The Use of Hematopoietic Growth Factors in the Treatment of Acute Leukemia

Cytokines are centrally involved in the regulation of normal hematopoiesis, the production of mature blood cells by bone marrow stem cells. Cytokines influence stem survival, proliferation, and differentiation commitment, as well as controlling the orderly maturation of progenitor cells into functional leucocytes, erythrocytes, and platelets. Acute leukemias result from malignant transformation of bone marrow stem cells. Although cytokines do not appear to be centrally involved in the pathogenesis of acute leukemias, leukemic cells express receptors for many of the cytokines regulating normal hematopoiesis, particularly GCSF, GM-CSF, IL-3, and stem cell factor. These molecules have demonstrable effects on acute leukemia cells in vitro, inducing proliferation and enhancing survival, but their biological activity when administered as recombinant proteins in pharmaceutical doses to patients with active leukemia are less well understood. Because of the stimulatory effects of cytokines such as G-CSF and GM-CSF on normal hematopoiesis in vitro and in normal individuals, these two molecules have been extensively studied in randomised clinical trials of chemotherapy for cancer, including acute leukemia. Concerns about the potential for G-CSF and GM-CSF to accelerate the growth of acute myeloid leukemia, which expresses receptors for both molecules, have not been realised. Conversely, the concept of using either of these two cytokines to induce acute myeloid leukemia cells into active DNA synthesis, thus potentially sensitising them to the effects of S-phase-specific drugs, has not been shown to be clinically beneficial. Both G-CSF and GM-CSF have been demonstrated to accelerate the recovery of normal granulopoiesis after intensive initial cytotoxic chemotherapy for acute leukemia, significantly shortening the duration of severe treatment-induced neutropenia, and resulting in a number of tangible benefits including reduction in infection, use of intravenous antibiotics, and duration of hospital stay. However, the final role for these agents in the treatment of acute leukemia remains controversial and still to be fully defined.