Phase I trial of recombinant macrophage colony-stimulating factor and recombinant gamma-interferon: toxicity, monocytosis, and clinical effects

Cancer Res. 1994 Aug 1;54(15):4084-90.

Abstract

Macrophage colony-stimulating factor (M-CSF) is a known inducer of proliferation and differentiation of cells of the mononuclear phagocyte lineage, and gamma-interferon (gamma-IFN) is a known activator of mononuclear phagocytes. In this Phase I clinical trial of combined therapy with M-CSF and gamma-IFN, 36 patients were treated with 14-day continuous infusions of M-CSF at doses ranging from 10 to 140 micrograms/kg/day. In all but five patients, gamma-IFN was administered by daily s.c. injection on days 8-14 of the M-CSF infusion at doses of 0.05 or 0.1 mg/m2/day. A total of 73 courses of M-CSF and 66 courses of gamma-IFN were administered. The maximally tolerated dose combination was 120 micrograms/kg/day M-CSF, 0.1 mg/m2/day gamma-IFN. The addition of gamma-IFN did not alter the maximally tolerated dose of M-CSF therapy, although some additional toxicities were noted with combined therapy. At the 140-micrograms/kg/day M-CSF dose level, grade 4 thrombocytopenia occurred in 2 of 3 patients, with a median platelet count nadir of 26,000/mm3 after 7-10 days of M-CSF infusion. At this dose level, there was one reversible grade 3 hepatic toxicity, and one grade 3 exacerbation of underlying chronic obstructive lung disease. Peripheral blood monocytosis was observed at all M-CSF dose levels exceeding 40 micrograms/kg/day, approaching 3-fold elevations at the 100-micrograms/kg/day M-CSF dose level. The induction of monocytosis was correlated with the development of thrombocytopenia. At the conclusion of therapy with 100 micrograms/kg/day M-CSF, 0.1 mg/m2/day gamma-IFN, 78% of peripheral blood monocytes expressed the low affinity Fc gamma receptor for aggregated immunoglobulin, Fc gamma RIII (CD16), and CD14 was expressed by only 36% of the cells. This phenotype has been shown previously to be associated with cellular activation. In contrast, 35% of monocytes from patients treated with M-CSF therapy alone at the same dose expressed CD16 and 88% expressed CD14. A partial clinical response was noted in a patient with metastatic renal cell carcinoma, and minor clinical responses were observed in patients with a diffuse/follicular lymphoma, metastatic renal cell carcinoma, and metastatic thymoma. At M-CSF doses exceeding 20 micrograms/kg/day within the maximally tolerated dose range, gamma-IFN did not modulate the ability of M-CSF to reliably induce peripheral blood monocytosis. This study shows that M-CSF and gamma-IFN therapy induces the proliferation and differentiation of circulating mononuclear phagocytes.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Humans
  • Interferon-gamma / adverse effects
  • Interferon-gamma / therapeutic use*
  • Leukocytosis / etiology
  • Macrophage Colony-Stimulating Factor / adverse effects
  • Macrophage Colony-Stimulating Factor / therapeutic use*
  • Male
  • Middle Aged
  • Monocytes
  • Neoplasms / blood
  • Neoplasms / therapy*
  • Phenotype
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / therapeutic use
  • Respiration Disorders / etiology
  • Thrombocytopenia / etiology

Substances

  • Recombinant Proteins
  • Macrophage Colony-Stimulating Factor
  • Interferon-gamma