Long‐term mutational analysis, clonal metrics, and dynamics in patients with chronic idiopathic neutropenia

Abstract Characterization of the presence and evolution of clonal hematopoiesis (CH) in patients with unexplained cytopenias is fundamental to risk‐stratifying patients and optimizing clinical surveillance for malignant progression. We investigated the mutational spectrum and clonal metrics in a cohort of 256 patients with chronic idiopathic neutropenia (CIN)—clinically overlapping with idiopathic cytopenia of undetermined significance with isolated neutropenia (ICUS‐N)—and assessed clonal presence and dynamics through longitudinal tracking of 104 patients with a median follow‐up of 32 months. CH was identified in 12.5% of patients, primarily involving single DNMT3A or TET2 mutations. Longitudinal analysis revealed two distinct mutational patterns: an age‐related pattern, predominantly involving DNMT3A and TET2 single mutations, which showed marginal changes in clone size and associated with stable disease course, and a high‐risk pattern, primarily driven by SRSF2 and IDH1/2 mutations, characterized by higher clonal expansion and a high risk of malignant progression. Malignant transformation in CIN was significantly associated with baseline variant allele frequency (VAF) (VAF > 10%), the presence of multiple mutations, and detection of specific driver mutations ( SRSF2 , IDH1/2 ). An annual VAF increase (ΔVAF/year) ≥7.5% was found to optimally predict evolution, thus showing that clonal dynamics can serve as an indicator of disease outcome. Longitudinal assessment of peripheral blood hematologic parameters was found not to display clinically significant changes. These findings provide important insight into high‐risk evolutionary patterns in CIN and underscore the importance of longitudinal monitoring with next‐generation sequencing (NGS) for clinical decision‐making and risk‐adapted management in CIN patients with clonal cytopenia.