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

• Published in: Blood Vol. 96; no. 2; pp. 429 - 436
• Main Authors: FREEDMAN, M. H, BONILLA, M. A, MORI, P. G, COTTLE, T, WELTE, K, DALE, D. C, FIER, C, BOLYARD, A. A, SCARLATA, D, BOXER, L. A, BROWN, S, CHAM, B, KANNOURAKIS, G, KINSEY, S. E
• Format: Journal Article
• Language: English
• Published: Washington, DC The Americain Society of Hematology 15-07-2000
• Subjects: Adolescent; Adult; Aging; Biological and medical sciences; Cell Transformation, Neoplastic; Child; Child, Preschool; Female; Granulocyte Colony-Stimulating Factor - adverse effects; Granulocyte Colony-Stimulating Factor - therapeutic use; Hematologic and hematopoietic diseases; Humans; Infant; Leukemia, Myeloid, Acute - etiology; Leukemia, Myeloid, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Myelodysplastic Syndromes - etiology; Myelodysplastic Syndromes - pathology; Neutropenia - congenital; Neutropenia - drug therapy; Neutropenia - genetics; Time Factors; Human; Immunopathology; Leukopenia; Congenital; Pathogenesis; Acute; Cytokine; Malignant hemopathy; Hemopathy; Kostmann syndrome; Immune deficiency; Myelodysplastic syndrome; Genetic disease; Concomitant disease; Granulocyte colony stimulating factor; Treatment; Polypeptide; Evolution; Acute myelocytic leukemia; Neutropenia
• ISSN: 0006-4971; 1528-0020

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)