Risk of myelodysplastic syndrome and acute myeloid leukemia in congenital neutropenias

Semin Hematol. 2002 Apr;39(2):128-33. doi: 10.1053/shem.2002.31912.


Granulocyte colony-stimulating factor (G-CSF) has had a major impact on the management of "severe chronic neutropenia" (SCN), 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 and Shwachman-Diamond syndrome (SDS) have developed myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The issue is complicated because both disorders have a propensity for MDS or AML as part of their natural history. To address this, the Severe Chronic Neutropenia International Registry (SCNIR) used its large database of chronic neutropenia patients treated with G-CSF to determine the incidence of malignant myeloid transformation in the two disorders, and its relationship to treatment and to other patient characteristics. No statistically significant relationships were found between age at onset of MDS or AML and patient gender, G-CSF dose, or duration of G-CSF therapy. What was observed, however, was the multistep acquisition of aberrant cellular genetic changes in marrow cells from patients who transformed, including activating ras oncogene mutations, clonal cytogenetic abnormalities, and G-CSF receptor mutations. In murine models, the latter produces a hyperproliferative response to G-CSF, confers resistance to apoptosis, and enhances cell survival. Since congenital neutropenia and SDS are inherited forms of bone marrow failure, G-CSF may accelerate the propensity for MDS/AML in the genetically altered stem and progenitor cells, especially in those with G-CSF receptor and ras mutations (82% and 50% of patients who transform, respectively). Alternatively, and equally plausible, G-CSF may simply be an "innocent bystander" that corrects neutropenia, prolongs patient survival, and allows time for the malignant predisposition to declare itself. In patients who transform to overt MDS or AML, hematopoietic stem cell transplantation is the only chance for cure. In those with "soft" signs of MDS, such as an isolated clonal cytogenetic change but without other evidence of MDS, or with an isolated G-CSF receptor mutation, there is room for conservative management. One option is to reduce the G-CSF dosage as much as possible, and observe the tempo of progression, if any, to more overt signs of malignancy.

Publication types

  • Review

MeSH terms

  • Acute Disease
  • Animals
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / pathology
  • Granulocyte Colony-Stimulating Factor / adverse effects
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • Humans
  • Leukemia, Myeloid / epidemiology
  • Leukemia, Myeloid / etiology*
  • Myelodysplastic Syndromes / epidemiology
  • Myelodysplastic Syndromes / etiology*
  • Neutropenia / complications*
  • Neutropenia / congenital
  • Neutropenia / epidemiology
  • Risk Factors


  • Granulocyte Colony-Stimulating Factor