Interferon-a, zidovudine, and granulocyte-macrophage colony-stimulating factor: A phase I AIDS clinical trials group study in patients with Kaposi's sarcoma associated with AIDS

Purpose: To increase the hematologic tolerance of interferon-α (IFNα) and zidovudine combination therapy by the addition of granulocyte-macrophage colonystimulating factor (GM-CSF), and to evaluate the safety, tolerance, and potential efficacy of the combination in patients with Kaposi's sarcoma and AIDS. Patients and Methods: Seventeen patients with Kaposi's sarcoma associated with AIDS received zidovudine 200 mg orally every 4 hours and GM-CSF 5 μg/kg/d subcutaneously. Successive cohorts received IFN-α2b at a daily subcutaneous dose of 5, 10, or 20 million units. The dose of GM-CSF was titrated to maintain the neutrophil count between 1 and 5 × 10⁹ cells/L. Doses of all three drugs were reduced, as required, for nonhematologic toxicities. Results: GM-CSF induced leukocytosis in all patients. On average, a dose of 1.25 μg/kg/d was sufficient to maintain the neutrophil count within the desired range. The combination of 20 million units of IFN-α with zidovudine and GM-CSF induced dose-limiting toxicty in four of six patients. The major side effects were constitutional symptoms, which included malaise, anorexia, fatigue, fever, and were dose-limiting in three patients. Severe anemia and/or thrombocytopenia developed in three patients. Seven patients (41%; 95% confidence interval [CI], 18% to 64%) showed objective tumor regression that persisted for a median of 51 weeks. A rapid decrease in free-serum p24 antigen levels was observed in seven patients who had measurable levels at baseline; the mean time required to isolate human immunodeficiency virus (HIV-1) from peripheral-blood cells was increased by 7 days. The number and percentage of CD4-positive lymphocytes showed no significant change. Conclusions: GM-CSF prevents neutropenia induced by the IFN-α and zidovudine combination and induced no adverse effects on immune function or HIV activity. However, nonhematologic toxicity precluded a major increase in the maximum-tolerated doses of IFN-α and zidovudine.