title: Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.
abstract: Granulocyte colony-stimulating factor (G-CSF) has had a major impact on management of "severe chronic neutropenia," a collective term referring to congenital, 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 myelodysplastic syndrome and acute myeloblastic leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The Severe Chronic Neutropenia International Registry (SCNIR), Seattle, WA, has data on 696 neutropenic patients, including 352 patients with congenital neutropenia, treated with G-CSF from 1987 to present. Treatment and patient demographic data were analyzed. 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 344 patients with idiopathic or cyclic neutropenia developed MDS/AML. Transformation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patients 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 addition to the 31 patients who developed MDS/AML, the SCNIR also has data on 9 additional neutropenic patients whose bone marrow studies show cytogenetic 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/AML. This issue is unclear because MDS/AML was not seen in cyclic or idiopathic neutropenia. Improved survival of congenital neutropenia patients receiving G-CSF therapy may allow time for the expression of the leukemic predisposition that characterizes the natural history of these disorders. However, other factors related to G-CSF may also be operative in the setting of congenital neutropenia. (Blood. 2000;96:429-436)
authors.affiliation: Severe Chronic Neutropenia International Registry, University of Washington, and the University of Washington Department of Medicine, Seattle, WA, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Freedman
authors.forename: M A
authors.initials: MA
authors.lastname: Bonilla
authors.forename: C
authors.initials: C
authors.lastname: Fier
authors.forename: A A
authors.initials: AA
authors.lastname: Bolyard
authors.forename: D
authors.initials: D
authors.lastname: Scarlata
authors.forename: L A
authors.initials: LA
authors.lastname: Boxer
authors.forename: S
authors.initials: S
authors.lastname: Brown
authors.forename: B
authors.initials: B
authors.lastname: Cham
authors.forename: G
authors.initials: G
authors.lastname: Kannourakis
authors.forename: S E
authors.initials: SE
authors.lastname: Kinsey
authors.forename: P G
authors.initials: PG
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Cottle
authors.forename: K
authors.initials: K
authors.lastname: Welte
authors.forename: D C
authors.initials: DC
authors.lastname: Dale
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging; D002471:Cell Transformation, Neoplastic; D002648:Child; D002675:Child, Preschool; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000209:etiology* / Q000473:pathology; D009503:Neutropenia / Q000151:congenital* / Q000188:drug therapy* / Q000235:genetics; D013997:Time Factors
chemical_list: D016179:Granulocyte Colony-Stimulating Factor