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Acute myeloid leukemia in a healthy hematopoietic stem cell donor following past exposure to a short course of G-CSF

Bone Marrow Transplantation volume 42, pages 431–432 (2008)Cite this article

The possibility of normal donors developing leukemia as a delayed adverse effect from short-term exposure to G-CSF has been postulated but remains controversial.1 We report on a 39-year-old man who developed AML 4.6 years after being the PBSC donor for his HLA-identical brother. His brother had AML subtype FAB M1, normal male karyotype, and an isolated skin lesion on his left calf consistent with leukemia cutis but no evidence of any other extramedullary disease. Our patient received a short course of G-CSF, 16 μg/kg/day for 5 days, prior to leukapheresis with no immediate adverse effects. One apheresis procedure yielded a total of 8.54 × 106 CD34+ cells per kg recipient weight. Cytofluorometric analyses of the PBSC product revealed normal staining intensity and side scatter properties of various cellular subpopulations expressing surface CD34, CD3, CD4, CD8, CD14, CD20 and/or CD56. However, 4.6 years later he presented with fatigue, a skin abscess and pancytopenia, and his BM aspirate was consistent with AML FAB M2, with a normal male karyotype. He was also found to have hypernatremia due to central diabetes insipidus. A ring-enhancing hypothalamic lesion was detected by cerebral magnetic resonance imaging, consistent with a leukemic central nervous system infiltrate. No malignant cells or infectious agents were identified in the cerebrospinal fluid. The patient's prior medical history was remarkable for hyperlipidemia and diet-controlled type II diabetes mellitus, with no prior exposure to toxins or chemicals. Aside from his brother, there was no other family history of leukemia. The patient received induction chemotherapy with cytarabine and daunorubicin followed by three cycles of high dose cytarabine for consolidation. The treatment for central nervous system involvement by leukemia consisted of intrathecal cytarabine and methotrexate, as well as whole brain radiation. Unfortunately, he developed a necrotizing leukoencephalopathy (confirmed by stereotactic brain biopsy), resulting in marked persistent neurological impairment.

To date, there are insufficient data to estimate the potential leukemogenic risk that G-CSF poses to healthy stem cell donors. Few cases have been reported in the literature; there has been one case report2 and several retrospective cohort studies.3, 4, 5, 6 There are three reported cases of AML in healthy sibling donors described in detail.2, 3 Two of these cases had skin rash, one of which was confirmed as leukemia cutis.2, 3 A third patient developed central nervous system leukemia at relapse after a matched unrelated Allo-SCT was also complicated by cyclosporine-associated leukoencephalopathy.3 The development of leukemia in HLA-identical sibling donors may simply reflect the inherent increased risk of these individuals to develop leukemia regardless of their exposure to G-CSF. It is known that family members of patients with myeloid leukemias are themselves at an increased risk of developing leukemia.7 Thus, it is difficult to assess the increased risk in this potentially susceptible population and any link between G-CSF exposure and the development of leukemia in this and other reported cases remains !unclear. The mechanism(s) whereby G-CSF use can predispose to leukemia is also unclear. G-CSF was shown to generate epigenetic and genetic alterations in lymphocytes in a small cohort of 18 normal volunteer donors8 and could induce tetraploidy in PBSCs of otherwise healthy donors.9 However, in another study, G-CSF did not appear to induce long-term DNA instability when the extent of double-stranded DNA relaxation and de novo synthesis of DNA were examined in healthy donors.10 In practice, reassuring data have come from follow-up of large cohorts like the one from the US National Marrow Donor Program, in which none of the 897 donors followed up for at least 4 years had developed leukemia or lymphoma.4

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  1. Division of Hematology, Department of Medicine, London Health Sciences Centre, London, Ontario, Canada

    C C Hsia, K Howson-Jan, J Mangel, I H Chin-Yee, S Collins & A Xenocostas

  2. Division of Hematology and Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA

    M Linenberger

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Hsia, C., Linenberger, M., Howson-Jan, K. et al. Acute myeloid leukemia in a healthy hematopoietic stem cell donor following past exposure to a short course of G-CSF. Bone Marrow Transplant 42, 431–432 (2008). https://doi.org/10.1038/bmt.2008.205

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