Sequential interleukin 3 and granulocyte-macrophage-colony stimulating factor therapy in patients with bone marrow failure with long-term follow-up of responses

BACKGROUND. interleukin-3 (IL-3) and granulocyte-macrophage-colony stimulating factor (GM-CSF) have synergistic, hematopoietic growth-promoting activity in preclinical studies. Because of the paucity of effective therapies for patients with chronic bone marrow failure states, the authors studied the biologic activity of sequential IL-3/GM-CSF in such patients. METHODS. IL-3 was given subcutaneously for 5 days (at escalating doses of 0.15 mug/kg, 0.3 mug/kg, 0.6 mug/kg, 1.2 mug/kg, 2.5 mug/kg, 5.0 mug/kg, 10.0 mug/kg, or 15.0 mug/kg per day), and GM-CSF for was given subcutaneously for 9 days (at a dose of 5 mug/kg per day; Phase I 3 + 3 design) followed by 14 days of rest (total, 2 courses), then maintenance therapy. RESULTS. The majority of 38 evaluable patients had aplastic anemia or myelodysplastic syndrome. Most patients (79%) had neutrophil responses. Ten patients (26%), all of whom were treated with IL-3 doses greater than or equal to 1.2 mug/kg per day, had platelet responses, with a median increase of 132 X 10(9)/L (range, 41-180 X 10(9)/L) over baseline in responders. Six patients (16%) had trilineage recovery, which could be durable (the longest ongoing at 6.5 years after therapy completion). The most common toxicities were low-grade fever, headache, and fatigue. The maximum tolerated doses were IL-3 at 10 mug/kg per day and GM-CSF at 5 mug/kg per day. CONCLUSIONS. Sequential IL-3/GM-CSF effectively raised blood counts in some patients with bone marrow failure at doses that were tolerated well. These results indicate that early-acting growth factors can induce durable, multilineage responses in a subset of individuals with bone marrow failure. (C) 2003 American Cancer Society.