Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine

Abstract

Twenty-two patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex and multilineage hematopoietic defects were treated with recombinant granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) in a phase I/II trial. All patients were neutropenic and anemic after withdrawal of all bone marrow-suppressive drugs. Daily, G-CSF was subcutaneously self-administered until an absolute neutrophil count (ANC) greater than 6,000/microL was achieved and maintained for 2 weeks. Subcutaneous EPO was added to the regimen and the dose increased until an increase of 15 g/L of hemoglobin was observed. Groups of patients were administered increasing doses of zidovudine to determine their tolerance. G-CSF and EPO therapy was continued with dose modification to maintain an ANC greater than 1,500/microL and hemoglobin greater than 100 g/L. The dose of zidovudine was not altered. All 22 patients responded to G-CSF with a mean 10-fold increase in neutrophils occurring in less than 2 weeks. Significant increases in CD4 and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in all 20 evaluable patients within 8 weeks. Sixteen patients received 1,000 mg and four patients received 1,500 mg of zidovudine per day. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in eight of the 20 patients, six of whom had the study medications stopped. No patient had the study medications stopped because of neutropenia or thrombocytopenia. Toxicities were mild and did not require dose modifications. Limiting dilution plasma and lymphocyte co-cultures for HIV as well as serum p24 antigen levels did not change significantly during G-CSF or combined G- CSF and EPO therapy. HIV p24 antigen decreased significantly with zidovudine therapy. Opportunistic infections occurred in 14 patients but were successfully treated with myelosuppressive antimicrobial agents, including ganciclovir, without the development of neutropenia. These results suggest that combined therapy with G-CSF and EPO may improve the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of full-dose zidovudine in most patients intolerant of the hematologic effects of zidovudine without apparent alteration of HIV expression or the efficacy of zidovudine.

The Effect of Long‐Term Treatment with Granulocyte Colony‐Stimulating Factor on Hematopoiesis in HIV‐Infected Individuals

“…Neutropenia is common in patients with advanced HIV infection. The cause vary, but neutropenia is often caused by the use of myelotoxic agents directed against HIV, myelosuppressive chemotherapy, or radiation therapy [1,2,4,25]. G-CSF is known to increase the absolute neutrophil count by stimulating proliferation and differentiation of neutrophil precursors including CD34 progenitor cells [25±27].…”

“…Interestingly, the CD4 count in HIV-infected patients treated with G-CSF increase as well [1±3, 9, 11±13], and in one study an increase in the number of naive CD4 cells was found [9]. In addition, short-term G-CSF administration may partially restore the in vitro interleukin (IL)-2 production and lymphocyte proliferative response in blood from HIV-infected patients [1,14], although one study has shown a decrease in these functions [12].…”

Clinical Guidelines and Pharmacist Intervention Program for HIV‐Infected Patients Requiring Granulocyte Colony‐Stimulating Factor Therapy

“…Therefore, less than the recommended dosage in HIV-infected patients may result in an adequate response. 16 Dosages of G-CSF were titrated to maintain a nadir ANC of 500-1500 cells/mm 3 in patients with HIV who had dose-limiting neutropenia due to ganciclovir. 8 All seven patients were maintained with the recommended dosage of ganciclovir and required only one to three doses of G-CSF/week.…”