Prediction of the optimal timing of bone marrow reinfusion after high dose chemotherapy

Autologous bone marrow transplantation allows the use of high dose chemotherapy by obviating dose limiting myelosuppression. The pharmacology of high dose chemotherapy has been inadequately explored, yet this information is critical to determine the timing of marrow infusion and assure that engraftment is not compromised. We have used the Salmonella mutagenesis test (SMT) and colony forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte assay to evaluate the optimal time for marrow infusion after therapy with high dose combinations of alkylating agents (Solid Tumor Autologous Marrow Support Program) in seven patients. The SMT is sensitive, rapidly performed, and has been used to detect mutagenic activity in urine following administration of cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea. In parallel, determination of colony forming ability of the patients own bone marrow (colony forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte assay), when cocultured with autologous serum obtained before and after treatment, provided an assay for circulating marrow toxic drugs or metabolites. The onset of mutagenic activity in the SMT and the in vitro appearance of myelotoxicity by autologous serum in the colony forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte assay were concurrent, and these activities returned to base line at the time of marrow infusion (72 h posttreatment). One patient of the seven was excreting mutagens (TA100 strain only) at the time of marrow reinfusion; he developed hepatic venoocclusive disease, and delayed engraftment. These observations suggest that as high dose regimens evolve the SMT may serve as a rapid, sensitive indicator of the circulation and excretion of toxic compounds, and thereby assist in predicting the optimum time of bone marrow reinfusion.