Severe congenital neutropenia (SCN) is a heterogeneous disorder of myelopoiesis characterized by an absolute neutrophil count (ANC) persistently below 0.50 x 109/L (500/[um]L), with maturation arrest of neutrophil precursors of the bone marrow at the promyelocyte/myelocyte stage. G-CSF treated and untreated SCN patients are at risk of developing MDS/AML. Clinicians caring for these patients must vigilantly observe for evidence of evolution to malignancy and continually consider hematopoietic transplantation as an alternative therapy. We have previously reported that SCN patients requiring higher daily doses of G-CSF treatment (> 8 mcg/kg/day) are at an increased risk of MDS/AML, and that this risk is not predicted by pre-treatment bone marrow examinations or the pre-treatment ANC. We have reviewed clinical data for 46 patients over a 15-year period who were referred to the Severe Chronic Neutropenia International Registry (SCNIR) and developed MDS/AML. Four patients referred with a history of SCN had increased blasts on the bone marrow evaluation prior to G-CSF treatment or enrollment in the SCNIR. Blood counts were not available for two patients. For the other 40 patients, all treated with G-CSF for a median of 79 months (range 0.8 to 182 months), comparison of blood counts for the periods 12–24 months and 0–3 months before the diagnosis of MDS/AML showed:


Changes in blood counts for the patient population may suggest a potential for malignant transformation. In these 40 cases, the principal clinical findings leading to the diagnosis of MDS/AML were: routine bone marrow surveillance 38%, decreased peripheral blood counts 26%, increased infections 10%, increased blasts in the blood 5%, decreased ANC with requirement for increased G-CSF dosage 2%, hepatosplenomegaly 2%, other (1 septal panniculitis and 1 leukemia cutis) 5%, and unknown 12%. The finding of mutations in the ELA2 gene in 10 of 15 cases (67%) did not influence the likelihood of MDS/AML. Previously we found that the duration and dose of G-CSF and alterations of the ANC on G-CSF therapy, suggest a high risk of transformation over time. Based on these data, the SCNIR recommends that patients with SCN have regular surveillance of blood counts every 1 to 2 months and annual bone marrow examinations with cytogenetic studies. Our findings suggest that a decline or change in blood counts of individual patients over a 3-month period may be informative in recognizing transformation to MDS/AML.

Author notes

Disclosure:Consultancy: Dr. David C. Dale is a consultant and receives research funds from Amgen. Research Funding: Dr. David C. Dale is a consultant and receives research funds from Amgen. Financial Information: Dr. Laurence A. Boxer has a close relative with Amgen stock.