Recombinant human granulocyte-macrophage colony-stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma.

Abstract

High-dose administration of anticancer agents is attractive both on theoretic and clinical grounds. Yet, high-dose regimens are usually used as salvage treatments, mainly as a consequence of their considerable hematologic toxicity. One pertinent example is represented by cyclophosphamide, an alkylating agent with a wide spectrum of marked antitumor activity. When used at doses up to 7 g/m2 (190 to 200 mg/kg) this drug does not cause myeloablation, but induces a severe, albeit transient, myelosuppression, which requires platelet transfusions in approximately 50% of treated patients, and is frequently complicated by infectious episodes, occasionally lethal. To accelerate hematopoietic recovery, we continuously infused for 14 consecutive days 5.5 micrograms/kg/d of the glycosylated human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) into 15 patients with breast cancer and non-Hodgkin's lymphoma treated with 7 g/m2 cyclophosphamide. This schedule was chosen having obtained the fastest hematopoietic recovery among four different options during an initial schedule-finding phase on 12 overall patients. Twenty-one comparable subjects with solid tumors served as controls. We report here that this relatively low, well-tolerated dose of rhGM-CSF reduces from 20 to 14 (median) and from 24 to 14, the number of days required to recover circulating granulocyte counts over 1,000 and 2,500/microL, respectively. The stimulatory effect was associated with a remarkable clinical benefit. In fact, treated patients experienced less infectious complications (7% v 24%) were eligible to receive chemotherapy earlier (median, by day +14 v day +20 for controls), and fewer required prophylactic platelet transfusions (13% v 43%). Our results show that even very high doses of cyclophosphamide can be administered with improved hematologic toxicity, tolerable morbidity, and reduced supportive care requirements. The increase in the therapeutic index made possible by rhGM-CSF infusion prompts the use of high-dose cyclophosphamide, and possibly of other agents with similar myelotoxic activity, early in the clinical course of chemotherapy-sensitive tumors.

Factors affecting both peripheral blood progenitor cell mobilization and hematopoietic recovery following autologous blood progenitor cell transplantation in multiple myeloma patients: a monocentric study

“…Thus, even if HGF could decrease the hematological toxicity of HDCYC, their use did not seem to change significantly this difference for the others. 29,32 As we observed, other parameters also involved in PBPC collection efficiency such as duration of therapy before HDCYC are important for HDCYC tolerance. Indeed, in a more recent study reporting results of total therapy, no death was observed after HDCYC 6 g/m 2 in newly diagnosed MM patients.…”

Paroxysmal atrial fibrillation after high-dose melphalan in five patients autotransplanted with blood progenitor cells

“…Three patients received bone marrow alone harvested under general anesthesia and 73 patients received PBPC mobilized with G-CSF after priming with cyclophosphamide 7 g/m 2 (42 patients), 18 DHAP regimen (21 patients), 19 etoposide 2 g/m 2 (six patients) 20 or VACOP-B regimen (four patients).…”

High-dose carboplatin, thiotepa and cyclophosphamide (CTC) with peripheral blood stem cell support in the adjuvant therapy of high-risk breast cancer: a practical approach

“…Studies with haematological growth factors such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have shown that the chemotherapy dose per unit of time can be increased by a factor 1.5-2.0 (as compared with 'standard' doses) in young patients with breast cancer (Bronchud et al, 1989;Gianni et al, 1990). At these dose levels, thrombocytopenia and organ toxicity become dose-limiting.…”