activator, represents a unique mechanism to mitigate ineffective erythropoiesis. Genetically modified autologous hematopoietic stem cell transplantation offers the potential for lifelong transfusion independence. Through a gene addition approach, lentiviral vectors have been used to introduce a β-globin gene into autologous hematopoietic stem cells. One such product, betibeglogene autotemcel (beti-cel), has reached phase 3 trials with promising results. In addition, 2 gene editing techniques (CRISPR-Cas9 and zinc-finger nucleases) are under investigation as a means to silence BCL11A to induce HbF with agents designated CTX001 and ST-400, respectively. Results from the many clinical trials for these agents will yield results in the next few years, which may end the era of relying on transfusion alone as the mainstay of thalassemia therapy.
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How I manage medical complications of β-thalassemia in adults.
Taher, AT, Cappellini, MD
Blood. 2018;(17):1781-1791
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Abstract
The complex pathophysiology in β-thalassemia can translate to multiple morbidities that affect every organ system. Improved survival due to advances in management means that patients are exposed to the harmful effects of ineffective erythropoiesis, anemia, and iron overload for a longer duration, and we started seeing new or more frequent complications in adult compared with younger patients. In this article, we highlight particular aspects of managing adult patients with β-thalassemia, using our own experience in treating such patients. We cover both transfusion-dependent and nontransfusion-dependent forms of the disease and tackle specific morbidities of highest interest.
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Iron Overload Leading to Torsades de Pointes in β-Thalassemia and Long QT Syndrome.
Refaat, MM, El Hage, L, Steffensen, AB, Hotait, M, Schmitt, N, Scheinman, M, Badhwar, N
Cardiac electrophysiology clinics. 2016;(1):247-56
Abstract
The authors present a unique case of torsades de pointes in a β-thalassemia patient with early iron overload in the absence of any structural abnormalities as seen in hemochromatosis. Genetic testing showed a novel KCNQ1 gene mutation 1591C>T [Gln531Ter(X)]. Testing of the gene mutation in Xenopus laevis oocytes showed loss of function of the IKs current. The authors hypothesize that iron overload combined with the KCNQ1 gene mutation leads to prolongation of QTc and torsades de pointes.
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Hepatocellular carcinoma in hepatitis-negative patients with thalassemia intermedia: a closer look at the role of siderosis.
Maakaron, JE, Cappellini, MD, Graziadei, G, Ayache, JB, Taher, AT
Annals of hepatology. 2013;(1):142-6
Abstract
Patients with thalassemia are often exposed to several risk factors for developing hepatocellular carcinoma (HCC) due to their repeated transfusions. However, even transfusion-independent patients with thalassemia intermedia (TI) can develop HCC, which is mainly attributed to a state of iron overload. We report here two cases and review the literature for the association between TI and HCC. Along with our cases, a total of 36 cases of HCC in thalassemic patients were reported in the literature. Of these, 22 (61%) were TI patients with 6 (27%) of them being hepatitis B and C negative. There was no consistency in their characteristics; therefore, we recommended screening thresholds for HCC in TI patients based on their total liver iron concentration (LIC).
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[Unusual aspect of pernicious anemia during association of beta-thalassemia: a new case report and literature review].
Diop, MM, Toure, PS, Leye, MY, Leye, A, El Fadjri, S, Diop, M, Ka, MM, Diop, OD, Fall, S, Ndiaye, FS
Le Mali medical. 2012;(1):71-2
Abstract
Pernicious anemia appears classically by macrocytosis. We report a case of a late discovered Biermer disease, on a 42-year-old young black woman. The reason was an unusual aspect of this disease in a context of betathalassemia. The patient presented chronic anemia which evolved during about ten year. Biology showed a normocytosis and signs of hemolysis according to beta-thalassemia. This was confirmed by an electrophoresis showing 9.1 % of fraction F some haemoglobin. Since this date, the patient was treated by folic acid alone with periodic transfusions of red blood cell. She presented eight years after the beginning of her disease, neurological deterioration. Diagnosis of pernicious anemia was finally established up on histological gastritis, low level of the blood rate of vitamin B12, macrocytosis, and presence of intrinsic anti-factor and parietal anti-cells antibodies.
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Deferiprone-related arthropathy of the knee in a thalassemic patient: report of a case and review of the literature.
Vlachaki, E, Tselios, K, Perifanis, V, Tsatra, I, Tsayas, I
Clinical rheumatology. 2008;(11):1459-61
Abstract
Deferiprone (DFP), the first oral iron chelator, has been used in patients with beta-thalassemia major to reduce serum ferritin levels and total iron burden, leading to decreased cardiac iron levels. Major side effects include embryotoxicity, agranulocytosis, zinc deficiency and gastrointestinal disorders, while arthropathy is rarely reported. Herein, we present a 29-year-old male patient with beta-thalassemia major, who developed severe arthritis of both knees while under deferiprone therapy. Arthritis was managed successfully with non-steroid antiinflammatory drugs after DFP withdrawal.