What role for mycophenolate mofetil in allogeneic hematopoietic cell transplantation? (2003)

Bühler et al. (1) conditioned baboons with a complex nonmyeloablative regimen for pig hematopoietic cell transplantation (HCT), which included postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CsA). They observed transient pig hematopoiesis for no more than 1 month. Subsequently, they investigated which components of their regimen might compromise growth of hematopoietic progenitors using a colony-forming unit (CFU) assay as a readout (2). They found complete inhibition of porcine and human CFUs at an MMF concentration of 1 μg/mL and of baboon CFUs at concentrations of 10 to 100 μg/mL. They concluded that high doses of MMF after HCT might compromise engraftment. When discussing their findings, they commented on a study (3) of 45 human patients given 2 Gy total-body irradiation (TBI), HCT from human leukocyte antigen (HLA)-matched siblings, and MMF at 15 mg/kg two times a day after transplantation along with CsA. They suggested that the observed 20% nonfatal graft rejection rate in that study might be attributable to MMF-associated hematopoietic toxicities. We do not concur with that suggestion for several reasons. First, the addition of MMF to CsA-enhanced sustained engraftment over CsA alone in a canine model of nonmyeloablative HCT. Second, MMF–CsA has been used in more than 600 human patients with hematologic diseases treated with nonmyeloablative conditioning and HLA-matched related or unrelated HCT. The initially observed 20% graft rejection rate among recipients of related grafts was interpreted to be caused by inadequate immunosuppression (3). Accordingly, three doses of fludarabine at 30 mg/m2 per day on days −4, −3, and −2 were added to the 2 Gy TBI to increase pretransplant host immunosuppression, whereas in other patients with large tumor burdens, this was achieved by consolidation with preceding autologous HCT. As a result of these changes, graft rejection rates declined to 3% among 118 fludarabine and TBI-treated patients and 0% among 77 patients given preceding autologous HCT (4). Third, an initial graft rejection rate of 15% was seen in recipients of unrelated HCT (5). We postulated that increasing postgrafting MMF doses might reduce rejection given the short (3 hour) blood T1/2 of mycophenolate acid (MPA, active metabolite of MMF) and the rapid reversibility of its binding to inosine monophosphate dehydrogenase. Changing MMF from 15 mg/kg two times a day to 15 mg/kg three times a day resulted in a decrease in rejection to 4% among 57 subsequent patients (unpublished data). Conceivably, differences in MMF administration and dosing could account for the hematopoietic toxicities observed by Bühler et al. With MMF at 15 mg/kg two times a day orally, the area under the curve (AUC) for MPA was 20.3 μg/mL per hour. With continued intravenous infusion of 110 mg/kg per day, the AUC would be approximately 3.7 times higher than that and more than twice that achieved with MMF three times a day. The peak concentration with MMF two times a day was 5.3 μg/mL, and this might be higher with 110 mg/kg per day continued infusion. In conclusion, MMF at two or three times a day, as first used in a canine HCT model and then translated to treat human patients with hematologic diseases, enhanced engraftment of MHC matched related and unrelated HCT and did not result in graft destruction at the drug doses used. Rainer Storb