Hematopoietic management in oncology practice. Part 1. Myeloid growth factors

Hematopoietic growth factors have transformed the practice of oncology. The two major factors in clinical use are recombinant human (rh) granulocyte colony-stimulating factor (G-CSF, filgrastin [Neupogen]) and granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]). These factors differ significantly in their role in hematopoiesis and the regulation of mature effector cell function. G-CSF regulates both basal and neutrophil production and increased production and release of neutrophils from the marrow in response to infection. GM-CSF mediates its effects on the neutrophil lineage through its effects on phagocytic accessory cells and its synergy with G-CSF, but it does not appear to have a role in basal hematopoiesis. Part 1 of this two-part series focuses on the use of the myeloid growth factors rhG-CSF and rhGM-CSF to shorten the duration of chemotherapy-induced neutropenia and thus prevent infection in cancer patients. In randomized trials, rhG-CSF has consistently decreased the duration of neutropenia during all cycles of chemotherapy and reduced the risk of infection by 50% or more. Trials of rhGM-CSF have not reported consistent results.     

造血生长因子在化疗患者中的应用

在肿瘤患者的化疗中,血液学毒副作用是非常突出和急需解决的主要问题,造血生长因子在减少血液学毒副作用、降低化疗风险和提高肿瘤患者生活质量方面都起着非常重要的作用。其中粒细胞集落刺激因子在化疗患者中应用最为广泛,NCCN指南建议对化疗后出现粒缺发热的高危患者预防性使用粒细胞集落刺激因子。红细胞生成素由于近期有几项临床试验表明可能增加死亡率,甚至减少总生存,因此其应用还有待进一步的研究。促血小板生成素目前仍处于Ⅲ期和Ⅳ期临床试验中,前景令人鼓舞。     

Hematopoietic growth factors.

Hematopoiesis is a complex process that underlines the production of multiple highly specialized cells. The intricate mechanisms involved in this process include both positive and negative feedback by humoral activities, pluripotent stem cell selfrenewal and differentiation, and local interactions between stromal components of the hematopoietic microenvironment and various stem and progenitor cells. A group of hematopoietic growth factors, as well as their genes and chromosomal locations, have been identified. Advances in biochemistry and molecular biology led to the purification, genetic sequencing and molecular cloning of these glycoproteins. They include interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and erythropoietin (EPO). The biologic specificity of these substances is defined by their ability to support proliferation and differentiation of hematopoietic cells in a semisolid clonal assay system. These factors share certain characteristics, including their ability to stimulate the function of mature cells, their overlapping activity affecting progenitor cells of several lineages, and their direct and indirect actions on nonhematopoietic cells. Trials using hematopoietic growth factors demonstrated their remarkable efficacy in a variety of clinical settings.     

Hematopoietic growth factors in AIDS.

Three hematopoietic growth factors, erythropoietin, GM-CSF, and G-CSF, have all been evaluated in the context of HIV infection. Recombinant human Epo is currently licensed for therapy of anemia related to zidovudine and is well tolerated in this patient population. Although myelosuppression can clearly be overcome using recombinant human GM-CSF or G-CSF in HIV-infected hosts, the clinical benefits for such patients are still not determined. It is likely that these growth factor therapies will allow for delivery of certain important myelosuppressive medications that otherwise could not be tolerated. Improvements in virological quantitation in vivo should help settle the controversies regarding modulation of HIV replication caused by cytokine treatment. The clinical use of hematopoietic growth factors in HIV disease requires further study with regard to the optimization of increases in blood cell number and/or modulation of blood cell function.     

Hematopoietic growth factors in myelodysplastic syndromes

Hematopoietic growth factors (HGFs) continue to be the most widely prescribed class of medications for patients with myelodysplastic syndromes (MDS), despite the advent of disease-modifying therapies for MDS (eg, azacitidine, decitabine, and lenalidomide) and the current absence of an MDS-specific US Food and Drug Administration (FDA)-approved indication for any of the HGFs. Erythropoiesis-stimulating agents (ESAs: epoetin alfa, darbepoetin alfa), myeloid growth factors (MGFs: filgrastim, pegfilgrastim, sargramostim), and the newest group of HGFs, thrombopoiesis-stimulating agents (TSAs: romiplostim, eltrombopag), can increase peripheral blood counts in some patients, and may ameliorate some of the signs and symptoms of MDS-associated bone marrow failure. Although HGFs are generally considered "supportive care" measures, recent data suggest that HGFs may alter the natural history of disease in MDS, either for better or worse. This review examines data on the safety and effectiveness of HGFs for patients with MDS.     

Hematopoietic management in oncology practice. Part 2. Erythropoietic factors

As the major regulator of erythropoiesis in man, erythropoietin inhibits the programmed cell death of committed erythroid precursors. In cancer patients, a relative erythropoietin deficiency is coupled with a decreased responsiveness to the substance mediated by the effects of inflammatory cytokines on the marrow and on ferrokinetics, leading to a high incidence of anemia. Two recombinant human erythropoietin (rhEPO) preparations--epoetin alfa (Epogen, Procrit) and epoetin beta (Marogen)--as well as a modified erythropoietic compound (darbepoetin alfa [Aranesp]) are in clinical use. Part 2 of this two-part series on hematopoietic agents reviews the use of these erythropoietic factors and their effect on the anemia that develops in cancer patients. Thrombopoietic factors and progenitor cell-mobilizing factors are also briefly addressed.     

Hematopoietic growth factors and leukemia.

Hematopoietic growth factors, particularly granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, can be used as supportive agents to enhance bone marrow recovery after the administration of myelosuppressive chemotherapy given for nonmyeloid neoplasms. The use of these agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome poses novel opportunities and challenges due to their direct effects on the neoplastic cells, which represent the transformed counterparts of normal hematopoietic stem cells. The interaction between hematopoietic growth factors and leukemic progenitor cells bearing a specific receptor for a given agent would be expected to result in proliferation, although maturation induction could occur. Hematopoietic growth factors have been employed as primary differentiating agents in myelodysplastic syndrome and as supportive agents after chemotherapy in acute myeloid leukemia. In either case, close monitoring for evidence of leukemic stimulation is required. Alternatively, pretreatment with colony-stimulating factors could induce cell cycling, thereby making the leukemic cells more susceptible to S-phase-specific chemotherapeutic agents, such as cytarabine.     

Use of hematopoietic growth factors in oncology

Myelosuppression is the main limiting factor in cancer chemotherapy. The development of recombinant hematopoietic growth factors which stimulate myeloid progenitors and mainly neutrophil precursor cells leads to the evaluation of their potential activity in numerous fields of oncology. The available clinical trials have demonstrated the ability of G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor) to accelerate neutrophil recovery following cytotoxic chemotherapy, and therefore to reduce the incidence of neutropenic febrile episodes and thereby improve the quality of life of patients receiving chemotherapy. The main goals of the future studies will be to determine to what extent the increase of dose intensity may lead to higher response rates and survival at least in patients with chemosensitive tumors.     

Hematopoietic growth factors: personalization of risks and benefits

A common side effect of cancer treatment is bone marrow suppression. The resulting myelosuppression and anemia can cause significant morbidity and mortality for patients. Agents such as granulocyte colony stimulating factors (GCSF) and erythropoietin stimulating agents (ESAs) may be helpful to ameliorate this depression of blood counts; however these agents have risks which also need to be carefully weighed.     

Hematopoietic growth factors: biology and clinical application.

A number of recently identified cytokines have been implicated in the development of blood cells and their functional activation. These include granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukins-1, -3, and -6. The two that have been studied most extensively clinically are G- and GM-CSF. Biologic differences between these two agents have important implications for their use in particular clinical settings. Whereas G-CSF for the most part has demonstrated lineage specificity in stimulating production of neutrophil granulocytes, GM-CSF stimulates production of all types of granulocytes and is a potent activator of monocytes and macrophages as well. In addition, GM-CSF has been found to induce other cytokines, such as tumor necrosis factor and interleukin-1. Functional differences such as influencing neutrophil migration have also been noted; GM-CSF can be a potent inhibitor of neutrophil migration. The interaction of these and other cytokines in inflammation and injury is the determinant of the ultimate clinical outcome. Potential clinical applications for these growth factors are discussed, and specific clinical studies during which recombinant human G-CSF was used are reviewed.     

Hematopoietic growth factors and autologous or allogeneic stem cell transplantation

Hematopoietic growth factors are usually administered in autologous and allogeneic stem cell transplantation. RhuG-CSF and rhuEPO are the most frequently used, either for mobilization of peripheral stem cells or after transplantation for the improvement of hematologic recovery. G-CSF (filgrastim or lenograstim) can be administered alone or in combination with stem cell factor to enhance stem cells mobilization. IL-3 and sargramostim are not used anymore. The protocol of administration of rhuG-CSF is well established. Furthermore, stem cell transplantation with peripheral cells is less expensive than with bone marrow. RhuEPO (erythropoietin) is not effective in mobilization. After transplantation, filgrastim or lenograstim can shorten the neutropenic period and decrease infectious complications. The potential effect of these growth factors on the incidence and the severity of GvHD is still unknown and under debate. The use of rhuEPO after transplantation might be of interest to reduce the need of red blood cell transfusion. Some studies suggest that the administration of rhuEPO should start before delivering the conditioning regimen. The new long acting growth factors such as pegfilgrastim are still under evaluation and their use in mobilization seems promising.     

Hematopoietic growth factors as supportive therapy for cancer- and chemotherapy-induced conditions

A number of human hematopoietic growth factors have been genetically cloned and recombinant proteins produced. Several phase I and II clinical trials have already been published and results from phase III studies are becoming available. The use of erythropoietin to alleviate chemotherapy-induced myelosuppression is being tested. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor have been extensively studied in patients receiving chemotherapy at standard or escalated doses and after bone marrow transplantation and appear to ameliorate chemotherapy-induced neutropenia and to speed bone marrow engraftment after high-dose cancer therapy. Interleukin-3 and interleukin-6 are quite early in their clinical development, but appear able to alleviate post-chemotherapy thrombocytopenia.