{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:17:41Z","timestamp":1791944261988,"version":"4.3.4"},"reference-count":44,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,12,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Allogeneic hematopoietic cell transplantation, gene therapy, and gene editing offer a potential cure for sickle cell disease (SCD). Unfortunately, myelodysplastic syndrome and acute myeloid leukemia development have been higher than expected after graft rejection following nonmyeloablative conditioning and lentivirus-based gene therapy employing myeloablative busulfan for SCD. Somatic mutations discovered in 2 of 76 patients who rejected their grafts were identified at baseline at much lower levels. While a whole-genome sequencing analysis reported no difference between patients with SCD and controls, a study including whole-exome sequencing revealed a higher prevalence of clonal hematopoiesis in individuals with SCD compared with controls. Genetic risk factors for myeloid malignancy development after curative therapy for SCD are currently being explored. Once discovered, decisions could be made about whether gene therapy may be feasible vs allogeneic hematopoietic cell transplant, which results in full donor chimerism. In the meantime, care should be taken to perform a benefit\/risk assessment to help patients identify the best curative approach for them. Long-term follow-up is necessary to monitor for myeloid malignancies and other adverse effects of curative therapies for SCD.<\/jats:p>","DOI":"10.1182\/hematology.2022000371","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T16:09:46Z","timestamp":1670602186000},"page":"266-271","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":20,"title":["Knowledge to date on secondary malignancy following hematopoietic cell transplantation for sickle cell disease"],"prefix":"10.1182","volume":"2022","author":[{"given":"Courtney D.","family":"Fitzhugh","sequence":"first","affiliation":[{"name":"Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"issue":"4, suppl","key":"2022120916080209900_hem2022000371C1","doi-asserted-by":"crossref","first-page":"S512","DOI":"10.1016\/j.amepre.2009.12.022","volume":"38","author":"Hassell","year":"2010","journal-title":"Am J Prev Med"},{"issue":"7","key":"2022120916080209900_hem2022000371C2","doi-asserted-by":"crossref","first-page":"e1001484","DOI":"10.1371\/journal.pmed.1001484","article-title":"Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions","volume":"10","author":"Piel","year":"2013","journal-title":"PLoS Med"},{"issue":"9","key":"2022120916080209900_hem2022000371C3","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1002\/ajh.25202","article-title":"Clustering of end-organ disease and earlier mortality in adults with sickle cell disease: a retrospective-prospective cohort study","volume":"93","author":"Chaturvedi","year":"2018","journal-title":"Am J Hematol"},{"issue":"2","key":"2022120916080209900_hem2022000371C4","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1177\/003335491312800206","article-title":"Mortality rates and age at death from sickle cell disease: U.S., 1979-2005","volume":"128","author":"Lanzkron","year":"2013","journal-title":"Public Health Rep"},{"issue":"11","key":"2022120916080209900_hem2022000371C5","doi-asserted-by":"crossref","first-page":"e585","DOI":"10.1016\/S2352-3026(19)30154-1","article-title":"Effect of donor type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study","volume":"6","author":"Eapen","year":"2019","journal-title":"Lancet Haematol"},{"issue":"12","key":"2022120916080209900_hem2022000371C6","doi-asserted-by":"crossref","first-page":"e543","DOI":"10.3324\/haematol.2019.216788","article-title":"Risk factors and outcomes according to age at transplantation with an HLA-identical sibling for sickle cell disease","volume":"104","author":"Cappelli","year":"2019","journal-title":"Haematologica"},{"issue":"4","key":"2022120916080209900_hem2022000371C7","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/bjh.17311","article-title":"Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres","volume":"192","author":"Alzahrani","year":"2021","journal-title":"Br J Haematol"},{"issue":"22","key":"2022120916080209900_hem2022000371C8","doi-asserted-by":"crossref","first-page":"4285","DOI":"10.1182\/blood-2012-07-438408","article-title":"HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease","volume":"120","author":"Bola\u00f1os-Meade","year":"2012","journal-title":"Blood"},{"issue":"11","key":"2022120916080209900_hem2022000371C9","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1182\/bloodadvances.2016002972","article-title":"Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT","volume":"1","author":"Fitzhugh","year":"2017","journal-title":"Blood Adv"},{"issue":"5","key":"2022120916080209900_hem2022000371C10","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.bbmt.2010.11.029","article-title":"The pentostatin plus cyclophosphamide nonmyeloablative regimen induces durable host T cell functional deficits and prevents murine marrow allograft rejection","volume":"17","author":"Mariotti","year":"2011","journal-title":"Biol Blood Marrow Transplant"},{"issue":"7","key":"2022120916080209900_hem2022000371C11","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJMoa2117175","article-title":"Biologic and clinical efficacy of LentiGlobin for sickle cell disease","volume":"386","author":"Kanter","year":"2022","journal-title":"N Engl J Med"},{"issue":"3","key":"2022120916080209900_hem2022000371C12","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1056\/NEJMoa2031054","article-title":"CRISPR-Cas9 gene editing for sickle cell disease and \u03b2-thalassemia","volume":"384","author":"Frangoul","year":"2021","journal-title":"N Engl J Med"},{"issue":"12","key":"2022120916080209900_hem2022000371C13","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1056\/NEJM198409203111207","article-title":"Bone-marrow transplantation in a patient with sickle-cell anemia","volume":"311","author":"Johnson","year":"1984","journal-title":"N Engl J Med"},{"issue":"8","key":"2022120916080209900_hem2022000371C14","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1177\/0141076816651037","article-title":"Risk of individual malignant neoplasms in patients with sickle cell disease: English national record linkage study","volume":"109","author":"Seminog","year":"2016","journal-title":"J R Soc Med"},{"issue":"13","key":"2022120916080209900_hem2022000371C15","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1182\/blood-2017-05-783233","article-title":"Increased risk of leukemia among sickle cell disease patients in California","volume":"130","author":"Brunson","year":"2017","journal-title":"Blood"},{"issue":"1","key":"2022120916080209900_hem2022000371C16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/sj.bmt.1701291","article-title":"Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium","volume":"22","author":"Vermylen","year":"1998","journal-title":"Bone Marrow Transplant"},{"issue":"11","key":"2022120916080209900_hem2022000371C17","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1182\/blood.2021011488","article-title":"Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both, or neither","volume":"138","author":"Jones","year":"2021","journal-title":"Blood"},{"issue":"2","key":"2022120916080209900_hem2022000371C18","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1056\/NEJMoa2109167","article-title":"Acute myeloid leukemia case after gene therapy for sickle cell disease","volume":"386","author":"Goyal","year":"2022","journal-title":"N Engl J Med"},{"key":"2022120916080209900_hem2022000371C19","article-title":"Increased incidence of hematologic malignancies in SCD after HCT in adults with graft failure and mixed chimerism [published online ahead of print 31 August 2022]","author":"Lawal","journal-title":"Blood"},{"issue":"1","key":"2022120916080209900_hem2022000371C20","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3324\/haematol.2018.213207","article-title":"Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France","volume":"105","author":"Bernaudin","year":"2020","journal-title":"Haematologica"},{"issue":"14","key":"2022120916080209900_hem2022000371C21","first-page":"1185","article-title":"Baseline TP53 mutations in adults with SCD developing myeloid malignancy following hematopoietic cell transplantation","volume":"135","author":"Ghannam","year":"2020","journal-title":"Blood"},{"issue":"26","key":"2022120916080209900_hem2022000371C22","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1056\/NEJMoa1409405","article-title":"Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence","volume":"371","author":"Genovese","year":"2014","journal-title":"N Engl J Med"},{"issue":"26","key":"2022120916080209900_hem2022000371C23","doi-asserted-by":"crossref","first-page":"2488","DOI":"10.1056\/NEJMoa1408617","article-title":"Age-related clonal hematopoiesis associated with adverse outcomes","volume":"371","author":"Jaiswal","year":"2014","journal-title":"N Engl J Med"},{"issue":"4","key":"2022120916080209900_hem2022000371C24","doi-asserted-by":"crossref","first-page":"e156060","DOI":"10.1172\/JCI156060","article-title":"Clonal hematopoiesis in sickle cell disease","volume":"132","author":"Liggett","year":"2022","journal-title":"J Clin Invest"},{"issue":"21","key":"2022120916080209900_hem2022000371C25","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1182\/blood.2021011121","article-title":"Clonal hematopoiesis in sickle cell disease","volume":"138","author":"Pincez","year":"2021","journal-title":"Blood"},{"issue":"26","key":"2022120916080209900_hem2022000371C26","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1182\/bloodadvances.2017007690","article-title":"Primum non nocere: the case against transplant for children with sickle cell anemia without progressive end-organ disease","volume":"1","author":"DeBaun","year":"2017","journal-title":"Blood Adv"},{"issue":"5","key":"2022120916080209900_hem2022000371C27","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/s41409-017-0077-1","article-title":"Haploidentical hematopoietic stem cell transplant for patients with sickle cell disease using thiotepa, fludarabine, thymoglobulin, low dose cyclophosphamide, 200 cGytbi and post transplant cyclophosphamide","volume":"53","author":"Frangoul","year":"2018","journal-title":"Bone Marrow Transplant"},{"issue":"8","key":"2022120916080209900_hem2022000371C28","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/j.bbmt.2018.03.031","article-title":"Haploidentical peripheral blood stem cell transplantation demonstrates stable engraftment in adults with sickle cell disease","volume":"24","author":"Saraf","year":"2018","journal-title":"Biol Blood Marrow Transplant"},{"issue":"1","key":"2022120916080209900_hem2022000371C29","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.bbmt.2017.08.039","article-title":"HLA haploidentical stem cell transplant with pretransplant immunosuppression for patients with sickle cell disease","volume":"24","author":"Pawlowska","year":"2018","journal-title":"Biol Blood Marrow Transplant"},{"issue":"6","key":"2022120916080209900_hem2022000371C30","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/j.bbmt.2018.11.027","article-title":"Haploidentical bone marrow transplantation with post-transplantation cyclophosphamide plus thiotepa improves donor engraftment in patients with sickle cell anemia: results of an international learning collaborative","volume":"25","author":"de la Fuente","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"issue":"4","key":"2022120916080209900_hem2022000371C31","doi-asserted-by":"crossref","first-page":"e183","DOI":"10.1016\/S2352-3026(19)30031-6","article-title":"Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial","volume":"6","author":"Bola\u00f1os-Meade","year":"2019","journal-title":"Lancet Haematol"},{"issue":"1","key":"2022120916080209900_hem2022000371C32","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1182\/blood-2020-141771","article-title":"Outcomes of non-myeloablative HLA-haploidentical bone marrow transplant with thiotepa and post- transplant cyclophosphamide in children and adults with severe sickle cell disease, a phase II trial: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)","volume":"136","author":"Kassim","year":"2020","journal-title":"Blood"},{"issue":"8","key":"2022120916080209900_hem2022000371C33","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.bbmt.2020.05.005","article-title":"CTLA4Ig in an extended schedule along with sirolimus improves outcome with a distinct pattern of immune reconstitution following post-transplantation cyclophosphamide-based haploidentical transplantation for hemoglobinopathies","volume":"26","author":"Jaiswal","year":"2020","journal-title":"Biol Blood Marrow Transplant"},{"issue":"9","key":"2022120916080209900_hem2022000371C34","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1038\/s41409-021-01302-0","article-title":"Successful mismatched hematopoietic stem cell transplantation for pediatric hemoglobinopathy by using ATG and post-transplant cyclophosphamide","volume":"56","author":"Oostenbrink","year":"2021","journal-title":"Bone Marrow Transplant"},{"issue":"2","key":"2022120916080209900_hem2022000371C35","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/s41409-020-01054-3","article-title":"Pre-transplant myeloid and immune suppression, upfront plerixafor mobilization and post-transplant cyclophosphamide: novel strategy for haploidentical transplant in sickle cell disease","volume":"56","author":"Kharya","year":"2021","journal-title":"Bone Marrow Transplant"},{"issue":"3","key":"2022120916080209900_hem2022000371C36","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1172\/JCI10726","article-title":"Sickle cell anemia as an inflammatory disease","volume":"106","author":"Platt","year":"2000","journal-title":"J Clin Invest"},{"issue":"10","key":"2022120916080209900_hem2022000371C37","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1158\/1541-7786.MCR-14-0028","article-title":"The role of hypoxia and exploitation of the hypoxic environment in hematologic malignancies","volume":"12","author":"Muz","year":"2014","journal-title":"Mol Cancer Res"},{"issue":"5","key":"2022120916080209900_hem2022000371C38","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1182\/blood.V97.5.1180","article-title":"Deleterious clinical effects of transfusion-associated immunomodulation: fact or fiction?","volume":"97","author":"Vamvakas","year":"2001","journal-title":"Blood"},{"issue":"1","key":"2022120916080209900_hem2022000371C39","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/ajh.26371","article-title":"Primary myelofibrosis in untreated sickle cell disease: are adult patients at higher risk for developing hematological myeloid neoplasms?","volume":"97","author":"Ribeil","year":"2022","journal-title":"Am J Hematol"},{"issue":"2","key":"2022120916080209900_hem2022000371C40","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/mic.11.2.129.151","article-title":"The endothelial biology of sickle cell disease: inflammation and a chronic vasculopathy","volume":"11","author":"Hebbel","year":"2004","journal-title":"Microcirculation"},{"issue":"1","key":"2022120916080209900_hem2022000371C41","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/MOH.0000000000000622","article-title":"Human hematopoiesis: aging and leukemogenic risk","volume":"28","author":"Adelman","year":"2021","journal-title":"Curr Opin Hematol"},{"issue":"1","key":"2022120916080209900_hem2022000371C42","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1080\/10428194.2017.1324158","article-title":"Accelerated leukemic transformation after haplo-identical transplantation for hydroxyurea-treated sickle cell disease","volume":"59","author":"Janakiram","year":"2018","journal-title":"Leuk Lymphoma"},{"issue":"12","key":"2022120916080209900_hem2022000371C43","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1038\/s41379-019-0325-6","article-title":"Myeloid neoplasms in the setting of sickle cell disease: an intrinsic association with the underlying condition rather than a coincidence; report of 4 cases and review of the literature","volume":"32","author":"Li","year":"2019","journal-title":"Mod Pathol"},{"issue":"9","key":"2022120916080209900_hem2022000371C44","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1182\/bloodadvances.2019001330","article-title":"Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease","volume":"4","author":"Hsieh","year":"2020","journal-title":"Blood Adv"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2022\/1\/266\/2021783\/266fitzhugh.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2022\/1\/266\/2021783\/266fitzhugh.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T16:10:07Z","timestamp":1670602207000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2022\/1\/266\/493525\/Knowledge-to-date-on-secondary-malignancy"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,9]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12,9]]},"published-print":{"date-parts":[[2022,12,9]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2022000371","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,9]]},"published":{"date-parts":[[2022,12,9]]}}}