Phenotype and Natural History of ELANE and NON ELANE Severe Congenital Neutropenia in Italy: Data from the National Registry

INTRODUCTION Severe Congenital Neutropenia includes several disorders characterized by absolute neutrophil count depletion appearing early in life, high propensity to potentially lethal infections and risk of myelodysplasia/acute leukemia. Mutations of ELANE and HAX 1 genes are often reported as the most frequent causes of SCN but many other genes are now recognized as causative of the disease.

AIM of The STUDY. To describe the clinical history and the outcome of SCN patients included in the Italian Neutropenia Registry (INR) and to investigate differences between ELANE and non- ELANE mutated groups

PATIENTS AND METHODS. Demographics, biochemical, clinical and genetic information were retrieved from the INR. OS probability was estimated by the Kaplan-Meier method.

RESULTS from June 2000 to June 2022 844 patients were reported to the INR and 106 (52% females) were diagnosed with SCN. Median age at diagnosis was 1 year (IQR 0.4-4.1) and at last follow up was 11years (IQR 6.0-19.4). Subjects were Caucasian in 90% of cases and of other ethnicities in 10% . Consanguinity occurred in 4/49 (8%) of the patients in which data were available.

Genetic testing performed in all patients, enabled a definite genetic diagnosis in 94% of the subjects whereas in the remaining 6% a genetic lesion was not found. Genetic lesions were distributed as follows: ELANE 54% of which 28% were cyclic , TAZ 10%, CXCR4 6%, SLC37A 4.6%, COH1 3%, JAGN1 3%, SDS 3%, G6PC3 3%, SRP54 2%, USB1 2%, HAX1 2%, CSFR3 1%, , GATA2 1%). Of 106 patients, 4 were also reported to specific Registries (SDS and GATA2) while 11% were lost to follow-up.

The 15 and 20-year overall survival of the 94 patients in active follow-up were respectively 93 % (83.6%-97.0%) and 87.4% (69.2%-95.2%) without differences between the ELANE and non ELANE groups. In the whole cohort 7/106 (7%) patients died and of them 3/7 for infections due to non compliance to G-CSF therapy, 2/7 for organ damage associated to the disease and 2/7 for complication after bone marrow transplantation. The cumulative incidence of MDS/AL after 20 yrs after diagnosis was 10,9% (3,2%-34%) that favorably compares with that from other Registries.

Total number of Infection episodes prior to SCN diagnosis, was 592 in 73 pts (42 in ELANE, 31 non- ELANE) and were: pharingytis and bronchitis (32%), skin and deep abscesses (22%), otitis/mastoidistis (17%), miscellaneous (29%) (enteritis, other upper respiratory , urinary tract infections and fever of unknown origin (14%), pneumonia (10%) and sepsis (5%)). In pre-diagnosis period otitis occurred more frequently in ELANE (64/316 episodes) vsnon ELANE (36/276) (p= 0,02). Sepsis were also more frequent, though non significantly in ELANE subset. On the contrary, urinary tract infections were more frequent in non-ELANE (27/35) vs ELANE (8/40) group ( p<0,001).

The post-diagnosis frequency of infections by age (0-5yrs, 6-10yrs and 10-15 yrs) in the whole group is shown in fig 1.

Apart from skin infections that increase in peri/pubertal period (11-15 years) we observed a progressive decrease of the number of all other infections with full disappearance of sepsis after the age of 5 years. No main differences was observed between ELANE and non- ELANE group.

Eighty-six % of patients were on G-CSF; 27% required doses>7,5 mcg/kg/day (12 ELANE and 1 HAX1), 22% needed 5 mcg/kg/day (8 ELANE, 1 USB1, 1 HAX1) and 51% (11 ELANE, 4 SCL37A, 7 TAZ, 1 JAGN1, 2 G6PC3, 1 CSFR3) required lower than 5 mcg/kg/day. Doses higher than 5 mcg/kg/day were more frequently used in ELANE vs non-ELANE group ( p=0.01).

Fourteen patients underwent bone marrow transplantation (12 ELANE, 1 SCN gene orphan, 1 HAX1 and 1 JAGN1) for leukemic transformation (3 patients), poor response to G-CSF (7) and center decision (4). The 10-year OS of transplanted subjects was 87.5% and was comparable with that of non-transplanted ones (93%) (p=0.21)

CONCLUSIONS. A genetic diagnosis was achieved in almost all SCN patents of the INR. ELANE mutations are the major cause of SCN and are associated to a more severe phenotype requiring higher doses of G-CSF and more frequent need for transplant. The relatively low incidence of MDS/AL in the whole cohort is consistent with a high proportion (73%) of patients receiving G-CSF dose ≤ 5 mcg/kg/day. Infection pattern improves overtime after diagnosis with disappearance of sepsis in both ELANE and non-ELANE subsets possibly reflecting the tight monitoring received by patients reported to registries.

Fioredda:X4 Pharmaceutics: Consultancy. Russo:Amgen, advisory board, Immune Thrombocytopenia: Membership on an entity's Board of Directors or advisory committees; Novartis, advisory Board, Immune Thrombocytopenia: Membership on an entity's Board of Directors or advisory committees; Junia Pharma, speaker at webinar, Iron deficiency anemia: Speakers Bureau; Grifols, advisory board, Immune Thrombocytopenia: Membership on an entity's Board of Directors or advisory committees. Dufour:Gilhead: Consultancy; Novartis: Consultancy; Biocryst: Consultancy; Pfizer: Consultancy.