A novel approach to defining progression in MDS and precursor myeloid conditions in the MDS Natural History Study.
Key claim: In a large prospective US cohort, progression from myeloid precursor conditions (ICUS/CCUS) to MDS was predicted by female sex, higher mutation burden, TP53 mutation, and poor cytogenetic score, with progression rates ranging from 17% in ICUS/IDUS to 73% in higher-risk MDS.
Abstract
Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.
Why this matters
Although focused on MDS rather than MPN, this study refines how precursor clonal states (ICUS/CCUS) evolve toward overt myeloid neoplasia, identifying mutation burden, TP53, and cytogenetic risk as progression drivers. These findings inform the MPN field’s parallel question of how CHIP and low-burden driver clones transition to overt MPN, reinforcing mutation burden and high-risk co-mutations as conserved progression markers across myeloid precursor conditions.