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| Growth Factor Support in Oncology |
I. INTRODUCTION. Myelosuppression is one of the most common dose-limiting toxicities of cytotoxic agents. An understanding of hematopoiesis and the roles of growth factors can significantly improve complications of treatment. Hematopoiesis is the process of production multiplication and specialization of blood cells in the bone marrow. The proliferation and differentiation of the pluripotent stem cell to the myeloid and the lymphoid progenitors and the further differentiation of those to the mature circulating blood cells involve complex interaction of the stem cells, bone marrow stromal cells, and cytokines. The cytokines also activate the mature hematopoietic cells. Hematopoietic growth factors’ action and effect on cell lines are still not fully understood; however, some identified growth factors and potential therapeutic options are described later.
II. MYELOID GROWTH FACTORS
A. Granulocyte colony-stimulating factor (G-CSF)
1. Endogenous G-CSF. G-CSF is a glycoprotein secreted by monocytes, fibroblasts, and endothelial cells. It targets G-CSF receptors on myeloid precursor cells in the bone marrow, promotes the maturation of the granulocyte colony-forming unit to the polymorphonuclear leukocyte, and enhances neutrophil function.
2. Recombinant preparations (rHuG-CSF). Filgrastim (Neupogen and Granix) and pegfilgrastim (Neulasta) are the two currently available formulations of recombinant G-CSF in the United States. Filgrastim and pegfilgrastim function through the same mechanism of action promoting neutrophil proliferation, differentiation, and activation. Filgrastim has a half-life of 3.5 hours. Pegfilgrastim, which is a covalent conjugate of filgrastim and monomethoxypolyethylene glycol, has a prolonged half-life of 15 to 80 hours.
3. Recommended dose. The recommended dose of filgrastim is 5 µg/kg administered subcutaneously daily until an absolute neutrophil count (ANC) of 10,000/mm3 has been reached following a chemotherapy-induced nadir. When filgrastim is used following high-dose chemotherapy with autologous stem cell rescue, a higher dose of filgrastim of 10 µg/kg daily is recommended. When used in this setting, filgrastim should be continued until an ANC of 1,000/mm3 is reached on three consecutive days. The dose of filgrastim should then be reduced to 5 µg/kg subcutaneously daily until ANC remains >1,000/mm3 for three consecutive days at which therapy can be discontinued. When filgrastim is utilized in stem cell mobilization and collection prior to stem cell transplantation, filgrastim is administered at a dose of 10 µg/kg daily 4 days prior to apheresis and continued until the stem cell collection is complete. Of note, filgrastim should not be administered within 24 hours from the administration of cytotoxic chemotherapy because of the potential cellular toxicities to rapidly dividing myeloid cells. Filgrastim administration should also be avoided in patients receiving concurrent chemotherapy with radiation to the chest.
Pegfilgrastim is administered at a dose of 6 mg given subcutaneously, one time 24 to 72 hours following the administration of chemotherapy, and at least 14 days prior to the initiation of subsequent doses of chemotherapy. The safety and efficacy of pegfilgrastim in the setting of concurrent chemotherapy and radiation have not been established. Pegfilgrastim is not currently indicated for stem cell mobilization (J Clin Oncol 2006;24:4451).
Filgrastim and pegfilgrastim doses do not need to be adjusted for renal or hepatic function.
4. Adverse effects. The most common adverse reactions associated with the use of recombinant G-CSF include bone pain, fever, and injection-site reactions. Rare adverse reactions including splenic rupture, adult respiratory distress syndrome (ARDS), and alveolar hemorrhage have also been reported. In patients with sickle cell anemia, the use of recombinant G-CSF has been associated with severe and potentially fatal sickle cell crisis (Blood 2001;97:3998). Allergic reactions of varying severity are also described with the use of recombinant G-CSF.
B. Granulocyte–macrophage colony-stimulating factor (GM-CSF)
1. Endogenous GM-CSF. GM-CSF is a protein that stimulates stem cell precursors to produce all types of white blood cells including neutrophils, lymphocytes, eosinophils, basophils, and monocytes. GM-CSF also enhances neutrophil and monocyte/macrophage function.
2. Recombinant granulocyte–macrophage colony-stimulating factor (rHuGM-CSF). Sargramostim (Leukine) is the only rHuGM-CSF formulation available in the United States. Administration of rHuGM-CSF results in increased production, differentiation, and activation of neutrophils, eosinophils, monocytes, and macrophages. When administered subcutaneously, sargramostim has a half-life of 2.7 hours.
3. Recommended dose. The recommended dose of sargramostim is 250 µg/m2/day for all indicated treatment settings. Subcutaneous and intravenous dosing are available; however, subcutaneous dosing is the preferred route of administration. Sargramostim is indicated following induction chemotherapy for AML in adults ≥55 years old, engraftment failure or delay following bone marrow transplant, myeloid reconstitution following autologous or allogeneic bone marrow transplant, and stem cell mobilization. In the setting of primary prophylaxis of neutropenia in patients receiving chemotherapy, GM-CSF is administered off label, 24 to 72 hours after chemotherapy, and is discontinued once the ANC has recovered to 10,000/mm3 or the ANC is more than 1,500/mm3 for 3 days. GM-CSF is contraindicated 24 hours preceding and following chemotherapy and radiation therapy. Hepatic and renal function should be monitored closely during the administration of sargramostim.
4. Adverse effects. The most common adverse effects associated with sargramostim include fever, headaches, diarrhea, bone pain, myalgias, arthralgias, and injection-site reactions. Fluid retention manifested by edema, capillary leak syndrome, pleural effusion, and pericardial effusion have also been reported. Sargramostim is contraindicated in patients with myeloid blast counts exceeding 10% in the peripheral blood or bone marrow. Allergic reactions to sargramostim are uncommon, but severe anaphylactic reactions have been described. Sargramostim is contraindicated in patients with previous reactions to GM-CSF, other products derived from yeast, or any of the other ingredients used to make sargramostim. In addition, a rare constellation of symptoms consisting of respiratory distress, hypoxia, hypotension, flushing, and tachycardia may be seen following the first dose of sargramostim. The “first dose” reaction is treated with supportive care and does not typically recur with subsequent doses.
C.
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