The incidence and prognosis of clonal hematopoiesis in patients with isolated neutropenia among patients with idiopathic cytopenia of undetermined significance (ICUS), known as ICUS-N or chronic idiopathic neutropenia (CIN) patients, is poorly defined. The current study sought to investigate the frequency and clinical significance of mutations of genes implicated in myeloid malignancies using next-generation sequencing in patients with CIN (n = 185) with a long follow-up. We found that 21 (11.35%) of 185 patients carried a total of 25 somatic mutations in 6 genes with a median variant allele frequency of 12.75%. The most frequently mutated genes were DNMT3A and TET2 involving >80% of patients, followed by IDH1/2, SRSF2, and ZRSR2. The frequency of transformation to a myeloid malignancy was low in the total group of patients (5 of 185 patients [2.70%]). However, from the transformed patients, 4 belonged to the clonal group (4 of 21 [19.05%]) and 1 to the nonclonal group (1 of 164 [0.61%]), indicating that the presence of mutation(s) confers a relative risk for transformation of 31.24 (P = .0017). The variant allele frequency of the mutant clones in the transformed patients was >10% in all cases, and the genes most frequently associated with malignant transformation were SRSF2 and IDH1. No significant differences were identified between the clonal and nonclonal groups in the severity of neutropenia. Patients with clonal disease were older compared with nonclonal patients. These data contribute to the better understanding of the heterogeneous entities underlying ICUS and highlight the importance of mutation analysis for the diagnosis and prognosis of patients with unexplained neutropenias.

There is remarkable morphologic and genetic heterogeneity in acute myeloid leukemia (AML). In a small percentage of cases of AML, increased eosinophils and/or basophils are present in the bone marrow and sometimes in the peripheral blood. This is often a puzzling diagnostic situation but also an important finding that requires special investigation. Unique chromosomal rearrangements have been correlated with an increased number of eosinophils and basophils in AML. The identification of the underlying genetic lesion that promotes eosinophilia and basophilia can dramatically change both the prognosis and the treatment of the patient. Thus, clinicians must be vigilant in searching for the cause of eosinophilia and basophilia in patients with AML, since the different causes may lead to different treatments and survival outcomes. In this article, we examine the significance of increased eosinophils and/or basophils in the context of AML, provide guidance that simplifies the differential diagnosis, and give prognostic and therapeutic information about specific subtypes of AML associated with eosinophilia and/or basophilia. Evidence supporting personalized (molecularly targeted) therapy for these patients is also presented.

There is remarkable morphologic and genetic heterogeneity in acute myeloid leukemia (AML). In a small percentage of cases of AML, increased eosinophils and/or basophils are present in the bone marrow and sometimes in the peripheral blood. This is often a puzzling diagnostic situation but also an important finding that requires special investigation. Unique chromosomal rearrangements have been correlated with an increased number of eosinophils and basophils in AML. Identification of the underlying genetic lesion that promotes eosinophilia and basophilia can dramatically change both the prognosis and the treatment of the patient. Thus clinicians must be vigilant in searching for the cause of eosinophilia and/or basophilia in patients with AML, since the different causes may lead to different treatments and survival outcomes. In this article we examine the significance of increased eosinophils and/or basophils in the context of AML, provide guidance that simplifies the differential diagnosis, and prognostic and therapeutic information about specific subtypes of AML associated with eosinophilia and/or basophilia. Evidence supporting personalized (molecularly targeted) therapy for these patients is also presented.

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.