PF349 57 PATIENTS WITH HAX1 ASSOCIATED CONGENITAL NEUTROPENIA: AN ANALYSIS OF THE EUROPEAN SEVERE CHRONIC NEUTROPENIA INTERNATIONAL REGISTRY (SCNIR)
Authors: C. Zeidler, S. Mellor‐Heineke, F. Froemling, N. Gerschmann, J. Skokowa, K. Welte
Journal: HemaSphere (2019)

Background: Congenital neutropenia (CN) is a heterogeneous group of rare inborn genetic defects with different gene mutations and different patterns of inheritance. Mutations in the HCLS1 associated Protein X‐1 ( HAX1) make up the largest cohort of autosomal recessive CN in Europe. There are two HAX1 splice isoforms. Mutations affecting one isoform (p.W44X) only can be found in consanguineous families of Turkic or Arabic origin while mutations affecting both isoforms were found in the original pedigree from Sweden (p.Q190X) and in Japanese pts (p.R86X). Independent of the mutation, HAX1 pts benefit from G‐CSF treatment, which improved the life expectancy and quality of life significantly. However, a significant risk of secondary leukemia has been unmasked for pts with HAX1 mutations (comparable to pts with ELANE mutations). Aims: Here we report on the genotype – phenotype correlation and outcome of pts revealing different HAX1 mutations. Methods: We identified 57 pts with HAX1 mutations within the CN cohort documented by the European Branch of the SCNIR since 1994. Results: HAX1 mutations have been identified in 57 (25 female; 32 male) of 501 pts with CN. The median age is 9.49 years ( range 0.28–38.69 years), with 664.83 pt years under observation. 45 of 57 pts reveal homozygous mutations in one transcript variant (p.W44X), in 1pt with an additional heterozygous ELANE mutation. In 2 of 57 pts, both isoforms are affected (p.Q190X). 5 of 57 pts have mutations at other sites of the HAX1 gene and in 5 pts the position was not reported. At diagnosis, all HAX1 pts presented with severe neutropenia and a maturation arrest at the promyelocyte/myelocyte stage in the bone marrow. All pts received long‐term G‐CSF treatment with a median dose of 4.25 μg/kg/day compared to 4.61 μg/kg/day for the total CN cohort of the SCNIR Europe. Median ANC increased from 160 to 1775/μL during G‐CSF treatment. Additional clinical features included cardiac defects in 4 pts, hypogonadism in 5 female pts and growth retardation in 6 pts, of whom 2 pts received growth hormone therapy. In addition to the 2 pts affecting both HAX1 isoforms, neurological involvement like mental retardation or epilepsia was identified in 3 pts. 8 of the 57 pts (14.04 %) developed secondary MDS or leukemia (age at diagnosis 0.98–15.98 years, median 8.59 years). 7 of the 8 pts carry mutation p.W44X, 1 pt carries p.Q190X. All 8 pts were treated with allogeneic SCT. In addition, 2 pts (age 0.88 and 18.11 years) received SCT for other reasons (prior to G‐CSF availability; cure of primary disease), but none for G‐CSF non‐responsiveness. G‐CSF doses were higher in pts with leukemia (7.05 μg/kg/day) compared to non‐leukemic pts (3.64 μg/kg/day) as previously reported for other CN pts. 54 of 57 pts are alive, 1 pt expired from sepsis at age 2 years after developing hemophagocytic lymphohistiocytosis, 2 pts transplanted for leukemia expired (1 of TRM at age 13 years; 1 of alveolar haemorrhage after leukemia relapse at age 11 years). Summary/Conclusion: All pts with HAX1 mutations present with profound neutropenia, but respond well to long‐term G‐CSF treatment. There are additional organ involvements in subsets of pts. All pts with HAX1 mutations have a significant risk for secondary leukemia. Registry and biobanks are extremely valuable for understanding the consequences of rare hematological diseases such as congenital neutropenia.