Incidence and prognosis of clonal hematopoiesis in patients with chronic idiopathic neutropenia

Abstract

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. In the present study we sought to investigate the frequency and clinical significance of mutations of genes implicated in myeloid malignancies using next generation sequencing, in CIN patients (n=185) with a long follow-up. We found that 21/185 patients (11.35%) carried totally 25 somatic mutations in 6 genes with median variant allele frequency (VAF) 12.75%. The most frequently mutated genes were DNMT3A and TET2 involving more than 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 (5/185 patients; 2.70%). However, from the transformed patients four belonged to the clonal (4/21; 19.05%) and one to the non-clonal (1/164; 0.61%) group, indicating that the presence of mutation(s) confers a relative risk for transformation 31.24 (P = 0.0017). The VAF of the mutant clones in the transformed patients was higher than 10% in all cases and the genes most frequently associated with malignant transformation were the SRSF2 and IDH1. No significant differences were identified between clonal and non-clonal groups in the severity of neutropenia. Patients with clonal disease were older compared to non-clonal patients. These data contribute to the better understanding of the heterogeneous entities underlying ICUS and highlight the importance of the mutation analysis for the diagnosis and prognosis of patients with unexplained neutropenias.

Abnormal Platelet Counts and Clonal Hematopoiesis in the General Population

“… 10 , 21 Recently, the association between CH and anemia as well as neutropenia and monocytosis has been studied. 7 , 22 , 23 In a population-based case–control study, a higher prevalence of CH, particularly with SF3B1 and TP53 mutations, has been observed in older individuals with anemia. The presence of CH did not affect the risk of death in anemic individuals.…”

“… 7 Furthermore, it has been shown that the presence of CH in patients with chronic idiopathic neutropenia did not significantly correlate with the severity of neutropenia but mutations in SRSF2 and IDH1 were associated with malignant transformation. 22 Recently, it was shown in a clinical cohort of cases with primary immune thrombocytopenia (ITP, n = 14) that the presence of CH in ITP patients was closely related to disease severity and treatment responsiveness. Previously, it was described that the presence of mutations in U2AF1 and PPM1D are associated with decreased platelet counts, whereas mutations in DNMT3A , CALR , and JAK2 are associated with increased platelet counts.…”

Dynamin-2 deficiency causes age- and sex-dependent neutropenia and myelodysplasia in mice

“…36,37,38,39 Among humans and in mice models, certain types of MDS (myelodysplasia)/leukemia preferentially develop in aging females, such as the 5q-syndrome, and in mouse models with haploinsufficiency of cytoskeletal effector mDia1, that recapitulates many features of 5q-syndrome. 40,41 While, clonal hematopoiesis emerges as a still incompletely understood contributor to myelodysplasia in aging humans, 42 a recent study has reported human cases of clonal hematopoiesis harboring hotspots for protein-altering mutations in DNM2. 9 Interestingly, in recent reports, DNM2 (in particular, with loss of function mutation) is associated in a molecular signature with RUNX/RUNXT1 leukemia, 43 and DNM2 was associated with MDS at risk for transformation in the Oncomine database.…”

Clonal hematopoiesis in idiopathic cytopenia of undetermined significance

“…conducted an observation study concentrating on the relation between ICUS-N and CH, and found that SRSF2 and IDH1 mutations contributed to a higher risk of myeloid malignancy transformation [15]. However, there was still little data about the mutation status and outcome of ICUS patients [14,20,21].…”

“…Recently, it was reported that CH happened only in a relatively small proportion of ICUS patients with neutropenia (ICUS-N), while it signi cantly increased the risk of malignant transformation [15]. So far, the clinical signi cance and the mutation landscapes of CH in ICUS remain largely unknown.…”