Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy

Granulocyte colony-stimulating factor (G-CSF) has had a major impact on man agement of "severe chronic neutropenia," a collective term referring to con genital, idiopathic, or cyclic neutropenia, Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival . Some responders with congenital neutropenia have developed myelodysplasti c syndrome and acute myeloblastic leukemia (MDS/AML), which raises the ques tion of the role of G-CSF in pathogenesis. The Severe Chronic Neutropenia I nternational Registry (SCNIR), Seattle, WA, has data on 696 neutropenic pat ients, including 352 patients with congenital neutropenia, treated with G-C SF from 1987 to present. Treatment and patient demographic data were analyz ed. The 352 congenital patients were observed for a mean of 6 years (range, 0.1-11 years) while being treated. Of these patients, 31 developed MDS/AML , for a crude rate of malignant transformation of nearly 9%, None of the 34 4 patients with idiopathic or cyclic neutropenia developed MDS/AML, Transfo rmation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patien ts manifested abnormalities of chromosome 21 (usually trisomy 21). For each yearly treatment interval, the annual rate of MDS/AML development was less than 2%, No significant relationships between age at onset of MDS/AML and patient gender, G-CSF dose, or treatment duration were found (P >.15). In a ddition to the 31 patients who developed MDS/AML, the SCNIR also has data o n 9 additional neutropenic patients whose bone marrow studies show cytogene tic clonal changes but the patients are without transformation to MDS/AML, Although our data does not support a cause-and-effect relationship between development of MDS/AML and G-CSF therapy or other patient demographics, we cannot exclude a direct contribution of G-CSF in the pathogenesis of MDS/AM L, This issue is unclear because MDS/AML was not seen in cyclic or idiopath ic neutropenia. Improved survival of congenital neutropenia patients receiv ing G-CSF therapy may allow time for the expression of the leukemic predisp osition that characterizes the natural history of these disorders. However, other factors related to G-CSF may also be operative in the setting of con genital neutropenia. (C) 2000 by The American Society of Hematology.