Chronic Idiopathic Neutropenia In Adults: Clinical Features In a 4-Year Prospective Study

Chronic idiopathic neutropenia (CIN) is a rare acquired hematological condition, defined by an absolute neutrophil count (ANCs) lower than 1.8 x10³/µL in white and 1.5 x10³/µL in black people for more than 3 months, either in the absence or in the presence of anti-neutrophils antibodies (autoimmune forms). CIN is usually diagnosed after the exclusion of congenital and secondary forms. The former are usually marked by frequent and severe infections, that occur early in life, and by and increased risk of evolution to acute myeloid leukemia or myelodisplastic syndromes. In this prospective study we followed up 56 patients with CIN (21 males and 35 females, median age 55 years, range 25-86 years) for a median time of 48 months from January 2009 (10 patients had a previous follow-up of 8 years and 2 of 10 years), focusing on 1) severity of neutropenia, 2) ANCs variations (by general estimating equations GEE models), 3) positivity for anti-neutrophil antibodies (by direct and indirect granulocyte immunofluorescence test), 4) bone marrow features, 5) incidence of infectious episodes, and 6) evolution to definite clonal hematologic diseases (hairy cell leukemia HCL, chronic expansion of NK cells and myelodisplastic syndrome MDS). The mean ANCs were stably under the normal range (1.5-6.5 x10³/µL) at all the time points considered; by GEE analysis, a great inter-subject variability was observed during the follow-up (p=0.012), whereas no significant intra-subject variations were found. Considering the severity of neutropenia, 21 patients (47%) showed neutrophils lower than 1x10³/µL at enrollment (median 0.49 x10³/µL, range 0.1-0.969 x10³/µL), and 8 cases <0.5 x10³/µL. The mean ANCs observed during the follow up were significantly lower in males than in females (p=0.023) and in cases with mild splenomegaly, although not significantly (11 cases, 20%, mean maximal diameter 11,4 cm by ultrasonography), independently from gender (multivariate analysis). Anti-neutrophil antibodies were detected in 19/56 patients (34%), and mean ANCs values over the follow up were significantly lower in positive versus negative cases (p=0.027). Lymphocyte values greater than the upper normal value of our series (3.4 x10³/µL) were observed in 5/56 patients (9%). By peripheral blood immunophenotyping (N=23), 13 (56.5%) patients displayed absolute NK+ cells greater than 0.2 x10³/mL (normal NK cut-off value), but all under below 2 x10³/µL. Bone marrow evaluation was performed in 27 patients: median cellularity was 35% (range 13-75), and 10/27 (37%) displayed a value lower than 25% (threshold for hypocellularity in aplastic anemia); 19/27 (70%) showed some dysplastic cells, even if less than 10% dysplastic cells and without coexistent MDS-related karyotype; cytogenetic was normal in 24 cases (89%), while 3 males, all older than 60 years, displayed a 45, X0 karyotype (7, 6 and 3 metaphases respectively. Finally, 10 patients (18%) showed monocytosis, and 6 (10%) a MGUS. An infection needing oral antibiotic or antiviral therapy occurred in 13 patients (25%) (2 pneumonias, 7 upper respiratory tract, 3 Herpes Zoster Virus and 1 urinary tract infections), without relationship with the patient’s mean ANCs value, the nadir of ANC value, nor with the presence of anti-neutrophil antibodies. During the follow-up, because of suspected progression/evolution, 14 patients were re-evaluated by bone marrow biopsy or peripheral immune-phenotyping: 4 cases were diagnosed with chronic NK expansion, 4 with HCL, and 2 with MDS, one refractory cytopenia with unilineage dysplasia (RCUD) and one with multilineage dysplasia (RCMD). No association was found between evolution and ANCs, both as values at enrolment and mean counts over the follow up, nor with gender, presence of anti-neutrophils antibodies, monocytosis, splenomegaly, electrophoresis abnormalities and infections. All 4 patients, who developed an NK-expansion, showed peripheral lymphocytes >3.4 x10³/µL at enrolment (>5x10³/µL in only 1 case), and 3 cases displayed increased NK cells at peripheral immune-phenotyping (p= 0.018). In conclusion, CIN in adults is a benign disease, with an infectious rate not superior to that of the general population and a great variability in ANCs values. During this prospective observation, 10 CIN patients evolved, reaching the criteria for clonal hematological diseases, suggesting that this condition deserves clinical follow up.