Although the three growth factors have similar effects on neutrophil counts, G-CSF and pegfilgrastim are used more frequently than GM-CSF because they are better tolerated. G-CSF and pegfilgrastim can cause bone pain, which clears when the drugs are discontinued. GM-CSF can cause more severe side effects, particularly at higher doses. These include fever, malaise, arthralgias, myalgias, and a capillary leak syndrome characterized by peripheral edema and pleural or pericardial effusions. Allergic reactions may occur but are infrequent. Splenic rupture is a rare but serious complication of the use of G-CSF for PBSC mobilization.
Patients with thrombocytopenia have a high risk of hemorrhage. Although platelet transfusion is commonly used to treat thrombocytopenia, this procedure can cause adverse reactions in the recipient; furthermore, a significant number of patients fail to exhibit the expected increase in platelet count. Thrombopoietin (TPO) and IL-11 both appear to be key endogenous regulators of platelet production. A recombinant form of IL-11 was the first agent to gain FDA approval for treatment of thrombocytopenia. Recombinant human thrombopoietin and a pegylated form of a shortened human thrombopoietin protein underwent extensive clinical investigation in the 1990s. However, further development was abandoned after autoantibodies to the native thrombopoietin formed in healthy human subjects and caused thrombocytopenia. Efforts shifted to investigation of novel, nonimmunogenic agonists of the thrombopoietin receptor, which is known as Mpl. Two thrombopoietin agonists (romiplostim and eltrombopag) are approved for treatment of thrombocytopenia.
Interleukin-11 is a 65to 85-kDa protein produced by fibroblasts and stromal cells in the bone marrow. Oprelvekin, the recombinant form of IL-11 approved for clinical use (Table 33–4), is produced by expression in Escherichia coli. The half-life of IL-11 is 7–8 hours when the drug is injected subcutaneously.
Romiplostim is a thrombopoietin agonist peptide covalently linked to antibody fragments that serve to extend the peptide’s half-life. The Mpl-binding peptide has no sequence homology with human thrombopoietin, and there is no evidence in animal or human studies that the Mpl-binding peptide or romiplostim induces antibodies to thrombopoietin. After subcutaneous administration, romiplostim is eliminated by the reticuloendothelial system with an average half-life of 3–4 days. Its half-life is inversely related to the serum platelet count; it has a longer half-life in patients with thrombocytopenia and a shorter half-life in patients whose platelet counts have recovered to normal levels. Romiplostim is approved for therapy of patients with chronic immune thrombocytopenia who have had an inadequate response to other therapies.
Eltrombopag is an orally active small nonpeptide thrombopoietin agonist molecule approved for therapy of patients with chronic immune thrombocytopenia who have had an inadequate response to other therapies, and for treatment of thrombocytopenia in patients with hepatitis C to allow initiation of interferon therapy. Following oral administration, peak eltrombopag levels are observed in 2–6 hours and the half-life is 26–35 hours. Eltrombopag is excreted primarily in the feces.