Myeloablative chemotherapy with autologous peripheral blood stem cell transplantation for metastatic breast cancer: immunologic consequences affecting clinical outcome

Abstract

Autologous peripheral blood stem cell transplantation following myeloablative chemotherapy is being increasingly utilized in the treatment of a variety of malignancies. We administered busulfan 16 mg/kg orally, thiotepa 500–700 mg/m² i.v., and carboplatin 800–1000 mg/m² i.v. to 56 women with metastatic carcinoma of the breast. Autologous peripheral blood stem cells, which had been collected after a combination of chemotherapy and granulocyte colony-stimulating factor, were infused on day 0. The major toxicities of the conditioning regimen included severe pancytopenia, stomatitis, nausea, emesis, diarrhea, fever, and infection. Transplant-related mortality was 1.8%. The incidence of opportunistic viral infections was 42.9%. Fourteen individuals achieved a complete response. The actuarial survival at 1223 days was 13.7% for the entire group of patients; the actuarial survival at 1009 days was 39.3% among complete responders. The functional status of the immune system was determined following transplantation in a subset of patients. Peripheral blood mononuclear cells were obtained before and after stem cell infusion, and were analyzed phenotypically and functionally. Proliferative and interleukin-2 synthetic ability of these cells was assessed following stimulation with phytohemagglutinin and anti-CD3 antibody. The response to influenza peptides was also ascertained. Proliferative and interleukin-2 synthetic capacity was markedly impaired for over a year. Memory response was virtually absent for up to 2 years following transplantation. The prolonged and marked immunosuppression following this myeloablative regimen was associated with a high incidence of opportunistic viral infections, and may have contributed to disease relapse and progression especially in patients who failed to achieve a complete response following transplantation.