Hematopoietic responses in patients with advanced malignancy treated with recombinant human granulocyte-macrophage colony-stimulating factor.

Abstract

The in vivo effect of yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) was investigated in 30 patients with advanced malignancy in a phase Ib trial. Patients were treated at four different dose levels (120 to 1,000 micrograms/m2/d) by either daily intravenous (IV) bolus injection or 24-hour continuous infusion. Administration of rh GM-CSF resulted in a broad spectrum of dose- and schedule-dependent hematopoietic effects. Sustained infusion of rh GM-CSF elicited a maximum 17-fold average peak increase of the total WBC count with mainly neutrophils, eosinophils, and monocytes accounting for this rise, and increases in bone marrow cellularity with a shift to immature myeloid elements. Elevation of lymphocytes, platelets, and reticulocytes was not induced. Within five days after discontinuation of treatment the leukocytosis had disappeared. Adverse reactions encountered with rh GM-CSF seen in 65% of the patients studied were never life-threatening and always rapidly reversible. They included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, dyspnea, and transient decline of platelet counts. These results suggest that rh GM-CSF can be safely administered at the doses and schedules used and that it can induce in vivo some of the biological effects reported in in vitro studies. Although no objective antitumour responses have been seen, the ability of rh GM-CSF to increase number and function of leukocytes in vivo may prevent neutropenia and infections when GM-CSF is added to cytotoxic cancer therapy.

Chemotherapy Dose and Survival in Advanced Hodgkin’s Disease

“…The only pa rameter of possible prognostic significance was the obser vation that patients treated with reduced doses of chemo therapy included a higher though statistically nonsig nificant proportion of slow responders (table 2). Hematopoietic growth factors like G-CSF [3] and GM- CSF have been shown to shorten the duration of chemo therapy-induced myelosuppression [2,4,4]. Therefore, it appears possible that the prophylactic use of such factors would allow one to administer full doses of chemotherapy that would cure the majority of patients with Hodgkin's disease, in particular at advanced stages where the main stay of treatment is chemotherapy.…”

“…Granulocyte-macrophage colo ny-stimulating factor (GM-CSF) enhances the growth of myeloid progenitors both in vitro [1], and in vivo [2], In particular, it hastens the recovery of granulocytes and macrophages following intensive chemotherapy [3,4], The drug is active in a broad dose range without severe adverse events [5]. One important application of drugs like GM-CSF could be the prevention of chemotherapy-induced leukopenia, thus augmenting the application of chemo therapy.…”

Hemopoietic Growth and Inhibitory Factors in Treatment of Malignancies: A review

“…Many clinical studies of GM-CSF now assess infection and secondary endpoints related to it. The pattern emerging is that there are significant reductions of serious infections and marked savings in antibiotic use, hospitalization and support measures such as isolation (17,41). However, it may be difficult to demonstrate a prophylactic anti-infective effect by direct comparisons with established antibiotic regimens.…”

Development of Immunotherapeutic Strategies for the Treatment of Malignant Neoplasia

“…Thus, therapy-lim iting edema, weight gain, myalgias, occur in most patients at higher doses of gm-CSF [77][78][79][80][81][82][83][84][85][86][87][88][89]99]. Further, pleural effusions, i.e.…”

“…In contrast, if the myelorestorative drug is administered after complete me tabolism of the agent, either alone or in con junction with autologous bone marrow transplants, accelerated myeloid reconstitu tion will occur. Several of the CSFs have been tested clinically including rHu gm-CSF [77][78][79][80][81][82][83][84][85][86][87][88][89], rHu g-CSF [90][91][92][93][94][95], and partially purified natural m-CSF [96][97][98], and all have demonstrated clinical efficacy. As a generality, these agents have shown as high as a 100-fold increase in the number of circu lating progenitor cells of a variety of lin eages, including granulocytic-monocytic, granulocytic, monocytic, and to a lesser ex tent, erythroid, and megakaryocytic precur sors.…”