Phase I trial of recombinant macrophage colony-stimulating factor and recombinant gamma-interferon: toxicity, monocytosis, and clinical effects.
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.
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
L M
LM
Weiner
W
W
Li
M
M
Holmes
R B
RB
Catalano
M
M
Dovnarsky
K
K
Padavic
R K
RK
Alpaugh
D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000009:adverse effects / Q000627:therapeutic use*; D007964:Leukocytosis / Q000209:etiology; D016173:Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D009369:Neoplasms / Q000097:blood / Q000628:therapy*; D010641:Phenotype; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012120:Respiration Disorders / Q000209:etiology; D013921:Thrombocytopenia / Q000209:etiology
D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma