P821: LATE ONSET AND/OR LONG LASTING NEUTROPENIA IN CHILDHOOD: CLINICAL AND HEMATOLOGICAL CHARACTERISTICS AND OUTCOMES

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Background: In contrast with primary autoimmune neutropenia of infants and pre-school children, characterized by the presence of anti-polymorphonuclear antibodies (anti-PNN), benign course and spontaneous resolution at age 3-5 years, late onset (LO) and/or long lasting (LL) neutropenia of childhood is vaguely described. Aims: To address characteristics and outcomes in a cohort of children with LO/LL diagnosed and followed by our Department. Methods: Cross-sectional study of patients aged 0-16 years with LO (age >5 years, in accordance with Fioredda et al, 2020) or LL (duration >3 years) neutropenia (1.5 G/L) +/- leukopenia (Z-score ≤2 according to age and gender); with a first visit or continued follow-up in our Department of Pediatric Hematology-Oncology (T.A.O.) during the period 2015-2020. Patients with severe congenital neutropenia (SCN) were excluded. Detection of anti-PNN using GAT and GIFT was centralized. Results: From 1972 to 2021, 534 cases of neutropenia/leukopenia were recorded (5, 40, 82, 134, 273 during 1970-1979, 1980-1989, 1990-1999, 2000-2009, 2010-2021, respectively); 152 were included in the cross-sectional study. Sixty-one (40%) had no LO/LL (age<5 years, resolution within≤3 years), 77 (51%0 had LO and 14 (9%) had LL. Male/female ratio was 47% vs 52% vs 28% in no LO/LL vs LO vs LL, respectively (P=0.27), median age 1 vs 11.1 vs 3.1 years (P<10-4), median neutrophil count 0.5 vs 1.2 vs 0.6 G/L (P<10-4), and with concomitant leukopenia in 27% vs 53% vs 36% (P=0.009) or lymphopenia in 3% vs 10% vs 7% of cases (P=0.27). Anti-PNN were detected in 83% vs 42% vs 60% of patients no LO/LL vs LO vs LL, respectively (P=0.12). Familial neutropenia was observed in three pairs of siblings/cousins with LL, possible ethnic neutropenia in 7 patients, probable genetic predisposition to cancer in 4 patients LO/LL and a congenital metabolic syndrome in one patient LL. Infection, mostly cutaneous, occurred in 17% vs 24% vs 66% no LO/LL vs. LO vs. LL (P=0.02). Bone marrow examination was performed in 8 patients (4 LO, 4 LL) and showed mild hypoplasia in 2 (LO). Mild peripheral blood lymphocytic subsets abnormalities were observed in ¼ of the patients, particularly in LO, and mild reduction of serum immunoglobulin class levels in ¼ of the patients, without difference between no LO/LL and LO. Genetic typing performed in 9% of patients LO/LL (targeted pediatric MDS panel N=2, primary immunodeficiency N=2, SCN N=1, whole-exome sequencing N=2) showed a heterozygous TACI mutation in one patient with LL and frequent infections of moderate severity. In total, MDS, immunodeficiency and autoimmunity was noted in 1%, 5% and 4% of patients LO and immunodeficiency in 14% of patients LL. One patient LL developed B-cell precursor ALL. One patient LO with Evans syndrome received eltrombopag, without response, and MMF with response. All patients are alive. Neutropenia resolved spontaneously in 54% of patients. Two-year probability of unresolved neutropenia was 26% vs 78% vs 100% in patients no LO/LL, LO and LL, respectively (P<10-4). Summary/Conclusion: LO/LL neutropenia might be associated with bone marrow failure syndromes, immunodeficiency or autoimmunity. Long-term follow-up and investigations are needed in children with LO/LL neutropenia. Genetic typing in specialized reference networks, like EuNet-INNOCHRON or EWOG, might identify diagnostic subgroups of clinical relevance.