{"title":"The dawn of the CRISPR/Cas9 gene therapy era","authors":"","doi":"10.1016/s2352-3026(23)00372-1","DOIUrl":"https://doi.org/10.1016/s2352-3026(23)00372-1","url":null,"abstract":"Abstract not available","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"198 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138770335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Catherine Cargo, Elsa Bernard, Tumas Beinortas, Kelly L Bolton, Paul Glover, Helen Warren, Daniel Payne, Rukhsaar Ali, Alesia Khan, Mike Short, Suzan Van Hoppe, Alex Smith, Jan Taylor, Paul Evans, Elli Papaemmanuil, Simon Crouch
{"title":"Predicting cytopenias, progression, and survival in patients with clonal cytopenia of undetermined significance: a prospective cohort study","authors":"Catherine Cargo, Elsa Bernard, Tumas Beinortas, Kelly L Bolton, Paul Glover, Helen Warren, Daniel Payne, Rukhsaar Ali, Alesia Khan, Mike Short, Suzan Van Hoppe, Alex Smith, Jan Taylor, Paul Evans, Elli Papaemmanuil, Simon Crouch","doi":"10.1016/s2352-3026(23)00340-x","DOIUrl":"https://doi.org/10.1016/s2352-3026(23)00340-x","url":null,"abstract":"<h3>Background</h3><p><span><span>Somatic mutations are frequently reported in individuals with </span>cytopenia but without a confirmed haematological diagnosis (clonal cytopenia of undetermined significance; CCUS). These patients have an increased risk of progression to a </span>myeloid malignancy and worse overall survival than those with no such mutations. To date, studies have been limited by retrospective analysis or small patient numbers. We aimed to establish the natural history of CCUS by prospectively investigating outcome in a large, well defined patient cohort.</p><h3>Methods</h3><p><span>This prospective cohort study was conducted at the </span>Haematological Malignancy<span> Diagnostic Service, a diagnostic laboratory in Leeds, UK. Patients aged at least 18 years who were referred for investigation of cytopenia were eligible for inclusion; those with a history of myeloid malignancy were not eligible. Targeted sequencing was conducted alongside routine clinical testing. Baseline mutation analysis was then correlated with the main study outcomes: longitudinal blood counts, disease progression to a myeloid malignancy, and overall survival with a median follow-up of 4·54 years (IQR 4·03–5·04). Data were collected manually from hospital records or extracted from laboratory or clinical outcome databases.</span></p><h3>Findings</h3><p><span>Bone marrow samples from 2348 patients were received at the Haematological Malignancy Diagnostic Service between July 1, 2014, and July 31, 2016. Of these, 2083 patients (median age 72 years [IQR 63–80, range 18–99]; 854 [41·0%] female and 1229 [59·0%] male) met the inclusion criteria and had samples of sufficient quality for further analysis. 598 (28·7%) patients received a diagnosis on the basis of their biopsy sample, whereas 1485 (71·3%) samples were classified as non-diagnostic; of these, CCUS was confirmed in 400 (26·9%) patients (256 [64·0%] male and 144 [36·0%] female). </span><em>TET2, SRSF2,</em> and <span><em>DNMT3A</em></span><span> were the most frequently mutated genes in patients with CCUS, with 320 (80%) of 400 patients harbouring a mutation in at least one of these genes. Age (p<0·0001), sex (p=0·0027), and mutations in </span><span><em>ASXL1</em></span> (p=0·0009), <em>BCOR</em> (p=0·0056), and <em>TP53</em> (p=0·0055) correlated with a worse overall survival; however, the number of mutations was the strongest predictor for progression to a myeloid malignancy (two mutations, p=0·0024; three or more mutations, p=0·0004). Extended sequencing of samples from a subgroup of patients with sequential samples and no mutations in the initial myeloid gene panel showed recurrent mutations in both <em>DDX41</em> and <em>UBA1</em>, suggesting that these genes should be included in clinical test panels.</p><h3>Interpretation</h3><p>Mutation analysis is advised in patients who have undergone bone marrow examination and have an otherwise-unexplained cytopenia. High-risk genetic mutations and increa","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138840147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A comprehensive view of pregnancy in patients with sickle cell disease in high-income countries: the need for robust data and further decline in morbidity and mortality","authors":"Laure Joseph, Marine Driessen","doi":"10.1016/s2352-3026(23)00310-1","DOIUrl":"https://doi.org/10.1016/s2352-3026(23)00310-1","url":null,"abstract":"<p><span>Sickle cell disease is a major </span>public health<span><span> concern due to its prevalence and associated morbidities. In high-income countries, diagnosis and treatment advancements have extended patient's lives and enabled women to embrace motherhood. Although the provision of care in specialist centres has reduced maternal–fetal complication rates, the mortality rate among pregnant women with sickle cell disease remains disproportionately high. Complications arise from vaso-occlusive events, worsening organ damage, thrombotic risks, infections, and pregnancy-related issues, such as pre-eclampsia, premature birth, small-for-gestational-age, and pregnancy loss. Effective management during pregnancy includes preconception planning, genetic counselling, education, and collaborative care. There is no consensus on the overall approach to managing pregnant women with sickle cell disease; however, fostering a collaborative relationship between health-care professionals and researchers is crucial for advancing the understanding and management of this illness. The </span>disparities in health-care outcomes associated with ethnicity and economic insecurity affect patients with sickle cell disease but have not been examined extensively. Hence, health-care personnel need sufficient training to address these issues alongside broader societal efforts to confront racism and discrimination. Comprehensive national and global action plans are required to address the multifaceted challenges of sickle cell disease.</span></p>","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138770628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lucrèce Delicat-Loembet: offering hope to young people with sickle cell disease","authors":"Tony Kirby","doi":"10.1016/s2352-3026(23)00374-5","DOIUrl":"https://doi.org/10.1016/s2352-3026(23)00374-5","url":null,"abstract":"Abstract not available","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138770277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Predicting the progression of patients with CCUS to myeloid neoplasia","authors":"Emma M Groarke","doi":"10.1016/s2352-3026(23)00361-7","DOIUrl":"https://doi.org/10.1016/s2352-3026(23)00361-7","url":null,"abstract":"Abstract not available","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138770345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guillermo Garcia-Manero, James McCloskey, Elizabeth A Griffiths, Karen W L Yee, Amer M Zeidan, Aref Al-Kali, H Joachim Deeg, Prapti A Patel, Mitchell Sabloff, Mary-Margaret Keating, Nancy Zhu, Nashat Y Gabrail, Salman Fazal, Joseph Maly, Olatoyosi Odenike, Hagop Kantarjian, Amy E DeZern, Casey L O’Connell, Gail J Roboz, Lambert Busque, Michael R Savona
{"title":"Oral decitabine–cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study","authors":"Guillermo Garcia-Manero, James McCloskey, Elizabeth A Griffiths, Karen W L Yee, Amer M Zeidan, Aref Al-Kali, H Joachim Deeg, Prapti A Patel, Mitchell Sabloff, Mary-Margaret Keating, Nancy Zhu, Nashat Y Gabrail, Salman Fazal, Joseph Maly, Olatoyosi Odenike, Hagop Kantarjian, Amy E DeZern, Casey L O’Connell, Gail J Roboz, Lambert Busque, Michael R Savona","doi":"10.1016/s2352-3026(23)00338-1","DOIUrl":"https://doi.org/10.1016/s2352-3026(23)00338-1","url":null,"abstract":"<h3>Background</h3><p><span><span>The DNA methyltransferase inhibitors </span>azacitidine and </span>decitabine<span><span><span> for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and </span>pharmacokinetics of oral decitabine plus the </span>cytidine deaminase<span> inhibitor cedazuridine versus intravenous decitabine.</span></span></p><h3>Methods</h3><p><span>We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia<span>, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine–cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m</span></span><sup>2</sup> per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine–cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine–cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC<sub>0–24</sub> for both oral decitabine–cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with <span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"8px\" viewbox=\"0 0 8 8\" width=\"8px\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg>, <span>NCT03306264</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"8px\" viewbox=\"0 0 8 8\" width=\"8px\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg>.</p><h3>Findings</h3><p>Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and fiv","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138770209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Oral decitabine plus cedazuridine versus intravenous decitabine","authors":"Theo de Witte","doi":"10.1016/s2352-3026(23)00363-0","DOIUrl":"https://doi.org/10.1016/s2352-3026(23)00363-0","url":null,"abstract":"Abstract not available","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138770461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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