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Severe chronic neutropenia (SCN) is defined as an absolute neutrophil (ANC) of less than

Background: In patients with severe congenital neutropenia (SCN), mortality from sepsis is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported in treated and untreated patients. Methods: We studied 374 patients with SCN and 29 patients with Shwachman-Diamond Syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. Results: In SCN, mortality from sepsis was stable at 0.9%/year. The hazard of MDS/AML increased significantly over time, from 2.9%/year after 6 years to 8.0%/year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for mortality from sepsis and 21% for MDS/AML. The hazard of MDS/AML increased with the dose of G-CSF. Twenty-nine percent of SCN patients received more than the median dose of G-CSF (≥8 μg/kg/day), but achieved less than the median absolute neutrophil count (ANC) response (ANC <2188 cells/μL at 6–18 months). In these less responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared to 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. An intermediate group achieved an ANC above the median on doses of G-CSF above the median; among them, the 10 year cumulative incidence was 15% for MDS/AML and 3% for mortality from sepsis. In secondary analyses, we found that pre-treatment blood cell counts could not predict the subsequent clinical outcome. Furthermore, on therapy, patients who were less responsive vis-à-vis their neutrophil counts had similar increases in eosinophils, basophils, monocytes, and lymphocytes, and similar decreases in platelets, as other patients maintained on ≥8 μg/kg/day. Consistent with the SCN results, in SDS patients, the limited available data do not suggest that G-CSF therapy is a risk factor for MDS/AML in SDS. Conclusions: The risk of MDS/AML was similarly low in all patients who achieved an ANC above the median on any dose of G-CSF. It appears that G-CSF has reduced mortality from sepsis, and revealed the underlying leukemic predisposition of SCN.

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Severe congenital neutropenia (CN) is a general term for a group of disorders characterized by extremely low blood neutrophil counts (ANC < 0.5 x 109 ), early stage maturation arrest of myelopoiesis, and recurrent bacterial infections. More than 90% of CN patients respond to daily G-CSF treatment with a sustained neutrophil increase associated with a significant reduction of infections and improved quality of life. However, prolonged survival unmasks an increased risk of leukemic transformation in some, but not all, subcategories of CN patients. The Severe Chronic Neutropenia International Registry (SCNIR) has collected longitudinal data on on more than 400 patients with various causes of CN. This unique resource allows classification of different subtypes of CN and estimation of the relative frequency of these conditions. Our new classification scheme is as follows: By inheritance - autosomal dominant severe congenital neutropenia (ADCN), autosomal recessive (ARCN, Kostmann syndrome), sporadic CN. By genetic aberrations - ELA2 related CN, SBDS related CN-(Shwachman-Diamond syndrome), G 4.5 on Xq28related neutropenia (Barth syndrome), CXCR4 related neutropenia (myelokathexis and WHIM syndrome). By clinical phenotype - associated symptoms (e. g. metabolic disorders, such as Shwachman-Diamond syndrome, glycogen storage disease 1b, Barth syndrome), G-CSF responsive or non-responsive CN, with or without G-CSF receptor mutations, with or without osteoporosis, or dysplastic features (e. g. organ abnormalities). By ethnic origin - e.g. CN in consanguineous Kurdish families, recessive neutropenia in Swedish family (Kostmann syndrome). Recent research and the work of the SCNIR now permit a much improved classification of CN. The identification of subtypes of CN, their distinctive risks of malignant transformation, and their responses to treatment has contributed substantially to our general understanding of the problem of neutropenia. This knowledge also now allows clinicians to give patients and families much improved prognostic information and better guidelines for therapy.