Predicting cytopenias, progression, and survival in patients with clonal cytopenia of undetermined significance: A prospective cohort study Journal Article

  

Authors:	Cargo, C.; Bernard, E.; Beinortas, T.; Bolton, K. L.; Glover, P.; Warren, H.; Payne, D.; Ali, R.; Khan, A.; Short, M.; Van Hoppe, S.; Smith, A.; Taylor, J.; Evans, P.; Papaemmanuil, E.; Crouch, S.
Article Title:	Predicting cytopenias, progression, and survival in patients with clonal cytopenia of undetermined significance: A prospective cohort study
Abstract:	Background Somatic mutations are frequently reported in individuals with cytopenia but without a confirmed haematological diagnosis (clonal cytopenia of undetermined significance; CCUS). These patients have an increased risk of progression to a 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.Methods This prospective cohort study was conducted at the Haematological Malignancy 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<middle dot>54 years (IQR 4<middle dot>03-5<middle dot>04). Data were collected manually from hospital records or extracted from laboratory or clinical outcome databases.Findings 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<middle dot>0%] female and 1229 [59<middle dot>0%] male) met the inclusion criteria and had samples of sufficient quality for further analysis. 598 (28<middle dot>7%) patients received a diagnosis on the basis of their biopsy sample, whereas 1485 (71<middle dot>3%) samples were classified as non-diagnostic; of these, CCUS was confirmed in 400 (26<middle dot>9%) patients (256 [64<middle dot>0%] male and 144 [36<middle dot>0%] female). TET2, SRSF2, and DNMT3A 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<middle dot>0001), sex (p=0<middle dot>0027), and mutations in ASXL1 (p=0<middle dot>0009), BCOR (p=0<middle dot>0056), and TP53 (p=0<middle dot>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<middle dot>0024; three or more mutations, p=0<middle dot>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 DDX41 and UBA1, suggesting that these genes should be included in clinical test panels.Interpretation Mutation analysis is advised in patients who have undergone bone marrow examination and have an otherwise-unexplained cytopenia. High-risk genetic mutations and increased numbers of mutations are predictive of both survival and progression within 5 years of presentation, warranting clinical surveillance and, when necessary, intervention.
Keywords:	risk; hematopoiesis; myelodysplastic syndromes; mds; somatic mutations; biological implications
Journal Title:	The Lancet Haematology
Volume:	11
Issue:	1
ISSN:	2352-3026
Publisher:	Elsevier Science, Inc.
Date Published:	2024-01-01
Start Page:	e51
End Page:	e61
Language:	English
ACCESSION:	WOS:001143636800001
PROVIDER:	wos
PUBMED:	38135373
DOI:	10.1016/S2352-3026(23)00340-X
Notes:	Article -- Source: Wos

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