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2009 The Authors Journal compilation 2009 Nordic Pharmacological Society.

. Basic & Clinical Pharmacology & Toxicology, 106, 210214

Doi: 10.1111/j.1742-7843.2009.00514.x

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Pharmacodynamic Effects of Haematopoietic Cytokines: The View of a Clinical Oncologist


Thomas K. Held1 and Ursula Gundert-Remy2
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Department of Haematology, Oncology and Tumour Immunology, Robert-Rssle-Klinik, HELIOS Klinikum Berlin-Buch, Berlin, Germany, and 2Arzneimittelkommission der deutschen rzteschaft, Berlin, Germany (Received 31 July 2009; Accepted 9 November 2009) Abstract: The production of haematopoietic cells is under the tight control of a group of haematopoietic cytokines. Each cytokine has multiple actions mediated by receptors whose cytoplasmic domains contain specialized regions initiating survival, proliferation, differentiation commitment, maturation and functional activation. Granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and thrombopoiesis-stimulating agents are in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. G-CSF regulates neutrophil production to maintain blood neutrophil counts in the normal range. G-CSF is used to prevent febrile neutropenia or to increase dose-density in chemotherapy regimens. Despite consistently showing a shorter duration of neutropenia, multiple prospective randomized trials have documented only modest clinical benefit. A clinical advantage of dose-dense chemotherapy has been shown only in specific chemotherapy regimens. Professional recommendations tailor the use of CSFs to patients with a high risk of adverse outcome of febrile neutropenia. EPO was used to prevent anaemia requiring red blood cell transfusion. However, recent studies strongly suggest a negative overall effect on mortality, without a plausible biological explanation. It is now proposed that its use should be restricted to patients in clinical trials. Thrombopoiesis-stimulating agents have only been recently introduced into the market for splenectomized and non-splenectomized patients with immune thrombocytopenic purpura, a rare disease. Before widely used in other conditions such as chemotherapy-induced thrombocytopenia, the lessons learned from the example of G-CSF and EPO should be taken seriously.

The bone marrow is a complex organ hosting several types of cells which maturate in this tissue to be released into the circulating blood as functionally specialized cells, such as erythrocytes, granulocytes, lymphocytes, monocytic cells and platelets. All the specialized cells evolve from a pluripotent haematopoietic stem cell and undergo differentiation into the specialized cells governed by haematopoietic cytokines which include growth factors, interleukins and other cytokines. First thought to be lineage-specific, it is now clear that the growth factors act on multiple cell lines at various stages of maturation. For example, erythropoietin (EPO) enhances not only erythropoiesis but megakaryocyte growth as well, and granulocyte colony-stimulating factor (G-CSF) takes action at the stages of short-term haematopoietic stem cells, colony-forming units granulocyte erythroid macrophage megakaryocyte, colony-forming units granulocyte-macrophage, colony-forming units granulocyte and neutrophils [1]. The mechanism of action of growth factors has been elucidated and shows similarities. Each cytokine has multiple actions mediated by receptors whose cytoplasmic

Author for correspondence: Thomas K. Held, Department of Haematology, Oncology and Tumour Immunology, Robert-RssleKlinik, HELIOS Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125 Berlin, Germany (fax +49-30-9401-55139, e-mail thomas. held@helios-kliniken.de).

domains contain specialized regions initiating the various responses-survival, proliferation, differentiation commitment, maturation and functional activation. Individual cytokines can be lineage-specific or can regulate cells in multiple lineages, and for some cell types, such as stem cells or megakaryocyte progenitors, the simultaneous action of multiple cytokines is required for proliferative responses. The same cytokines control basal and emergency haematopoietic cell proliferation. Three cytokines, erythropoietin, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, have now been in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. They act upon binding to a single transmembrane-specific receptor, which in turn dimerizes (in case of G-CSF or thrombopoietin) or undergoes conformational changes (in case of EPO) resulting in phosphorylation of the intracellular domain, activation of several pathways, mainly the JAK-STAT pathways and activation of several genes [2]. However, there is a long way from the molecular events which regulate the growth and development of haematopoietic stem cells and the clinical application of haematopoietic growth factors in patients. The usefulness of pharmacokinetic pharmacodynamic modelling in drug development is widely accepted [3]. For example, semi-mechanistic models have been developed to optimize the doses and dosing interval for chemotherapeutic drugs

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taking into account patient characteristics [46]. However, in pharmacokinetic pharmacodynamic modelling, the endpoints chosen are mostly surrogate end-points although in recent times examples have been given how to incorporate clinical meaningful end-points into the model [7]. In the field of oncology, haematopoietic growth factors are used in patients treated with chemotherapeutic agents having an effect on the bone marrow either as an intended therapeutic action or an undesired side effect. Mathematical and also physiologically based modelling approaches have been applied to describe the relationship between kinetics and dynamics in this field [8, 9], but there is still a gap between the measured and modelled surrogate end-points and the clinical outcome. It is the clinician who has to ask whether the effects measured in terms of surrogate end-points translate into a clinical benefit for the patients in terms of morbidity and prolonged survival. Hence, this review focuses on the clinical application and problems arising with the use of therapeutically important haematopoietic growth factors EPO, G-CSF, thrombopoietin and thrombopoiesis-stimulating agents. It also presents evidence-based therapeutic recommendations which are the conclusion resulting from systematic reviews. G-CSF It has long been known that incidence and severity of bacterial and fungal infections depend on the number of circulating neutrophil granulocytes and on the duration of neutropenia [10]. Synthesized by monocytes, macrophages, fibroblasts and endothelial cells [11], the cytokine G-CSF prolongs neutrophil survival by inhibition of apoptosis and enhances their oxidative burst [12] amongst many other effects on these cells. G-CSF stimulates myeloid progenitors and is routinely used to accelerate neutrophil recovery in the treatment of haematological malignancy and blood or marrow transplantation. Despite numerous studies, a first Cochrane Review was not able to demonstrate an effect of G-CSF on the death rate of patients developing neutropenia after chemotherapy or to show a clear effect on infection-related mortality [13]. The review which dates from 2000, however, included only 13 randomized, controlled trials with 1518 patients. Moreover, six studies were included investigating granulocyte-macrophage colony stimulating factor, which is no longer in clinical use in Europe. Another Cochrane review investigated the role of G-CSF as an adjunct to antibiotics in the treatment of pneumonia in adults [14]. It evaluated six studies with a total of 2018 patients, who were non-neutropenic. The authors concluded that G-CSF was safe with no increase in the incidence of total serious adverse events, but the use of G-CSF was not associated with improved 28-day mortality. A more recent meta-analysis of randomized, controlled trials of G-CSF in febrile neutropenia when used as a primary prophylaxis looked at 17 trials with a total of 3493 patients [15]. Although G-CSF reduced infection-related mortality, all-cause mortality during chemotherapy, and the rate of febrile neutropenia, there

were insufficient data for the impact of G-CSF on diseasefree and overall survival. Therefore, current recommendations both of the EORTC [16] as well as the National Comprehensive Cancer Network [17] endorse the routine use of G-CSF in primary prophylaxis of febrile neutropenia only if the risk of febrile neutropenia exceeds 20%. If the overall risk is less than 10%, G-CSF should not be given as primary prophylaxis, but only if the patient suffered such an episode. Of note, not only the frequency and severity of neutropenia reported for a specific chemotherapy should be taken into consideration, but patient age, underlying disease, treatment intent, gender, history of prior febrile neutropenia, disease stage, and patient performance status as well. The issue whether G-CSF permits a more dose-dense chemotherapy and enables therefore a prolonged disease-free and overall survival in cancer patients has not been resolved to date. There are preliminary data, however, that this could be the case [18], although an overall survival advantage has been shown only up to 90 days. Clearly, more data are needed here. Granulocyte colony-stimulating factor also shows effects in healthy individuals which could be of some concern. In the peripheral blood of stem cell donors treated with G-CSF, tetraploid myeloid cells could be observed [19], and there was loss of synchrony in allelic replication timing similar to leukemic patients and aneuploidy (either monosomy or multisomy) involving chromosome 17 [20]. Moreover, G-CSF changes the level of expression of about 300 genes, lasting for some months [21], and it increases serum levels of vascular endothelial growth factor [22] and tissue growth factor-b [23]. Especially the vascular endothelial growth factor data are of some concern since angiogenesis is a major factor in cancerogenesis and hence, G-CSF may interfere with antiangiogenetic therapy of solid tumours, at least hypothetically. Up to this date, however, no cases of leukaemia induction due to G-CSF use have been reported. Based on the information available, the administration of G-CSF to healthy donors of peripheral blood stem cells has a favourable riskbenefit profile. Erythropoietin and Erythropoiesis-Stimulating Agents (EPO) Licensed for the use in symptomatic anaemia in patients with chronic renal failure and in adult patients with non-myeloid malignancies receiving chemotherapy, the debate over the use of EPO in cancer patients went on for years. Doubts about the safety of EPO in cancer patients arose as early as in 2003, when results of a double-blind, randomized multicenter trial were published. In that study, patients with cancer of the head and neck received EPO in order to enhance oxygen delivery to tumour tissue rendering it more sensitive to radiation therapy [24]. Patients treated with EPO, however, showed a significantly shorter progression-free survival (406 days versus 745 days with placebo; p < 0.001), which was the primary end-point of the study. Even more disturbing, there was a trend to reduced overall survival, being one of the secondary end-points of the study, in the EPO group.

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There was an increased risk for progressive disease and for death in the EPO group. However, a negative effect of EPO on loco-regional progression-free survival was not seen in the subgroup of patients who had a complete resection of their tumours before EPO therapy and radiation indicating that the results were depending on tumour stage. Moreover, EPO was given to patients with a haemoglobin concentration of less than 130 g l (less than 120 g l in female patients) regardless of the initial haemoglobin values, and univariate and subgroup analyses showed that a significant poor outcome depended on the initial haemoglobin value. Hence, it cannot be excluded that in certain subgroups of patients, EPO may have indeed a positive effect on radiosensitivity of tumours without a detrimental influence on survival. A second randomized, controlled trial in women with metastatic breast cancer receiving first-line chemotherapy investigated the effect of EPO on overall survival and quality of life when haemoglobin levels were maintained in the range of 120 140 g l using EPO [25]. The trial was stopped early because of excess mortality in the EPO group (overall survival in the final analysis, 70% versus 76% in the placebo group; p = 0.01). Optimal tumour response and time to disease progression were similar between groups, and the reason for increased mortality could not be determined in this study. Recently, two meta-analyses have been published showing an increased risk of venous thromboembolism in cancer patients receiving EPO as well as an increased mortality risk (hazard ratio, 1.10) [26]. The second meta-analysis analysed data from a total of 13,933 patients with cancer in 53 trials and demonstrated an increased mortality during the active study period (combined hazard ratio 1.17) and worsened overall survival (combined hazard ratio 1.06) with little heterogeneity between trials [27]. There was also little evidence for a difference between trials of patients given different anticancer treatments. Hence, outside of clinical studies, there is in our opinion no indication for EPO in cancer patients for relieving anaemia or enhancing quality of life, since with red blood cell transfusions, there exist alternatives with a reasonable safety profile providing immediate relief of anaemia. At least, the increased risk of death associated with treatment with these drugs, albeit small, should be discussed with the patient and be balanced against any benefit. Thrombopoiesis-Stimulating Agents Promoting proliferation and survival of megakaryocytic progenitors by initiating many of the mechanisms that are triggered by erythropoietin and G-CSF, thrombopoietin is the primary regulator of platelet production. Thrombopoietin levels in blood are inversely related to the number of platelets in the blood and megakaryocytes in the bone marrow; unlike erythropoietin production, however, the regulation of thrombopoietin levels is multi-faceted [2]. For clinical use, thrombopoietin has been truncated, modified with polyethylene glycol, and termed megakaryocyte growth and differentiation factor. When administered subcutaneously to platelet donors, some of the donors produced antibodies against

megakaryocyte growth and differentiation factor that crossreacted with endogenous thrombopoietin, thereby causing severe thrombocytopenia [28]. Moreover, a patient suffering from thrombocytopenia after multiple chemotherapies for ovarian cancer developed a severe trilinear hypoplasia after receiving thrombopoietin itself [29]. These adverse events - an important lesson in the engineering of recombinant proteins meant for clinical use - led to the abandonment of the use of megakaryocyte growth and differentiation factor and full-length forms of thrombopoietin as therapeutic proteins. Recently, small peptides and molecules have been developed which bind to the thrombopoietin receptor leading to stimulating events on megakaryocytes similar to thrombopoietin. Two of them entered clinical trials with promising results. The first one is a small peptide, four copies of which are bound on an immunoglobulin scaffold. Originally termed AMG 531, it now entered the market as Romiplostim (Nplate; AMGEN, Thousand Oaks, CA, USA). In a phase 12 study and a randomized, controlled trial, romiplostim was well tolerated and increased and maintained platelet counts in splenectomized and non-splenectomized patients with immune thrombocytopenic purpura [30, 31]. Romiplostim, however, has to be injected subcutaneously once a week. The competitor on the market is eltrombopag (Promacta; GlaxoSmithKline, Research Triangle Parc, NC, USA), an orally active thrombopoietin receptor agonist. It, too, has been shown to increase platelet counts in a dose-dependent manner in patients with relapsed or refractory immune thrombocytopenic purpura [32, 33]. Moreover, its activity in thrombocytopenia due to HCV-related liver cirrhosis has been demonstrated as well [34]. For both substances, however, long-term side effects are yet not known, as is the performance of the drugs over longer periods. This is important because the main indication in the future surely will be chemotherapy-induced thrombocytopenia, often in cancer patients in whom the therapy is curative and who therefore have a normal or near normal life expectancy. Conclusion When, in the 1990s, the new haematopoietic growth factors became available, they were greeted with much enthusiasm. The availability of new therapeutic tools in treatment of cancer patients offered the hope that the effect on haematopoiesis would translate into clinical benefit by allowing to increase the dose of chemotherapeutic agents by counteracting the increased risks of high doses on the bone marrow. However, after two decades of experience with G-CSF, several professional guidelines recommend the restricted use in patients with febrile neutropenia to patients with special features and a high risk. Furthermore, it is still not resolved whether G-CSF permits a more dose-dense chemotherapy and enables therefore a prolonged disease-free and overall survival in cancer patients to date. Erythropoietin has also been introduced into the therapeutic market for cancer patients with great hopes. With respect

2009 The Authors Journal compilation 2009 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 106, 210214

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to recent meta-analyses strongly suggesting a negative overall effect on mortality the positive risk benefit relationship turned into the contrary. Recently, new agents went onto the markets which enhance platelet production. Whereas their pharmacodynamic properties have been elucidated and their clinical effect demonstrated the effects after long-term treatment are still not known. Hence, the drugs should only be used after careful consideration. In conclusion, while developments on two haematopoietic growth factors came to a hold, the field on thrombopoietic stimulation just evolves and may lead to improvements similar to or even exceeding those achieved with G-CSF and erythropoiesis stimulating agents, respectively. Despite all excitement about these possibilities, caution should be used against an unjustified optimism. References
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2009 The Authors Journal compilation 2009 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 106, 210214

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