Cyclophosphamide and fludarabine monophosphate dose optimization for the non-myeloablative condition in non-human primates to induce transient mixed chimerism via bone marrow transplantation

Abstract

Bone marrow preconditioning using cyclophosphamide (CP) is generally used for bone marrow transplantation (BMT). However, because of CP's hepatotoxicity and nephrotoxicity, additional fludarabine (FDR) administration and a reduced dose of CP are used for reduced-intensity preconditioning. Recently, preclinical studies using non-human primates (NHPs) were performed to induce immune tolerance after solid organ transplantation by conducting BMT simultaneously. However, dose optimization of CP and FDR for BMT preconditioning in cynomolgus monkeys has not been conducted. Therefore, the objective of this study was to evaluate the efficacy and tolerability of induction protocols using different doses of CP and FDR. Our results showed that relatively low-dose CP (30 mg/kgx2) combined with additional high dose FDR (60 mg/m(2)x4) was associated with sufficient suppression in periphery as well as in bone marrow compared with high dose CP (60 mg/kgx2) combined with low-dose FDR (30 mg/m(2)x4) and did not show hepatic or renal toxicity. CD34(+) stem cells were also well suppressed with both doses. Therefore, we concluded that the combination of 60 mg/kg of CP with 240 mg/m(2) of FDR can be used effectively and safely for non-myeloablative preconditioning for BMT in cynomolgus monkeys.