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Ivo P. Touw, Marijke Bontenbal, Granulocyte Colony-Stimulating Factor: Key (F)actor or Innocent Bystander in the Development of Secondary Myeloid Malignancy?, JNCI: Journal of the National Cancer Institute, Volume 99, Issue 3, 7 February 2007, Pages 183–186, https://doi.org/10.1093/jnci/djk057
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Granulocyte colony-stimulating factor (G-CSF), the major cytokine involved in the control of neutrophil production, is used in the clinic for treatment of congenital and acquired neutropenias and to reduce febrile neutropenia before or during courses of intensive cytoreductive therapy. In addition, healthy stem cell donors are treated with G-CSF for mobilization of hematopoietic stem cells in the peripheral blood. Recent studies have uncovered novel roles for G-CSF in myocardial regeneration following cardiac infarction ( 1 – 3 ) and in ameliorating programmed cell death in neuronal cells caused by acute ischemic stroke, thereby reducing the volume of the brain infarct ( 4 ). Thus, it may be anticipated that the therapeutic application of G-CSF will increase considerably in the near future, making careful and timely risk assessment of vital importance.
In this issue of the Journal, Hershman et al. ( 5 ) report a twofold increased risk of secondary myelodysplasia (MDS) or acute myeloid leukemia (AML) in breast cancer patients who received G-CSF (or granulocyte-macrophage CSF) during adjuvant chemotherapy, compared with patients who did not receive growth factor treatment. This and other recent studies raise questions concerning the underlying molecular and cellular mechanisms whereby myeloid growth factors would initiate or accelerate the development of MDS/AML and how to deal with the potential hazards and benefits of G-CSF administration to patients and healthy stem cell donors ( 6 – 8 ).
G-CSF has a nonredundant role in steady-state neutrophil production, and G-CSF- or G-CSF receptor–deficient mice are severely neutropenic ( 9 , 10 ). G-CSF is also required for “stress” granulopoiesis in response to bacterial infections and enhances multiple neutrophil effector functions, such as generation of reactive oxygen species ( 11 – 13 ). The receptor for G-CSF (G-CSFR) belongs to the cytokine receptor type I superfamily. The major signaling mechanism engaged by these receptors is the Janus kinase (Jak) and signal transducer and activator of transcription (STAT) pathway ( Fig. 1 ). When activated by the G-CSFR, Jaks tyrosine phosphorylate STAT complexes, which then translocate to the nucleus where they activate transcription ( 14 ). In addition, Jaks phosphorylate tyrosines in the cytoplasmic tail of the receptors, which then form recruitment sites for signaling molecules with phosphotyrosine-interacting domains ( 15 ). The G-CSFR also activates the p21Ras/mitogen activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI-3K)/protein kinase B (PKB) pathways, both of which contribute to G-CSF–induced survival and proliferation ( 16 ). Negative regulators of G-CSF signaling include the protein tyrosine phosphatases SHP-1 and SHP-2 and the suppressor of cytokine signaling (SOCS) protein SOCS3. Multiple members of the Jak/STAT, p21Ras/MAP kinase, and PI-3K/PKB pathways have been associated with hematopoietic malignancy or with syndromes with a high leukemia predisposition ( 17 – 20 ), accentuating the need to carefully examine a possible relationship between perturbed growth factor responses and leukemogenesis.
Since the early 1990s, recombinant G-CSF has been administered to patients with chronic neutropenia on a daily or alternate-day basis. These patients serve as a valuable cohort to study the long-term side effects of G-CSF treatment. From 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has monitored patients with different forms of neutropenia, including cyclic neutropenia, severe congenital neutropenia, and idiopathic neutropenia ( 21 ). Among the 387 patients with severe congenital neutropenia, 35 developed MDS or AML, with a cumulative risk of 13% after 8 years of G-CSF treatment. In contrast, none of the patients with cyclic neutropenia (n = 145) or idiopathic neutropenia (n = 238) showed signs of leukemic progression ( 21 , 22 ). These observations suggest that continuous treatment with G-CSF is not, or at least not strongly, leukemogenic in patients with cyclic neutropenia or idiopathic neutropenia but might somehow contribute to leukemic progression of patients with severe congenital neutropenia. This latter notion is further supported by the discovery that acquired mutations in the gene encoding the G-CSF receptor ( CSF3R ) are found in 30%–35% of patients with severe congenital neutropenia and are strongly associated with disease progression to MDS or AML ( 23 , 24 ). Most frequently, these mutations are nonsense mutations resulting in C-terminal truncation of the G-CSF receptor ( Fig. 1 ).
The role of these CSF3R mutations has been studied in knock-in mouse models ( 25 , 26 ). Despite the fact that these mice exhibit prolonged Jak/STAT signaling and hyperproliferation of myeloid progenitors in response to G-CSF, they do not develop leukemia, even after continuous administration of G-CSF for 3 months ( 16 ). This would argue against a strong leukemia-initiating role of CSF3R mutations, at least within the relatively short life span of mice. On the other hand, a recent study has demonstrated that G-CSF–induced reactive oxygen species production is substantially increased in bone marrow cells expressing truncated G-CSF receptors, which might be associated with increased DNA damage ( 27 ). By analogy to Fanconi anemia, the bone marrow stem cell and myeloid progenitor cell compartment of patients with severe congenital neutropenia may be unable to maintain its genomic integrity in response to genotoxic stress and therefore undergoes senescence, leading to bone marrow failure. This would provide a mechanism by which activation of truncated G-CSF receptors could result both in an increased mutation rate in myeloid progenitor cells during G-CSF treatment, leading to escape from senescence, and in enhanced clonal outgrowth owing to the hyperproliferative signaling function of these receptor mutants ( 16 ).
An updated analysis of the SCNIR shows that patients with severe congenital neutropenia who need high dosages of G-CSF and nonetheless do not fully reach acceptable threshold levels of circulating neutrophils show an alarmingly high incidence (40%) of leukemic progression ( 28 ). Arguably, the hematopoietic stem cell compartment in severe congenital neutropenia patients who respond poorly to G-CSF therapy is more damaged and therefore less susceptible to growth factors, which would support the notion that secondary leukemia arises predominantly because of high genotoxic stress and the resulting genomic instability in hematopoietic stem cells, with G-CSF possibly playing a role in the clonal expansion of (pre-)leukemic cells, particularly on acquisition of CSF3R mutations ( 16 ).
Adjuvant chemotherapy for breast cancer has substantially increased the number of long-term survivors. Progress has been made because new, potent, non–cross-resistant cytotoxic agents became available and because incorporation of hematopoietic growth factors in the treatment schedules allowed the use of dose intensification and densification of the most active cytotoxic agents. Several studies exploring dose-intense regimens have shown that they improve disease-free and overall survival. The dose-dense regimen of doxorubicin, paclitaxel, and cyclophosphamide and the docetaxel, doxorubicin, and cyclophosphamide regimen are now widely used as adjuvant treatments in patients with lymph node–positive disease ( 6 , 29 ). Both treatment schedules are routinely administered with growth factor support to counteract severe and prolonged neutropenia. Because adherence to dose and schedule is a prerequisite for an optimal treatment effect ( 30 ), growth factors are also being used more often in the “standard” less intensive chemotherapy regimens. Furthermore, the efficacy of adjuvant chemotherapy is increasingly being explored in elderly patients who were in the past often excluded from participation in chemotherapy trials. Because the risk of neutropenia following chemotherapy increases with age, it is to be expected that growth factor support will become more often incorporated in (higher dosed) chemotherapy schedules in this group of patients ( 31 ). The advantages of these manipulations must, however, be carefully balanced against potential risks—especially in the adjuvant setting, where cure is the goal.
Leukemia has been observed in patients treated with radiotherapy, alkylating agents, and topoisomerase II inhibitors. Recently, Smith et al. ( 7 ) retrospectively investigated the occurrence of AML/MDS in six adjuvant breast cancer trials. They observed an increased rate of AML/MDS in patients treated with AC chemotherapy employing intensified doses of cyclophosphamide requiring G-CSF support. Hershman et al. ( 5 ) have now observed a doubling in the risk of AML/MDS in a population of women aged 65 years or older treated with adjuvant chemotherapy and growth factor support for stage I–III breast cancer. This age group, which has been underrepresented in most of the adjuvant breast cancer trials, could be more susceptible to treatment-related leukemia than younger women. The strength of this study is that it uses data from a large database that it is not confined to clinical trials but reflects daily clinical practice. There are, however, some issues concerning this type of observational study. First, the raw data were derived from coded health insurance claims. However, Medicare claims have not been validated, and the sensitivity of claims information in the Surveillance, Epidemiology, and End Results Program database for primary cancers is not known. Second, no information was available about the indication to use G-CSF, the cumulative dose and duration of G-CSF treatment, or the administered dose of chemotherapy. Finally, the risk of growth factor–related leukemia may have been underestimated because in this mainly lymph node–positive patient group, women might have died from breast cancer in the first years of follow-up.
Although the absolute risk of secondary leukemia remains low, the authors ask for confirmative studies and state that the application of myeloid growth factors may not be harmless and that this risk should be factored into clinical decisions. In clinical practice, however, the benefits of adjuvant chemotherapy are of a different order of magnitude than the risk of secondary MDS or AML. Furthermore, given all the unknown factors, associations could be found that have no causal relationship. The evidence for a potential role of G-CSF in the onset of AML/MDS, derived from only a few retrospective studies, thus has to be qualified as hypothesis generating rather than conclusive.
It is now essential to develop new treatment guidelines for patients with severe congenital neutropenia, particularly for the group of patients who are at the highest risk of malignant transformation ( 28 ). It is also necessary to regularly monitor these patients for early clinical and molecular signs (e.g., acquisition of CSF3R mutations) of leukemic transformation and to investigate the possibility of matched sibling or matched unrelated hematopoietic stem cell transplantation. Whether a causal relationship exists between G-CSF administration and leukemia in healthy hematopoietic stem cell donors remains controversial. Bennett et al. ( 8 ) suggest that formal comprehensive studies would be needed to prove or disprove this connection, although such studies would require follow-up of large cohorts of normal donors (2000 or more) for at least 10 years. But even then it would be difficult to control for confounding effects. Only when such studies are coupled to genome-wide single-nucleotide polymorphism analysis or comparable approaches to identify genes involved in leukemia predisposition will it be possible to predict whether G-CSF treatment of normal hematopoietic stem cell donors or cancer patients receiving adjuvant chemotherapy should be avoided in certain individuals.
I. P. Touw is supported by grants from the Dutch Cancer Society “KWF kankerbestrijding.”
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