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Rotin LE, Viswabandya A, Kumar R, Patriquin CJ, Kuo KHM. A systematic review comparing allogeneic hematopoietic stem cell transplant to gene therapy in sickle cell disease. HEMATOLOGY (AMSTERDAM, NETHERLANDS) 2023; 28:2163357. [PMID: 36728286 DOI: 10.1080/16078454.2022.2163357] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Allogeneic hematopoietic stem cell transplant (HSCT) and gene therapy (GT) are two potentially curative approaches for sickle cell disease (SCD), but they have never been compared in clinical trials. OBJECTIVE To compare the safety and efficacy of HSCT and GT to assist clinicians and patients in making informed treatment decisions. METHODS Phase I-III clinical trials and case reports/series were included. Regimens included HSCT from all stem cell sources, lentiviral gene therapy, and gene editing, with any conditioning regimen. We searched Medline and EMBASE databases as of 1st June 2020 for studies reporting HSCT and GT outcomes in SCD. The Newcastle-Ottawa scale was used to assess the risk of bias. Descriptive statistics and post-hoc imputation for standard deviations of mean change in FEV1 and FVC were performed. RESULTS In total, 56 studies (HSCT, n = 53; GT, n = 3) representing 1,198 patients met inclusion criteria (HSCT, n = 1,158; GT, n = 40). Length of follow-up was 3,881.5 and 58.7 patient-years for HSCT and GT, respectively. Overall quality of evidence was low, with no randomized controlled trials identified. Two-year overall survival for HSCT was 91%; mortality was 2.5% for GT. Acute chest syndrome and vaso-occlusive episodes were reduced post-HSCT and GT. Meta-analysis was not possible due to lack of comparator and heterogeneity in outcome measures reporting. Very few studies reported post-transplant end-organ function. Six secondary malignancies (5 post-HSCT, 1 post-GT) were reported. DISCUSSION Reporting of SCD-related complications and patient-important outcomes is lacking for both strategies. We advocate for standardized reporting to better compare outcomes within and between treatment groups.
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Affiliation(s)
- Lianne E Rotin
- Division of General Internal Medicine, Department of Medicine, University of Toronto, Toronto, Canada.,Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Auro Viswabandya
- Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada.,Messner Allogeneic Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Rajat Kumar
- Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada.,Messner Allogeneic Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Christopher J Patriquin
- Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada.,Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Canada
| | - Kevin H M Kuo
- Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada.,Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Canada.,Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
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Bedrick BS, Kohn TP, Pecker LH, Christianson MS. Fertility preservation for pediatric patients with hemoglobinopathies: Multidisciplinary counseling needed to optimize outcomes. Front Endocrinol (Lausanne) 2022; 13:985525. [PMID: 36353243 PMCID: PMC9638952 DOI: 10.3389/fendo.2022.985525] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/30/2022] [Indexed: 01/19/2023] Open
Abstract
Hemoglobinopathies are autosomal recessive disorders that occur when genetic mutations negatively impact the function of hemoglobin. Common hemoglobinopathies that are clinically significant include sickle cell disease, alpha thalassemia, and beta thalassemia. Advancements in disease-modifying and curative treatments for the common hemoglobinopathies over the past thirty years have led to improvements in patient quality of life and longevity for those who are affected. However, the diseases, their treatments and cures pose infertility risks, making fertility preservation counseling and treatment an important part of the contemporary comprehensive patient care. Sickle cell disease negatively impacts both male and female infertility, primarily by testicular failure and decreased ovarian reserve, respectively. Fertility in both males and females with beta thalassemia major are negatively impacted by iron deposition due to chronic blood transfusions. Hematopoietic stem cell transplant (HSCT) is currently the only curative treatment for SCD and transfusion dependent beta thalassemia. Many of the conditioning regimens for HSCT contain chemotherapeutic agents with known gonadotoxicity and whole-body radiation. Although most clinical studies on toxicity and impact of HSCT on long-term health do not evaluate fertility, gonadal failure is common. Male fertility preservation modalities that exist prior to gonadotoxic treatment include sperm banking for pubertal males and testicular cryopreservation for pre-pubertal boys. For female patients, fertility preservation options include oocyte cryopreservation and ovarian tissue cryopreservation. Oocyte cryopreservation requires controlled ovarian hyperstimulation (COH) with ten to fourteen days of intensive monitoring and medication administration. This is feasible once the patient has undergone menarche. Follicular growth is monitored via transvaginal or transabdominal ultrasound, and hormone levels are monitored through frequent blood work. Oocytes are then harvested via a minimally invasive approach under anesthesia. Complications of COH are more common in patients with hemoglobinopathies. Ovarian hyperstimulation syndrome creates a greater risk to patients with underlying vascular, pulmonary, and renal injury, as they may be less able to tolerate fluids shifts. Thus, it is critical to monitor patients undergoing COH closely with close collaboration between the hematology team and the reproductive endocrinology team. Counseling patients and families about future fertility must take into consideration the patient's disease, treatment history, and planned treatment, acknowledging current knowledge gaps.
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Affiliation(s)
- Bronwyn S. Bedrick
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Taylor P. Kohn
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Lydia H. Pecker
- Department of Medicine, Division of Adult Hematology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Mindy S. Christianson
- Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology and Infertility, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Baldwin Z, Jiao B, Basu A, Roth J, Bender MA, Elsisi Z, Johnson KM, Cousin E, Ramsey SD, Devine B. Medical and Non-medical Costs of Sickle Cell Disease and Treatments from a US Perspective: A Systematic Review and Landscape Analysis. PHARMACOECONOMICS - OPEN 2022; 6:469-481. [PMID: 35471578 PMCID: PMC9283624 DOI: 10.1007/s41669-022-00330-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/15/2022] [Indexed: 05/06/2023]
Abstract
BACKGROUND Sickle cell disease (SCD) is a complex genetic disorder that manifests in infancy and progresses throughout life in the form of acute and chronic complications. As the upfront costs of potentially curative, genetic therapies will likely be high, an assessment and comprehensive characterization of the medical and non-medical cost burden will inform future decision making. OBJECTIVE We sought to systematically summarize the existing literature surrounding SCD medical and non-medical costs. METHODS We searched MEDLINE and EMBASE (2008-2020) and identified US-based studies that detailed medical or non-medical costs. Eligible studies provided empirical estimates about any aspect of cost or SCD individuals of all ages and their caregivers. Study quality was assessed using the Newcastle-Ottawa Scale, and costs were adjusted to 2019 US$. RESULTS Search queries returned 479 studies, with 342 from medical burden searches and 137 from non-medical burden searches, respectively. Herein, we report the results of the 40 studies that contained relevant cost information: 39 detailed medical costs and 1 detailed non-medical costs. Costs were higher for SCD patients when compared with non-SCD individuals (cost difference range: $6636-$63,436 annually). The highest medical cost component for SCD patients was inpatient ($11,978-$59,851 annually), followed by outpatient and then pharmacy. No studies characterized the cost burden throughout the lifetime disease trajectory of an SCD individual, and no studies captured caregiver or productivity costs. CONCLUSION Our results reveal an incomplete characterization of medical and non-medical costs within SCD. A deeper understanding of the medical and non-medical cost burden requires completion of additional studies that capture the burden across the patient's lifetime, in addition to expression of the impact of existing and emergent health technologies on disease trajectory.
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Affiliation(s)
- Zachary Baldwin
- The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, University of Washington, 1959 NE Pacific Street, H-375T, Box 357630, Seattle, WA, 98195-7630, USA
| | - Boshen Jiao
- The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, University of Washington, 1959 NE Pacific Street, H-375T, Box 357630, Seattle, WA, 98195-7630, USA
| | - Anirban Basu
- The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, University of Washington, 1959 NE Pacific Street, H-375T, Box 357630, Seattle, WA, 98195-7630, USA
- Department of Health Services, University of Washington, Seattle, WA, USA
| | - Joshua Roth
- Division of Public Health Sciences and Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - M A Bender
- Department of Pediatrics, University of Washington and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Zizi Elsisi
- The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, University of Washington, 1959 NE Pacific Street, H-375T, Box 357630, Seattle, WA, 98195-7630, USA
| | - Kate M Johnson
- The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, University of Washington, 1959 NE Pacific Street, H-375T, Box 357630, Seattle, WA, 98195-7630, USA
| | - Emma Cousin
- Department of Pharmacy, University of Washington, Seattle, WA, USA
| | - Scott D Ramsey
- The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, University of Washington, 1959 NE Pacific Street, H-375T, Box 357630, Seattle, WA, 98195-7630, USA
- Division of Public Health Sciences and Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Beth Devine
- The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, University of Washington, 1959 NE Pacific Street, H-375T, Box 357630, Seattle, WA, 98195-7630, USA.
- Department of Health Services, University of Washington, Seattle, WA, USA.
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American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv 2021; 5:3668-3689. [PMID: 34581773 DOI: 10.1182/bloodadvances.2021004394c] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 06/23/2021] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Sickle cell disease (SCD) is a life-limiting inherited hemoglobinopathy that results in significant complications and affects quality of life. Hematopoietic stem cell transplantation (HSCT) is currently the only curative intervention for SCD; however, guidelines are needed to inform how to apply HSCT in clinical practice. OBJECTIVE These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and health professionals in their decisions about HSCT for SCD. METHODS The multidisciplinary guideline panel formed by ASH included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews (through 2019). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS The panel agreed on 8 recommendations to help patients and providers assess how individuals with SCD should consider the timing and type of HSCT. CONCLUSIONS The evidence review yielded no randomized controlled clinical trials for HSCT in SCD; therefore, all recommendations are based on very low certainty in the evidence. Key recommendations include considering HSCT for those with neurologic injury or recurrent acute chest syndrome at an early age and to improve nonmyeloablative regimens. Future research should include the development of a robust SCD registry to serve as a comparator for HSCT studies.
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Iqbal M, Reljic T, Corbacioglu S, de la Fuente J, Gluckman E, Kumar A, Yassine F, Ayala E, El-Jawahri A, Murthy H, Almohareb F, Hashmi SK, Cappelli B, Alahmari A, Scigliuolo GM, Kassim A, Aljurf M, Kharfan-Dabaja MA. Systematic Review/Meta-Analysis on Efficacy of Allogeneic Hematopoietic Cell Transplantation in Sickle Cell Disease: An International Effort on Behalf of the Pediatric Diseases Working Party of European Society for Blood and Marrow Transplantation and the Sickle Cell Transplantation International Consortium. Transplant Cell Ther 2020; 27:167.e1-167.e12. [PMID: 33830027 DOI: 10.1016/j.jtct.2020.10.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/28/2020] [Accepted: 10/21/2020] [Indexed: 11/28/2022]
Abstract
Sickle cell disease (SCD) affects more than 300,000 children annually worldwide. Despite improved supportive care, long-term prognosis remains poor. Allogeneic hematopoietic cell transplantation (allo-HCT) is the sole validated curative option, resulting in sustained resolution of the clinical phenotype. The medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated allo-HCT efficacy in adults. Here, we conducted a systematic review/meta-analysis to assess the totality of evidence on the efficacy, or lack thereof, of allo-HCT in treating SCD. We performed a comprehensive literature search using PubMed/Medline, Embase, and Cochrane library databases on November 13, 2019. Four authors independently extracted data on clinical outcomes related to benefits (overall survival [OS] and disease-free survival [DFS]) and harms (acute graft-versus-host disease [aGVHD], chronic graft-versus-host disease [cGVHD], nonrelapse mortality [NRM], and graft failure [GF]). Our search identified a total of 1906 references. Only 33 studies (n= 2853 patients) met our inclusion criteria. We also performed a subset analysis by age. Analyses of all-age groups showed pooled rates of 96% for OS, 90% for DFS, 20% for aGVHD, 10% for cGVHD, 4% for NRM, and 5% for GF. In the pediatric population, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 97%, 91%, 26%, 11%, 5%, and 3%, respectively. In adults, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 98%, 90%, 7%, 1%, 0%, and 14%, respectively. Our data show that allo-HCT is safe and effective, yielding pooled OS rates exceeding 90%. The high GF rate of 14% in adults is concerning and emphasizes the need to evaluate new strategies.
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Affiliation(s)
- Madiha Iqbal
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, Florida
| | - Tea Reljic
- Program for Comparative Effectiveness Research, Morsani College of Medicine, University of South Florida, Tampa, Florida
| | - Selim Corbacioglu
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg, Germany
| | - Josu de la Fuente
- Centre for Haematology, Imperial College London, London, United Kingdom
| | - Eliane Gluckman
- Eurocord, Paris-Diderot University Equipe d'Accueil 3518, Hospital Saint Louis, Paris, France; Monacord, Centre Scientifique de Monaco, Monaco
| | - Ambuj Kumar
- Program for Comparative Effectiveness Research, Morsani College of Medicine, University of South Florida, Tampa, Florida
| | - Farah Yassine
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, Florida
| | - Ernesto Ayala
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, Florida
| | - Areej El-Jawahri
- Department of Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Hemant Murthy
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, Florida
| | - Fahad Almohareb
- Adult Hematology/Bone Marrow Transplantation, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Shahrukh K Hashmi
- Adult Hematology/Bone Marrow Transplantation, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Hematology, Mayo Clinic, Rochester, Minnesota
| | - Barbara Cappelli
- Eurocord, Paris-Diderot University Equipe d'Accueil 3518, Hospital Saint Louis, Paris, France; Monacord, Centre Scientifique de Monaco, Monaco
| | - Ali Alahmari
- Adult Hematology/Bone Marrow Transplantation, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Graziana Maria Scigliuolo
- Eurocord, Paris-Diderot University Equipe d'Accueil 3518, Hospital Saint Louis, Paris, France; Monacord, Centre Scientifique de Monaco, Monaco
| | - Adetola Kassim
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - Mahmoud Aljurf
- Adult Hematology/Bone Marrow Transplantation, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mohamed A Kharfan-Dabaja
- Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, Florida.
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Dhédin N, Paillard C, Dalle JH, Ouachée M, Buchbinder N, Brissot E, Beguin Y, Masouridi-Levrat S, Yakoub-Agha I, Bernit E, Pondarre C. [Allogeneic hematopoietic stem cell transplant in children and adults with sickle cell disease: Indications and modalities]. Bull Cancer 2020; 107:925-933. [PMID: 32921398 DOI: 10.1016/j.bulcan.2020.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 06/01/2020] [Accepted: 06/05/2020] [Indexed: 11/30/2022]
Abstract
Sickle cell disease is associated with severe complications and early mortality in adults. In children, hematopoietic stem cell transplant from HLA-identical sibling can stop the progression of the disease and leads to more than 95% long-term free survival without sickle cell disease. The aim of this workshop was to define indications and modalities of allogeneic hematopoietic stem cell transplant in children and adults with sickle cell disease. Patient and sibling HLA typing should be proposed, early in the course of the disease, when intensification therapies are required. Indications of transplant from HLA-identical sibling in children and adults are, cerebral vasculopathy, occurrence of vaso-occlusive events despite hydroxycarbamide, renal and hepatic diseases related to SCD, chronic anemia<7g/dL despite hydroxycarbamide, need to maintain transfusion programs longer than six months, and major transfusion difficulties related to red blood cell alloimmunization. In children with an HLA-identical sibling donor, we recommend a myeloablative conditioning regimen associating high dose busulfan, cyclophosphamide and ATG, considering the excellent results of this approach In patients over 15 years of age, we recommend the NIH approach consisting of a reduced intensity conditioning regimen by alemtuzumab, and 3Gy total body irradiation, followed by peripheral hematopoietic stem cells and post-transplant immunosuppression by sirolimus In the absence of HLA-identical sibling donor, there is no definitive data for preferring transplant from unrelated versus haplo-identical donors but we recommend to evaluate these approaches in prospective trials.
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Affiliation(s)
- Nathalie Dhédin
- Hôpital Saint-Louis, service d'hématologie adolescents jeunes adultes, Paris, France.
| | - Catherine Paillard
- CHU de Strasbourg, service d'onco-hématologie pédiatrique, Strasbourg, France.
| | - Jean-Hugues Dalle
- Hôpital Robert-Debré, université Paris 7 - Denis Diderot, service d'hémato-immunologie, Paris, France.
| | - Marie Ouachée
- Service de pédiatrie IHOP, 1, place Joseph-Renaut, 69373 Lyon cedex 08, France.
| | | | - Eolia Brissot
- Hôpital Saint-Antoine, Sorbonne université, service d'hématologie et thérapie cellulaire, 184, rue du Faubourg Saint-Antoine, Paris, France.
| | - Yves Beguin
- Université de Liège, CHU de liège, service d'hématologie, 1, avenue de l'Hôpital, 4000 Liège, Belgique.
| | | | - Ibrahim Yakoub-Agha
- Université de Lille, CHU de Lille, Inserm, Infinite, U1286, 59000 Lille, France.
| | - Emmanuelle Bernit
- Assistance publique-Hôpitaux de Marseille, service de médecine interne, Marseille, France.
| | - Corinne Pondarre
- Paris XII université, centre hospitalier intercommunal de Créteil, centre de référence de la drépanocytose, service de pédiatrie, Inserm unité 955, Créteil, France.
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de Azevedo JTC, Malmegrim KCR. Immune mechanisms involved in sickle cell disease pathogenesis: current knowledge and perspectives. Immunol Lett 2020; 224:1-11. [PMID: 32437728 DOI: 10.1016/j.imlet.2020.04.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 04/02/2020] [Accepted: 04/18/2020] [Indexed: 12/18/2022]
Abstract
Sickle cell disease (SCD) is caused by a single point mutation in the β-chain of the hemoglobin gene that results in the replacement of glutamic acid with valine in the hemoglobin protein. However, recent studies have demonstrated that alterations in several other genes, especially immune related genes, may be associated with complications of SCD. In fact, higher chronic inflammatory status is related to more severe clinical symptoms in SCD patients, suggesting crucial roles of the immune system in SCD physiopathology. Nevertheless, although participation of innate immune cells in SCD pathogenesis has been broadly and extensively described, little is known about the roles of the adaptive immune system in this disease. In addition, the influence of treatments on the immune system of SCD patients and their complications (such as alloimmunization) are not yet completely understood. Thus, we reviewed the current knowledge about the immune mechanisms involved in SCD pathogenesis. We suggest recommendations for future studies to allow for a broader understanding of SCD pathogenesis, helping in the development of new therapies and improvement in the life quality and expectancy of patients.
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Affiliation(s)
- Júlia Teixeira Cottas de Azevedo
- Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Kelen Cristina Ribeiro Malmegrim
- Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil; Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
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Phillips LN, Krishnamurti L, Rytting H, Olson TA. Ovarian Sertoli-Leydig tumor after bone marrow transplant for sickle cell disease. Pediatr Blood Cancer 2018; 65:e27367. [PMID: 30039911 DOI: 10.1002/pbc.27367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 05/31/2018] [Accepted: 06/21/2018] [Indexed: 11/12/2022]
Abstract
As bone marrow transplant for sickle cell disease becomes increasingly common, long-term outcomes including secondary malignancies are beginning to be described. Here, we report a case of ovarian Sertoli-Leydig tumor that occurred after allogeneic bone marrow transplant for sickle cell disease.
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Affiliation(s)
- Lia Neu Phillips
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
| | - Lakshmanan Krishnamurti
- Pediatric Hematology/Oncology and Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia
| | - Heather Rytting
- Department of Pathology, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia
| | - Thomas A Olson
- Pediatric Hematology/Oncology and Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia
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Park BK, Kim HS, Kim S, Lee JW, Park YS, Jang PS, Chung NG, Jeong DC, Cho B. Allogeneic hematopoietic stem cell transplantation in congenital hemoglobinopathies with myeloablative conditioning and rabbit anti-thymocyte globulin. Blood Res 2018; 53:145-151. [PMID: 29963521 PMCID: PMC6021564 DOI: 10.5045/br.2018.53.2.145] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 02/21/2018] [Accepted: 02/22/2018] [Indexed: 11/22/2022] Open
Abstract
Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for β-thalassemia major (TM) and sickle cell disease (SCD) in children. Graft-versus-host disease (GVHD) and treatment-related mortality (TRM) remain significant challenges to improving survival after HSCT. Here, we analyzed the outcome of TM and SCD patients, who received allogeneic HSCT with myeloablative conditioning at our institution. Methods Twenty-two patients (15 TM, 7 SCD), with a median age of 9 years (range, 1.6–16.9), underwent allogeneic HSCT using busulfan, cyclophosphamide and rabbit anti-thymocyte globulin-based conditioning. Cells were derived from either the bone marrow (8 patients), or peripheral blood stem cells (14 patients). The majority of patients received HSCT from a matched sibling donor (N=18). GVHD prophylaxis included cyclosporine and short course methotrexate. Results All patients achieved donor engraftment. Two SCD patients died from TRM-related grade IV gut GVHD (N=1) or severe bronchiolitis obliterans (BO) (N=1). Cumulative incidence of acute and chronic GVHD was 36.4% and 32.7%, respectively. Veno-occlusive disease (VOD) occurred in 8 patients (36.4%), but resolved in all instances. Epstein-Barr virus (EBV)-related post-transplantation lymphoproliferative disease (PTLD) occurred in 1 patient. The overall survival (OS) was 90.9% (TM 100%, SCD 71.4%), with all patients achieving transfusion independence, while 8 achieved complete donor chimerism. Conclusion Busulfan, cyclophosphamide, and ATG-based conditioning for HSCT of TM and SCD patients did not result in graft failure, although modifications may be required to reduce VOD incidence. Further changes to donor type and cell source prioritization are necessary to minimize TRM and morbidity caused by GVHD.
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Affiliation(s)
- Bo-Kyoung Park
- Department of Pediatrics, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyo-Sup Kim
- Department of Pediatrics, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seongkoo Kim
- Department of Pediatrics, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae-Wook Lee
- Department of Pediatrics, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young Shil Park
- Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea
| | - Pil-Sang Jang
- Department of Pediatrics, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Nack-Gyun Chung
- Department of Pediatrics, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Dae-Chul Jeong
- Department of Pediatrics, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Bin Cho
- Department of Pediatrics, Catholic Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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10
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Demirci S, Uchida N, Tisdale JF. Gene therapy for sickle cell disease: An update. Cytotherapy 2018; 20:899-910. [PMID: 29859773 PMCID: PMC6123269 DOI: 10.1016/j.jcyt.2018.04.003] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 04/03/2018] [Accepted: 04/07/2018] [Indexed: 01/14/2023]
Abstract
Sickle cell disease (SCD) is one of the most common life-threatening monogenic diseases affecting millions of people worldwide. Allogenic hematopietic stem cell transplantation is the only known cure for the disease with high success rates, but the limited availability of matched sibling donors and the high risk of transplantation-related side effects force the scientific community to envision additional therapies. Ex vivo gene therapy through globin gene addition has been investigated extensively and is currently being tested in clinical trials that have begun reporting encouraging data. Recent improvements in our understanding of the molecular pathways controlling mammalian erythropoiesis and globin switching offer new and exciting therapeutic options. Rapid and substantial advances in genome engineering tools, particularly CRISPR/Cas9, have raised the possibility of genetic correction in induced pluripotent stem cells as well as patient-derived hematopoietic stem and progenitor cells. However, these techniques are still in their infancy, and safety/efficacy issues remain that must be addressed before translating these promising techniques into clinical practice.
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Affiliation(s)
- Selami Demirci
- Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
| | - Naoya Uchida
- Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
| | - John F Tisdale
- Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
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Shenoy S, Angelucci E, Arnold SD, Baker KS, Bhatia M, Bresters D, Dietz AC, De La Fuente J, Duncan C, Gaziev J, King AA, Pulsipher MA, Smith AR, Walters MC. Current Results and Future Research Priorities in Late Effects after Hematopoietic Stem Cell Transplantation for Children with Sickle Cell Disease and Thalassemia: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2017; 23:552-561. [PMID: 28065838 DOI: 10.1016/j.bbmt.2017.01.009] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 01/04/2017] [Indexed: 12/17/2022]
Abstract
Sustained donor engraftment after allogeneic hematopoietic cell transplantation (HCT) converts to healthy donor hemoglobin synthesis and halts disease symptoms in patients with sickle cell disease and thalassemia major. A disease-free survival probability that exceeds 90% has been reported when HCT using an HLA-matched sibling donor is performed in young patients with low-risk disease or treatment-related risk factors. Alternate donor HCT and HCT in adults is performed infrequently because of a higher risk profile. Transplant-specific risks include conditioning regimen-related toxicity, graft-versus-host disease, graft rejection with marrow aplasia or disease recurrence, and infections associated with immunosuppression and delayed immune reconstitution. The magnitude of risk depends on patient age, clinical status of the underlying disease (eg, organ injury from vasculopathy and iron overload), donor source, and intensity of the conditioning regimen. These risks are commonly monitored and reported in the short term. Documenting very late outcomes is important, but these data are rarely reported because of challenges imposed by patient drop-out and insufficient resources. This report summarizes long-term follow-up results after HCT for hemoglobin disorders, identifies gaps in knowledge, and discusses opportunities for future investigations. This consensus summary will be followed by a second article detailing comprehensive long-term follow-up recommendations to aid in maintaining health in these individuals and identifying late complication risks that could facilitate interventions to improve outcomes.
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Affiliation(s)
- Shalini Shenoy
- Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri.
| | - Emanuele Angelucci
- Department of Hematology, Ospedale Oncologico di Riferimento Regionale "Armando Businco", Cagliari, Italy; Department of Hematology, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
| | - Staci D Arnold
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
| | - K Scott Baker
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Monica Bhatia
- Department of Pediatrics, Columbia University Medical Center, New York, New York
| | - Dorine Bresters
- Willem-Alexander Children's Hospital, LUMC, Leiden, The Netherlands
| | - Andrew C Dietz
- Division of Hematology, Oncology, and BMT, Children's Hospital Los Angeles, Los Angeles, California
| | - Josu De La Fuente
- Department of Pediatrics, Imperial College Healthcare, London, United Kingdom
| | - Christine Duncan
- Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts
| | - Javid Gaziev
- International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy
| | - Allison A King
- Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri; Program in Occupational Therapy, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Michael A Pulsipher
- Division of Hematology, Oncology, and BMT, Children's Hospital Los Angeles, Los Angeles, California
| | - Angela R Smith
- Department of Pediatrics, University of Minnesota Children's Hospital, Minneapolis, Minnesota
| | - Mark C Walters
- Department of Pediatrics, UCSF Benioff Children's Hospital, Oakland, California
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Nickel RS, Seashore E, Lane PA, Alazraki AL, Horan JT, Bhatia M, Haight AE. Improved Splenic Function After Hematopoietic Stem Cell Transplant for Sickle Cell Disease. Pediatr Blood Cancer 2016; 63:908-13. [PMID: 26757445 DOI: 10.1002/pbc.25904] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 12/15/2015] [Accepted: 12/17/2015] [Indexed: 01/06/2023]
Abstract
BACKGROUND Splenic dysfunction is a significant complication of sickle cell disease (SCD). Hematopoietic stem cell transplant (HSCT) is a proven cure for SCD; however, its long-term effect on splenic function is not well characterized. PROCEDURE We conducted a retrospective cohort study of pediatric patients who had HSCT for SCD at two transplant centers. (99m) Tc liver-spleen (LS) scans were blindly reviewed and classified as demonstrating absent, decreased, or normal splenic uptake. RESULTS Considering all engrafted nonsplenectomized Hb SS and Sβ(0) -thalassemia patients with LS scans available, at a median of 2.0 years post-HSCT (range 1.0-9.3 years) eight of 53 (15%) had normal, 40 of 53 (75%) decreased, and five of 53 (9%) absent splenic uptake. More patients had splenic uptake after HSCT: pre-HSCT 14/38 (37%) versus post-HSCT 34/38 (89%), P < 0.0001. Older age at HSCT was associated with worse splenic function post-HSCT (median age at HSCT for absent uptake 16.6 years vs. present uptake 8.0 years, P = 0.030). Extensive chronic GVHD was also more common in patients with absent splenic uptake compared to patients with present uptake (absent 40% vs. present 6%, P = 0.064). CONCLUSIONS HSCT significantly improves splenic function for most pediatric patients with SCD, but older patient age at time of HSCT and extensive chronic GVHD appear to be risk factors for poor post-HSCT splenic function.
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Affiliation(s)
- Robert Sheppard Nickel
- Division of Hematology, Children's National Health System, Washington, District of Columbia
| | - Elizabeth Seashore
- Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center, New York, New York
| | - Peter A Lane
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
| | - Adina L Alazraki
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia
| | - John T Horan
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
| | - Monica Bhatia
- Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center, New York, New York
| | - Ann E Haight
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
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Iughetti L, Bigi E, Venturelli D. Novel insights in the management of sickle cell disease in childhood. World J Clin Pediatr 2016; 5:25-34. [PMID: 26862499 PMCID: PMC4737690 DOI: 10.5409/wjcp.v5.i1.25] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 10/13/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Sickle cell disease (SCD) is a life-threatening genetic disorder characterized by chronic hemolytic anemia, vascular injury and multiorgan dysfunctions. Over the last few decades, there have been significant improvements in SCD management in Western countries, especially in pediatric population. An early onset of prophylaxis with Penicillin and a proper treatment of the infections have increased the overall survival in childhood. Nevertheless, management of painful episodes and prevention of organ damage are still challenging and more efforts are needed to better understand the mechanisms behind the development of chronic organ damages. Hydroxyurea (Hydroxycarbamide, HU), the only medication approved as a disease-modifying agent by the United States Food and Drug Administration and the European Medicines Agency, is usually under-used, especially in developing countries. Currently, hematopoietic stem-cell transplantation is considered the only curative option, although its use is limited by lack of donors and transplant-related toxicity. SCD symptoms are similar in children and adults, but complications and systemic organ damages increase with age, leading to early mortality worldwide. Experts in comprehensive care of young patients with SCD, especially those approaching the transition age to adulthood, are missing, leading people to rely on urgent care, increasing health care utilization costs and inappropriate treatments. It would be important to establish programs of comprehensive healthcare for patients with SCD from birth to adulthood, to improve their quality and expectancy of life.
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Abstract
PURPOSE OF REVIEW Hematopoietic cell transplantation (HCT) is a curative therapy for sickle cell disease (SCD) that is utilized very rarely because of limited allogeneic donor availability, limited healthcare resources needed to expand the treatment to regions in the world where most affected individuals reside, and by a view among SCD experts that HCT lacks the evidential rigor with short and long-term toxicity profiles that together might support its broader application. RECENT FINDINGS In this update, recent advances focused on donor selection, reduced toxicity preparation for HCT, and treatment of young adults will be presented. The current status of conventional bone marrow transplantation with a human leukocyte antigen-identical sibling donor is summarized. SUMMARY HCT for SCD is curative in almost all children who have a human leukocyte antigen-matched sibling donor. The future of this therapy will hinge on expanding the number of individuals who might be treated.
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Affiliation(s)
- Mark C Walters
- Jordan Family Director, Blood and Marrow Transplant Program, Division of Hematology/Oncology/BMT, UCSF Benioff Children's Hospital, Oakland, California, USA
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Friedrich P, Steinfield E, Kim F, Hays MM, Lehmann L, Sprinz P. Lessons Learned From Talking With Parents About the Role of Hematopoietic Stem Cell Transplantation in the Treatment of Children With Sickle Cell Disease. AMERICAN JOURNAL OF HEALTH EDUCATION 2015. [DOI: 10.1080/19325037.2015.1021059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Strocchio L, Zecca M, Comoli P, Mina T, Giorgiani G, Giraldi E, Vinti L, Merli P, Regazzi M, Locatelli F. Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in children with sickle cell disease. Br J Haematol 2015; 169:726-36. [PMID: 25818248 DOI: 10.1111/bjh.13352] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 01/20/2015] [Indexed: 12/01/2022]
Abstract
Although allogeneic haematopoietic stem cell transplantation (HSCT) still represents the only consolidated possibility of cure for sickle cell disease (SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen (HLA)-matched sibling or unrelated donor-HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan-based regimen. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III-IV regimen-related toxicity. The 7-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD-related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan-based conditioning regimen is able to ensure engraftment with excellent OS/DFS and low regimen-related toxicity in patients with SCD.
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Affiliation(s)
- Luisa Strocchio
- Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Marco Zecca
- Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Patrizia Comoli
- Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Tommaso Mina
- Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Giovanna Giorgiani
- Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Eugenia Giraldi
- Unità Pediatria, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Luciana Vinti
- Dipartimento di Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy
| | - Pietro Merli
- Dipartimento di Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy
| | - Mario Regazzi
- Farmacocinetica Clinica dei Trapianti e delle Malattie Autoimmuni, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Franco Locatelli
- Dipartimento di Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.,Università degli Studi di Pavia, Pavia, Italy
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Fitzhugh CD, Abraham AA, Tisdale JF, Hsieh MM. Hematopoietic stem cell transplantation for patients with sickle cell disease: progress and future directions. Hematol Oncol Clin North Am 2014; 28:1171-85. [PMID: 25459186 DOI: 10.1016/j.hoc.2014.08.014] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Research has solidified matched sibling marrow, cord blood, or mobilized peripheral blood as the best source for allogeneic hematopoietic stem cell transplantation for patients with sickle cell disease, with low graft rejection and graft-versus-host disease (GVHD) and high disease-free survival rates. Fully allelic matched unrelated donor is an option for transplant-eligible patients without HLA-matched sibling donors. Unrelated cord transplant studies reported high GVHD and low engraftment rates. Haploidentical transplants have less GVHD, but improvements are needed to increase the low engraftment rate. The decision to use unrelated cord blood units or haploidentical donors depends on institutional expertise.
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Affiliation(s)
| | - Allistair A Abraham
- Division of Blood and Marrow Transplantation, Children's National Health System, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, North West, Washington, DC 20010, USA
| | - John F Tisdale
- 9000 Rockville Pike, Building 10/9N112, Bethesda, MD 20892, USA
| | - Matthew M Hsieh
- 9000 Rockville Pike, Building 10/9N112, Bethesda, MD 20892, USA.
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