Contents
29.1 Principles of Treatment . . . 425
29.2 Method of Delivery . . . 427
29.3 Future Perspectives . . . 428
References . . . 429
29.1 Principles of Treatment
Growth factors are proteins that bind to receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation. Many growth factors are quite versatile, stimulating cellular division in numerous different cell types, whereas others are specific to a particular cell type. The lists in the following tables as well as the descriptions of sev- eral factors are intended neither to be comprehensive nor complete, but rather a look at some of the more commonly known factors and their principal activi- ties.
Cytokines are a unique family of growth factors.
Secreted primarily from leukocytes, cytokines stimu- late both the humoral and cellular immune respons- es as well as the activation of phagocytic cells. Cy- tokines that are secreted from lymphocytes are termed lymphokines, whereas those secreted by monocytes or macrophages are termed monokines.
A large family of cytokines is produced by various cells of the body. Many of the lymphokines are also known as interleukins (ILs) because they are not only secreted by leukocytes but are also able to affect the cellular responses of leukocytes. Specifically, inter- leukins are growth factors targeted to cells of hematopoietic origin (Table 29.1). The list of identi- fied interleukins grows continuously, with the total number of individual activities now at 22.
Placebo-controlled clinical trials of recombinant human interleukin-11 (rhIL-11, also known as oprelvekin [Neumega, Wyeth]) in patients with non- myeloid malignancies have demonstrated significant efficacy in preventing post-chemotherapy platelet nadirs ≤20,000/ml, and reducing the need for platelet
Growth Factors
Nancy E. Kline
transfusions while chemotherapy can continue with- out dose reductions. The recommended pediatric dose of rhIL-11 is 75 mcg/kg subcutaneously(SQ) once daily, beginning 6–24 hours after the adminis- tration of chemotherapy until a post-nadir platelet count ≥50,000/microL is reached (Reynolds, 2000).
Laboratory studies including a complete blood count (CBC) should be done twice or three times weekly while the child is receiving IL-11.
Erythropoietin (Epo) is synthesized by the kidney in response to the amount of oxygen available to the tissues and renal cells and is the primary regulator of erythropoiesis. It was the first hematopoietic growth factor to be identified as an important regulatory fac- tor in erythropoiesis. Epo stimulates the proliferation and differentiation of immature erythrocytes; it also stimulates the growth of erythroid progenitor cells (e.g., erythrocyte burst-forming and colony-forming units) and induces the differentiation of erythrocyte colony-forming units into proerythroblasts. When patients suffering from anemia due to kidney failure are given Epo, the result is a rapid and significant
increase in red blood cell count. It can be given to people with cancer who have anemia either be- cause of the disease or the chemotherapy treatment (Table 29.2).
Colony-stimulating factors (CSFs) are cytokines that stimulate the proliferation of specific pluripotent stem cells of the bone marrow in adults. Granulocyte- CSF (G-CSF) is specific for proliferative effects on cells of the granulocyte lineage. G-CSF also increases the activity of erythropoietin. G-CSF has been used to treat myelosuppression since the early 1990s.
Granulocyte-macrophage-CSF (GM-CSF) has pro- liferative effects on both classes of lymphoid cells.
Epo is also considered a CSF as well as a growth fac- tor because it stimulates the proliferation of erythro- cyte colony-forming units. IL-3 (secreted primarily from T-cells) is also known as multi-CSF because it stimulates stem cells to produce all forms of hematopoietic cells.
Myeloid growth factors are widely used in both pe- diatric and adult oncology. Although the literature supporting the use of growth factors in pediatric on-
Table 29.1. Source and activity of selected interleukins and interferons
Interleukins Primary source Primary activity
IL1-a and -b Monocytes Activation of natural killer cells, hematopoiesis Macrophages Activation of natural killer cells, hematopoiesis
IL-3 Activated T-cells Growth and differentiation of hematopoietic progenitor cells IL-6 Monocytes Acute phase response, B-cell proliferation, thrombopoiesis,
cell differentiation
Macrophages Acute phase response, B-cell proliferation, thrombopoiesis, cell differentiation
Stromal cells Acute phase response, B-cell proliferation, thrombopoiesis, cell differentiation
IL-9 T-cells Hematopoietic and thymopoietic effects
IL-11 Stromal cells Synergistic hematopoietic and thrombopoietic effects IL-12 B-cells, macrophages Activates and induces a proliferation of cytotoxic T-cells
and natural killer (NK) cells
INF-a and -b Macrophages, neutrophils Antiviral effects, induction of class I MHC on all somatic cells, and some somatic cells activation of NK cells and macrophages
INF-g Activated TH1and NK cells Activates macrophages, neutrophils, NK cells, promotes cell-mediated immunity, antiviral effects
cology is less extensive than the adult-related litera- ture, some uses are clearly established. Both granulo- cyte colony-stimulating factor and granulocyte- macrophage colony-stimulating factor shorten the duration of febrile neutropenia after myelosuppres- sive chemotherapy, effectively mobilize hematopoiet- ic stem cells for transplantation, and enhance neu- trophil engraftment after hematopoietic stem cell transplantation (Levine and Boxer, 2002).
Thrombopoietin (TPO) is a colony-stimulating factor that stimulates the production of blood cells, especially platelets, during chemotherapy. It is a cy- tokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. In clinical trials, TPO has proven useful in shortening the time for platelet recovery after chemotherapy, but it is not currently approved for routine use (Table 29.2). It is quite clear, however, that TPO does not regulate the release of platelets by megakaryocytes. This final step in platelet formation seems to be regulated by a sep- arate process. Most people with thrombocytopenia have a normal or high TPO level in their blood. It is not clear whether additional doses of this investiga- tional drug would improve platelet production (Wolff et al., 2001).
29.2 Method of Delivery
Erythropoietin is generally given as an injection un- der the skin (SQ), although it can be given intra- venously (IV). It usually needs to be given three times a week. Recombinant human erythropoietin is gener- ally well tolerated and may offer the benefit of reduc- ing the need for blood transfusions in pediatric pa- tients. G-CSF and GM-CSF are also well tolerated but need to be given daily, either SQ or IV. Laboratory monitoring is needed to determine when therapy can be discontinued (Table 29.3).
Approval of thrombopoietin for clinical use has been delayed because studies showed less impressive platelet recovery after chemotherapy than expected, and because a small percentage of recipients devel- oped an immune reaction to the drug (Table 29.4).
Table 29.2. Colony stimulating factors
Factor Commercial product Principle source Indication Primary activity Erythropoietin Epoetin-alpha Kidney Anemia related to chronic Promotes proliferation
(Epogen, Amgen); renal failure, zidovudine- and differentiation of (Procrit, Ortho-Biotech) treated HIV infection, erythrocytes
cancer chemotherapy
G-CSF Filgrastim Monocytes Neutropenia related to Promotes growth of
(Neupogen, Amgen) Macrophages cancer chemotherapy; granulocytes, primarily mobilize stem cells prior neutrophils
to PBSC transplant
GM-CSF Sargramostim T-cells
(Leukine, Immunex) Epithelial cells Fibroblasts
Thrombopoietin E. coli Thrombocytopenia Stimulates the produc-
(not approved by FDA tion and maturation
for use) of megakaryocytes
29.3 Future Perspectives
Pegfilgrastim (SC/01), a long-acting pegylated G-CSF preparation, is being studied as a one-time dose per cycle given 24 hours after the completion of chemotherapy to prevent prolonged neutropenia fol- lowing cancer chemotherapy. Initial studies suggest that the one-time dose per cycle is as effective as dai- ly doses of G-CSF (Holmes et al., 2002). If this is found to be the case, it would certainly have a positive effect on quality of life.
IL-3 is capable of stimulating multipotential hematopoietic stem cells to differentiate. It has been tested in adult patients with bone marrow failure, but its role in the treatment of children with cancer is not certain. It does not seem to be superior to G-CSF and is less well tolerated (Maslak and Nimer, 1998).
Recombinant human TPO remains in active clini- cal development. Unquestionably, the need to devel- op a more effective platelet growth factor remains for the treatment of treatment-related thrombocytope- nia, especially in myelodysplasia, idiopathic throm- bocytopenic purpura (ITP), and lymphoproliferative
Table 29.3. Doses of selected growth factors
Factor Dose Laboratory monitoring
Erythropoietin Cancer chemotherapy: CBC and reticulocyte count at least weekly;
150 units/kg IV or SQ three times weekly check iron level and endogenous serum
Chronic renal failure: erythropoietin levels at baseline
50 units/kg IV or SQ three times weekly Zidovudine -treated HIV infection:
100 units/kg SQ three times weekly
G-CSF Neutropenia: CBC two to three times per week
5–10 mcg/kg/dose SQ or IV daily until post-nadir ANC≥10,000 cells/mm3. First dose administered 24 hours after last dose of chemotherapy PBSC mobilization:
10 mcg/kg/day SQ for at least 4 days prior to leukopheresis
GM-CSF Neutropenia: Neutropenia related to cancer chemo-
250 mcg/m2/day for 3 weeks or until post-nadir therapy; mobilize stem cells prior ANC≥1,500 cells/mm3for 3 consecutive days to PBSC transplant
PBSC mobilization:
250 mcg/m2/day IV over 24 hours, or SQ daily
Table 29.4. Potential side effects
Factor Reported side effects
Erythropoietin High blood pressure, skin rash, headaches, flu-like symptoms, bone pain, seizures G-CSF Headache, fever, chills, nausea, vomiting, diarrhea, fatigue, weakness, decreased appetite,
thrombosis, flushing, muscle and bone pain, local reactions at site of injection, rashes, decreased kidney or liver function
GM-CSF Redness at the injection site, low-grade fever, muscle aches, fatigue, rash, headache, nausea, dizziness
Thrombopoietin Thrombocytosis, thrombosis, marrow fibrosis, veno-occlusive disease, interactions with other growth factors
disorders. This type of growth factor would also im- prove the yield of platelet donations, thus perhaps de- creasing the number of donors needed.
References
Holmes, F. A., O’Shaughnessy, J. A., Vukelja, S., Jones, S. E., Shogan, J., Savin, M., Glaspy, J., Moore, M., Meza, L., Wiz- nitzer, I., Neumann, T. A., Hill, L. R., Liang, B. C. (2002) Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily fil- grastim as an adjunct to chemotherapy in patients with high-risk stage I or stage III/VI breast cancer. Journal of Clinical Oncology, 20:727–731
Levine, J.E., Boxer, L.A. (2002) Clinical applications of hematopoietic growth factors in pediatric oncology. Cur- rent Opinions in Hematology, 9:222–227
Maslak, P., Nimer, S. D. (1998). The efficacy of IL-3, SCF, IL-6 and IL-11 in treating thrombocytopenia. Seminars in Hematol- ogy, 35:253–260
Reynolds, C.H. (2000). Clinical efficacy of rhIL-11. Oncology 14(9 Suppl 8):32–40
Wolff, S. N., Herzig, R., Lynch, J., Ericson, S. G., Greer, J.P., Stein, R., Goodman, S., Benyunes, M. C.,Ashby, M., Jones, D.V., Fay, J. (2001) Recombinant human thrombopoietin (rhTPO) af- ter autologous bone marrow transplantation: A phase I pharmacokinetic and pharmacodynamic study. Bone Mar- row Transplantation 27:261–268
