Abstract • 25
Background: Over the last decade recombinant human granulocyte-colony stimulating factor (G-CSF) has had a major impact on management of "severe chronic neutropenia", a term used collectively that refers to congenital, idiopathic or cyclic neutropenia. More tan 90% of patients respond to G-CSF with an increase in neutrophils to >1.5×109/l, and with a marked reduction in infections and a vastly improved survival. Several reports indicate that responders with congenital have developed myelodysplastic syndromes and acute myeloblastic leukemia (MDS/AML) raising the question of the role of G-CSF in the pathogenesis of the malignant transformation.
Methods: The Severe Chronic Neutropenia International Registry (SCNIR) has collected data of 531 neutropenic patients from 13 countries treated with G-CSF from 1987 to 1997, including 302 patients with congenital neutropenia. To clarify the risk of MDS/AML in congenital neutropenia and the potential role of G-CSF in pathogenesis, these data were analyzed with respect to treatment and patient demographics.
Results: The 302 patients with congenital neutropenia were observed on G-CSF treatment for a mean of five years (range 0.1 to 10 years). Twenty-seven developed MDS/AML giving a crude rate of malignant transformation of nine percent. Twenty-six had Kostmann's type of congenital neutropenia and one had Shwachman-Diamond syndrome. None of 229 patients with idiopathic or cyclic neutropenia for whom similar data were maintained developed MDS/AML. Conversion to MDS/AML was frequently associated with acquired marrow cytogenetic clonal changes: 14 developed partial or complete loss of chromosome 7, and nine manifested abnormalities of chromosome 21 (usually trisomy 21). The annual rate for MDS/AML for each yearly interval was less than two percent per year of treatment. No statistically significant relationship between age at onset of MDS/AML and patient gender, dose of G-CSF or duration of treatment with G-CSF was found (p values for all >0.15).
Conclusion: In the pre-cytokine era there were reports of MDS/AML developing spontaneously in patients with congenital forms of neutropenia indicating a propensity for malignant myeloid transformation. Our data do not support a cause-and-effect relationship between development of MDS/AML and G-CSF or duration of therapy in congenital neutropenia, nor with any other patient demographics. It is likely that the improved survival of congenital neutropenia patients with G-CSF therapy allows time for the expression of the leukemic predisposition that characterizes the natural history of these disorders.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Freedman, M., Bonilla, M., Fier, C. et al. Improved Survival From Granulocyte-Colony Stimulating Factor Therapy for Congenital Neutropenia Unmasks Predisposition to Myelodysplasia and Acute Myeloid Leukemia. Pediatr Res 45 (Suppl 5), 747 (1999). https://doi.org/10.1203/00006450-199905010-00055
Issue Date:
DOI: https://doi.org/10.1203/00006450-199905010-00055