New approaches to idiopathic neutropenia in the era of clonal hematopoiesis

Isolated chronic idiopathic neutropenia (CIN) is a rare disease with multiple contributing etiologies that must be ruled out before establishing a diagnosis. We studied clinical and molecular data of 238 consecutive adult patients with CIN. Autoimmune neutropenia was present in 28% of our cohort. In contrast, T cell-mediated neutropenia was the main underlying pathological mechanism among patients with T cell expansions, such as T-cell large granular lymphocytic leukemia (T-LGL) and T cell clonopathy of undetermined significance, found in 37% and 8% of cases, respectively. Patients with neutropenia also had hypogammaglobulinemia (6%) and/or monoclonal gammopathy of undetermined significance (5%). NGS application has further broadened the spectrum of causes of CIN by including manifestations of clonal hematopoiesis, present in 12% of cases. TET2 (3%), TP53 (2%), and IDH1/IDH2 (2%) mutations were the most commonly found and were enriched in cases with T-LGL. We show that these clinico-molecular associations can be simultaneously present, complicating a proper diagnostic distinction within the broader entity of seemingly idiopathic neutropenia of autoimmune origin. Identification of etiologic culprits may also guide rational selection of therapies.