Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes--a phase I/II trial

Abstract

In a phase I/II study, 11 patients with myelodysplastic syndromes (MDS) and severe transfusion-dependent cytopenia were treated with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to investigate the effects of rhGM-CSF on normal hematopoiesis and leukemic cells. The treatment schedule included dose escalation from 15 micrograms/m2 to 150 micrograms/m2 administered by continuous intravenous (IV) infusion for seven to 14 days and was repeated after a two-week treatment-free interval. The blood leukocyte counts increased dose dependently by 130% to 1,800% in ten patients; a rise of monocytes and eosinophils occurred in seven and six patients, respectively. No sustained increase in reticulocytes or platelets was observed. Lymphocyte counts increased in all patients affecting both T- helper and T-suppressor cells; however, the lymphocytes were not activated as analyzed by the expression of the interleukin-2 receptor. In four of the patients, all with greater than 14% blast cells in the bone marrow, the percentage of bone marrow blast cells increased during treatment with rhGM-CSF. Cytogenetic data indicated induction of both proliferation and differentiation of the leukemic clones by rhGM-CSF. Toxic side effects were minor with slight fever, phlebitis at the infusion site, and bone pain in the minority of patients. In conclusion, rhGM-CSF effectively stimulates hematopoiesis in vivo in patients with myelodysplastic syndromes. However, as the leukemic cell population can be stimulated in patients with a higher initial blast cell count, the combination of rhGM-CSF with other differentiation- inducing or cytotoxic agents has to be considered.

Recombinant human granulocyte-macrophage colony-stimulating factor plus erythropoietin for the treatment of cytopenias in patients with myelodysplastic syndromes

“…Our results also confirm that in neutropenic patients with MDS a substantial increase of the ANC can be achieved with low doses of rhGM-CSF. This is well in line with previously reported data (Ganser et al, 1989;Schuster et al, 1990;Hansen et al, 1993;Runde et al, 1995;Bernell et al, 1996). On the other hand, rhGM-CSF treatment was associated with significant and, in three cases intolerable, side-effects.…”

“…Published clinical trials of recombinant human erythropoietin (rhEPO) in MDS indicate that on average about 20% of patients respond with a decrease in transfusion requirements or normalization of haemoglobin levels (Hellström-Lindberg, 1995), with a range of 0-40% (Legare & Gilliland, 1995). On the other hand, studies using cytokines with myeloid activity such as recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) have shown consistent elevations in granulocyte counts, with little success in elevating haemoglobin concentrations or platelet counts (Vadhan-Raj et al, 1987;Antin et al, 1988;Ganser et al, 1989;Negrin et al, 1990;Yoshida et al, 1991;Kurzrock et al, 1991;Schuster et al, 1990). As in vitro experiments have indicated a synergy between myeloid cytokines and EPO for the production of normal and MDS erythroid precursors (Donahue et al, 1985;Broxmeyer et al, 1989;Aoki & Shibata, 1992;Merchav et al, 1991), clinical studies have been undertaken to evaluate the combination of these growth factors in patients with MDS.…”

Effects of interleukin‐5 on acute myeloid leukemias

“…Responding cells have been shown to express surface receptors for these cytokines that are similar in structure and affinity to those present on normal hematopoietic progenitors [ 1 11. Non-lymphocytic leukemias exhibit variable in vitro responses to granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-3, substances originally characterized by their ability to support the growth of normal hematopoietic progenitor cells [12][13][14]. Because IL-5 is known to support the lineage-specific growth of eosino-phi1 progenitors [ 151, we tested whether IL-5 would have an effect on the growth of a well-characterized subtype of leukemia, M4Eo [7,8], that differentiates partially along the eosinophil lineage.…”

Hematopoietic growth factors in cancer

“…Elevated blast cell counts returned to normal after discontinuation of In a Phase 1/11 study of 1 I patients with MDS and severe transfusion-dependent cytopenia, GM-CSF was administered by continuous infusion for 7 to 14 days with dose escalation from I5 to 150 pg/m2. 35 This was repeated after a 2-week treatment interval. A dose-dependent increase in blood leukocytes was noted in ten patients and an increase in monocytes and eosinophils occurred in seven and six patients, respectively.…”