Granulocyte colony-stimulating factors and risk of acute myeloid leukemia and myelodysplastic syndrome

Abstract

Granulocyte colony-stimulating factors (G-CSFs) in patients receiving cancer chemotherapy have been shown to reduce the severity and duration of neutropenia as well as the risk of febrile neutropenia, documented infection, and infection-related mortality while enabling an increase in delivered chemotherapy dose intensity [1, 2]. Meta-analyses of randomized controlled trials (RCTs) of the myeloid growth factors have been reported for both adults and children consistently demonstrating the impact of these agents on neutropenia and its complications [3-5]. Clinical practice guidelines have been put forward by the American Society of Clinical Oncology and other professional organizations for the use of these agents [6-8]. Systemic cancer chemotherapy and radiation therapy have been associated with an increased risk of secondary acute myeloid leukemia (AML) in a number of previous studies [9, 10]. Multiple studies of cancer survivors have confirmed an association of treatment with myelosuppresive chemotherapy across a range of malignancies and chemotherapeutic programs [11-14]. Recent retrospective studies have suggested a possible increased risk of AML and myelodysplastic syndrome (MDS) in patients receiving chemotherapy with myeloid growth factor support [15, 16]. Interpretation of those studies has been difficult due to their post hoc design and to the limited ability to adjust for relevant confounding factors since the G-CSF was not randomly assigned and pre-existing hematologic disorders, chemotherapy and radiation therapy, low baseline blood counts as well as unrecognized inherited or acquired childhood, occupational, and other environmental exposures could not be adjusted for. None of the reported RCTs of the myeloid growth factors were adequately powered to address any possible risk for second malignancies including AML or MDS associated with the colony-stimulating factors. Previous meta-analyses of RCTs searched for studies where the chemotherapy was the same in both arms and the primary outcome was a reduction in neutropenic complications [5, 17, 18]. Perhaps the greatest challenge in understanding the potential risk of G-CSF for the occurrence of AML and MDS is the acknowledged leukemogenicity of many of the commonly employed cancer chemotherapeutic agents given in conjunction with these agents. In addition to ionizing radiation, several chemotherapeutic agents are considered to be leukemogenic in both animals and humans [11-13, 19-21]. Since G-CSF is frequently utilized to minimize chemotherapy dose reductions and delays and to enable the delivery of dose-intense and dose-escalating chemotherapy regimens, the use of these agents is often accompanied by greater chemotherapy dose intensity or greater cumulative exposure to chemotherapy. © 2011 Springer Science+Business Media, LLC.