Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia

International Center for Transplantation in Thalassemia and Sickle Cell Anemia-Mediterranean Institute of Hematology, Policlinic of the University of Rome Tor Vergata, Tor Vergata, Italy.
Cold Spring Harbor Perspectives in Medicine (Impact Factor: 9.47). 05/2012; 2(5):a011825. DOI: 10.1101/cshperspect.a011825
Source: PubMed


The globally widespread single-gene disorders β-thalassemia and sickle cell anemia (SCA) can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT treatment of thalassemia has substantially improved over the last two decades, with advancements in preventive strategies, control of transplant-related complications, and preparative regimens. A risk class-based transplantation approach results in disease-free survival probabilities of 90%, 84%, and 78% for class 1, 2, and 3 thalassemia patients, respectively. Because of disease advancement, adult thalassemia patients have a higher risk for transplant-related toxicity and a 65% cure rate. Patients without matched donors could benefit from haploidentical mother-to-child transplantation. There is a high cure rate for children with SCA who receive HSCT following myeloablative conditioning protocols. Novel non-myeloablative transplantation protocols could make HSCT available to adult SCA patients who were previously excluded from allogeneic stem cell transplantation.

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    • "Normal homeostasis of the erythropoietic system requires an appropriate balance between the rate of erythroid cell production and red blood cell destruction. Growing evidence indicates that apoptotic mechanisms play a relevant role in the control of erythropoiesis under physiologic and pathologic conditions.10 Death receptors of the TNF receptor superfamilies (Fas-Ligand (Fas-L), TNF-α, TRAIL) activate the extrinsic apoptotic pathway. "
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    ABSTRACT: Background and Purpose Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for sickle cell anemia (SCA). We report our experience with transplantation in children with the Black African variant of SCA and the effects of transplant on erythroid compartment in bone marrow (BM). Patients and methods Twenty-seven consecutive patients who underwent BM transplantation from HLA-identical donors following a myeloablative conditioning regimen were included. Using both CD71 and FSC parameters, we obtained three erythroid populations: EryA–C. Ery A (CD71high FSChigh) are basophilic; Ery B (CD71high FSClow) are late basophilic and polychromatic; and Ery C (CD71low FSClow) are orthochromatic erythroblasts and reticulocytes. To analyze the effect of transplantation on intramedullary apoptosis, we studied Fas (CD95+) and caspase-3 expression in erythroblast subpopulations. Results All patients experienced sustained engraftment, and all surviving patients remained free of SCA-related events after transplantation. The erythroid population showed expansion in the BM at baseline. After transplant, levels decreased, especially of Ery C, in parallel to reduced Fas expression and an initial caspase 3 increase in erythroid population, similar to reported later steps of “normal” erythroid maturation. Conclusions The results suggest a good chance of cure for children with SCA, with an excellent survival rate. We also observed “normalization” of erythroid populations in parallel with a decreased intramedullary apoptosis rate, suggesting normal erythroid maturation in ex-SCA patients after HSCT.
    Mediterranean Journal of Hematology and Infectious Diseases 01/2014; 6(1):e2014054. DOI:10.4084/MJHID.2014.054
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    ABSTRACT: ABSTRACT : Though the field has moved with glacial speed, gene therapies have been carried out successfully in patients with bone marrow disorders including immune deficiencies. The field may be poised to move forward more rapidly, but many barriers have yet to be surmounted.
    Genome Medicine 02/2009; 1(4):38. DOI:10.1186/gm38 · 5.34 Impact Factor
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    ABSTRACT: β-thalassemias are a heterogeneous group of monogeneic disorders affecting the β-globin chain synthesis. They are caused by more than 200 mutations, which result in reduced or no β-globin chain synthesis. As a consequence, there is excess of α-globin molecules precipitating in red blood precursors, leading to impaired erythrocyte maturation, mechanical damage and ultimately to apoptosis. Current therapeutic approaches include blood transfusions, often combined with iron chelation and splenectomy, while the only so far definite treatment is that of HLA-matched hematopoietic stem cells transplantation. Multiple side-effects from regular blood transfusions, such as iron accumulation in vital organs, as well as the reduced number of HLA-matched donors, has pointed towards the need of alternative treatments, such as gene therapy. The major breakthrough in β-thalassemia gene therapy occurred a decade ago with the development of globin lentiviral vectors, employed to deliver the therapeutic transgene, while the first proof that gene therapy can be curative came only recently from France, where a 18-year old thalassemic patient became transfusion independent, following bone marrow transplantation of lentivirally transduced hematopoietic stem cells. Moreover, the emergence of new ‘key players’ in globin switching control and HbF expression, such as BCL11A and KLF1, and the evolutionary discovery of induced pluripotent stem cells are quite promising tools towards more effective gene therapy strategies.
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