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Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide and is associated with substantial morbidity, high health care utilization, and premature mortality. Although hydroxyurea (HU), chronic blood transfusions, and L-glutamine decrease SCD-associated complications, they do not eliminate them and thus need to be continued indefinitely. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only currently available curative option for patients with SCD. Disease-free survival (DFS) in children and young adults with SCD is >95% after a myeloablative regimen using a human leukocyte antigen (HLA)-matched sibling donor. Mixed donor chimerism with ≥20% donor myeloid cells is associated with predominant donor-derived erythropoiesis due to normal donor red blood cell (RBC) survival compared to the ineffective erythropoiesis of SCD. Thus, reduced-intensity conditioning (RIC) and nonmyeloablative conditioning appear efficacious and safe for adults with an HLA-identical sibling donor who may otherwise be unable to tolerate myeloablative conditioning. HSCT is still largely underused in part due to the lack of available matched donors for patients with SCD and concerns about morbidity and mortality from transplantation conditioning, graft-versus-host disease (GVHD), and graft rejection. Approaches to improve the safety, efficacy, and applicability of HSCT for SCD that are currently being tested in clinical trials include novel low-intensity conditioning, novel graft manipulation techniques to reduce the risk of GVHD, novel strategies for GVHD prophylaxis, and the use of alternate sources of hematopoietic progenitor cells including HLA-haploidentical donors (matched at 50% of HLA alleles), umbilical cord blood (UCB), and matched unrelated donors. Simultaneously, significant advances in gene therapy suggest that a universal cure(s) for SCD might soon be available that eliminates major limitations of allogeneic transplantation, and this is being investigated in multiple clinical trials.


SCD encompasses a group of disorders caused by the homozygous inheritance of sickle hemoglobin (HbS) or the inheritance of HbS in a variety of double heterozygous states with other β-globin gene variants. Although there are various clinical phenotypes, the hallmarks of SCD include chronic anemia, chronic inflammation, recurrent vaso-occlusive crises, acute and chronic pain, stroke, organ damage and risk of failure, and early mortality.1

SCD is a global health problem with a need for cure. Approximately 5% of the world’s population carries trait genes for hemoglobin disorders, mainly SCD and thalassemia.2 Approximately 300,000 babies with severe hemoglobin disorders are born each year, although by 2050, this is estimated to increase to >400,000.3 In well-resourced countries, >94% of children with SCD now survive until age 18 years because of significant reductions in excess early childhood mortality though newborn screening, penicillin prophylaxis, and vaccinations.4,5 Thus, disease management has shifted to a chronic disease model that addresses long-term complications, reduced quality of life, and early mortality faced in adulthood.6 In the United States, SCD is a public health concern with high health care costs,7 affecting approximately 100,000 Americans who have fewer US Food and Drug ...

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