High dose cyclophosphamide therapy in solid tumors. Therapeutic, toxic, and immunosuppressive effects

Cyclophosphamide (CY) in a total dose of 120 mg/kg was given over 2 days on one to three occasions to 12 patients with a variety of nonlymphoid solid tumors. Two of 10 patients with measurable disease had a partial response. One had embryonal rhabdomyosarcoma and the other had ovarian carcinoma. In the 20 treatment courses, the mean leukocyte count was less than 1,000/mm for 7 days. Thrombocytopenia was variable with a mean nadir of 87,000/mm on day 12. There were four instances of local infection, one of bacteremia, and 11 of fever of undetermined origin. Weight gain of 2 or more kg occurred after 12, and EKG changes compatible with cardiotoxicity after six courses of CY. Serial skin testing with recall antigens revealed a frequent transient loss, and in three patients a later overall gain, in responsiveness. All patients were immunized with Vi antigen before CY, and with Vi and sheep red blood cells (SRBC) after CY. Specific immune tolerance to Vi, with a satisfactory response to SRBC, was found in six of 12 patients. Patients' responses to the lymphocytes of 2 ABO compatible normal subjects were measured in mixed lymphocyte culture (MLC) before and after CY. Patients were given 500 ml of whole blood from one of the subjects prior to CY. Following CY, the patients' responses to the blood donors' cells were not significantly lower than their responses to non-donor cells. Thus, tolerance to HL-A antigens was not demonstrable in MLC. Three patients had an increase from subnormal to normal reactivity to non-donor cells in MLC.