Blood Cell Stimulating Factors in Pediatrics Part II: Granulocyte and Platelet S
June 1, 1997 4 minutes read
Blood Cell Stimulating Factors in Pediatrics Part II: Granulocyte and Platelet Stimulating Factors
By Howard A. Pearson, MD, FAAP
The hematopoietic growth factors are a group of polypeptide substances (cytokines) that act on specific cell surface receptors of primitive hematopoietic stem cells to stimulate proliferation and differentiation into specific blood cell lines, erythrocytes, granulocytes, and platelets. The human genes for these growth factors have been identified and cloned. Using recombinant DNA technology, the human genes have been inserted into the genome of cultured bacteria, yeast, or mammalian cells. The transfected cells can be stimulated to produce large amounts of the hematopoietic growth factor and can be purified for clinical use. The current uses of recombinant human erythropoietin (EPO) were described in the May 1997 issue of Pediatric & Adolescent Medicine Reports. This article will discuss the use of granulocyte and granulocyte-macrophage stimulating factors (G-CSF and GM-CSF) and platelet/megakaryocyte growth and development factor (MGDF).
Granulocyte and Granulocyte/Macrophage Cell Stimulating Factors
There are two granulocyte stimulating factors currently available for clinical useG-CSF (Neupogen, produced by Amgen, Inc.) and GM-CSF (Leukine, produced by Immunex Corp.). GM-CSF stimulates both granulocyte and the macrophage production, while the activity of G-CSF is more narrow. GM-CSF is produced by transfected yeast culture. G-CSF is produced by an E. coli expression system. Both are glycoproteins made up of about 125 amino acids.
In patients with cancer but intact bone marrows, treatment with G-CSF produces a rapid, dose-dependent rise in circulating granulocytes (also monocytes with GM-CSF). These agents appear to be safe with few side effects. Clinical indications are similar.
Chemotherapy-Associated Neutropenia
Many of the modern protocols for childhood malignancies involve high doses of chemotherapeutic drugs that are toxic to the bone marrow (cyclophosphamide, cisplatinum, adriamycin, etc). Treatment often is followed by 2-3 weeks of profound neutropenia, with absolute neutrophil counts (ANC) of 500 mm3 or less. During this time, there is a high susceptibility to bacterial infections. The syndrome of "fever/neutropenia" is a common cause for readmission to the hospital of children undergoing cancer chemotherapy. A number of studies have shown that administration of GM-CSF or G-CSF 24-48 hours after marrow suppressive chemotherapy significantly reduces the period of severe neutropenia and results in fewer antibiotic and hospital days.1 GM-CSF is administered intravenously, and G-CSF is administered subcutaneously. The current standard practice of the national multi-institutional Pediatric Oncology Group (POG) is a recommended administration of s.c. G-CSF in a dose of 5-10 mcg/kg beginning 48 hours after myelosuppressive chemotherapy. Daily injections are continued until the ANC is greater than 10,000 mm3. Families can be trained to give the injections for out-patients. Use of these factors reduces the period of profound neutropenia after bone marrow transplantation. G-CSF is also being used to increase the numbers of peripheral blood stem cells of individuals who are donors for stem cell transplantation.
Aplastic Anemia
Small numbers of patients with aplastic anemia have been treated with GM-GCF with increases in granulocytes in a some of them. There was no effect on platelets or red cells.2
In general, the most severely affected patients had a poor or no response that suggests a depleted stem cell compartment that could not be stimulated.
Chronic Neutropenia
Chronic treatment with recombinant G-CSF has been effective in reversing the profound neutropenia of Kostman’s syndrome (infantile lethal agranulocytosis), preventing the recurrent bacterial infections and early deaths of these children. There are few side effects.3 Response to G-CSF has also been described in patients with other forms of chronic neutropenia and in cyclic neutropenia.4
Megakaryocyte Growth and Development Factor (MGDF)
MGDF, sometimes designated as thrombopoietin, is a recombinant factor that specifically and directly stimulates the differentiation of megakaryocyte maturation and promotes platelet production. In its therapeutic form, MGDF is conjugated with propylene glycol that enhances its activity. MGDF has been shown to increase platelet count in experimental animals and humans.6 It has also been shown to have potent stimulatory effects on the thrombocytopenia associated with cancer chemotherapy in a selected group of adult patients. Patients with lung cancer were treated. Of 38 patients who received MGDF after receiving high-dose myelosuppressive chemotherapies, lowest mean platelet count was 188,000/mm3 (range, 68-373,000) compared to 110,000/mm3 (range, 21,000-307,000) in 12 patients treated with a placebo. The platelet count returned to baseline levels in 14 days in the treated patients compared with 21 days in the placebo group.6
Severe thrombocytopenia is a regular consequence of many chemotherapeutic protocols for childhood malignancies that often requires treatment with platelet transfusions. These must be given frequently because of the short survival of platelets (8-10 days). In addition, many patients become refractory to platelet transfusion owing to the development of anti-platelet antibodies. MGDF, produced by Amgen, will doubtless be available for studies in children in the very near future. It is likely that, just like G-CSF only a few years ago, MGDF will become part of the management of children with chemotherapy-induced thrombocytopenia.
Future Directions
EPO and G-CSF have become standard therapy for a number of pediatric conditions. It is likely that MGDF will be increasingly used. There have been few studies of the combined use of these factors. Do G-CSF and MGDF compete for a limited number of the same totipotential stem cells? Will there be an antagonistic or synergistic effect when the different growth factors are administered at the same time? We will have to await the studies. A regimen that could reduce both post-chemotherapy neutropenia and thrombocytopenia would be valuable.
References
1. American Society of Clinical Oncology: J Clin Oncol. 1994;12: 2471-2508.
2. Kojima S, et al: Blood 1991;77:1991-1995.
3. Bonilla MA, et al. N Engl J Med 1989;320:1574-1580.
4. Hammond WP, et al. N Engl J Med l989;320: 1306-1311.
5. Basser RL, et al. Lancet 1996;348:1279-1281.
6. Fanucci M, et al. N Engl J Med 1997;336:404-409.
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