Late Development of Acute Myeloid Leukemia in Two Peripheral Blood Stem Cell Donors Mobilized with G-CSF.

The long-term risk to healthy donors following recombinant human granulocyte colony stimulating factor (rhG-CSF) mobilization for peripheral blood stem cell collection is unknown. Here we report two cases of acute myeloid leukemia (AML) arising in healthy donors following peripheral blood stem cell mobilization (SCM). The first patient was a 55-year-old woman who underwent SCM with rhG-CSF 10 mcg/kg/day for 5 days followed by apheresis, collecting 2.22 x 106 CD34+ cells/kg which were donated for an HLA-identical sibling with AML in April of 1996. She was found to be pancytopenic 4 years later in December of 2000, and a bone marrow aspirate and biopsy confirmed AML FAB M6. She underwent standard induction and consolidation chemotherapy followed by matched unrelated donor stem cell transplantation (SCT) in May of 2001, but died of progressive disease in November of 2001. The second healthy donor was a 40 year old man who was mobilized twice, two weeks apart, with rhG-CSF 10 mcg/kg/day for 5 days followed by apheresis in August of 1998. His first collection yielded 31.3 x 106 CD34+ cells/kg and his second collection yielded 31.6 x 106 CD34+ cells/kg, which were donated for an HLA-identical sibling with AML. He was well until 5 years later when in November of 2003 he was diagnosed with AML FAB M5A. He underwent induction chemotherapy followed by consolidation which included autologous SCT in March of 2004, and currently remains in remission. Both recipients died of progressive disease within one year of transplantation, well before either of their donors was diagnosed with acute leukemia. At our institution, 297 donors have undergone growth factor mobilization and stem cell collection since 1999, with the development of AML in these 2 previously healthy donors. The SEER Cancer Statistics Review 1975–2001 describes an incidence of AML for all ages in 2001 of 2.6/100,000, with an incidence of 1.8/100,000 in persons age age 65 from 1997–2001. The longest follow-up to date of healthy donors who received rhG-CSF for mobilization found that none of the 101 donors evaluated was diagnosed with a hematologic malignancy after a median follow-up of 3.7 years (Bone Marrow Transplantation, 2000, 25:85–89). Other studies have evaluated the safety of long-term use of G-CSF in both aplastic anemia (AA) and congenital neutropenia. A study of 87 AA patients treated with rhG-CSF found no increased incidence of AML/MDS during a median follow-up of 3.8 years compared with 57 patients who did not receive rhG-CSF during the same period (Lancet, 357, January 6, 2001). A report from the Severe Congenital Neutropenia International Registry which evaluated patients with congenital neutropenia (CN), cyclic neutropenia (CyN), and idiopathic neutropenia (IN) found no cases of AML or MDS in patients with CyN or IN treated with prolonged G-CSF, while 31 CN patients developed malignant myeloid transformation (Blood, 15 July 2000, Vol 96 No 2), some of which may have been related to mutations in the G-CSF receptor (N Engl J Med 1995: 333:487–93). This case report highlights the need for long-term prospective studies evaluating the incidence of hematologic disorders in mobilized stem cell donors. While any increased risk of leukemia found in donors could be due to genetic and/or environmental influences, the potential contribution of stimulation of a quiescent population of stem cells in individuals with a family history of AML must be considered.