Unrelated Donor Peripheral Blood Stem Cell (PBSC) Transplantation Using Nonmyeloablative Conditioning and Mycophenolate Mofetil (MMF) TID Results in High Engraftment Rates.

We have shown safety of unrelated donor hematopoietic cell transplantation (HCT) using nonmyeloablative conditioning with fludarabine (FLU, 90 mg/m²) and 2 Gy total body irradiation (TBI) and post-HCT immunosuppression with MMF (15 mg/kg) and cyclosporine (CSP 5–6.25 mg/kg) both given BID (Maris Blood 2003 Vol 102, No 6). The graft rejection rate in the first 89 pts was 23% and more frequent for marrow (8/18; 44%) than PBSC (13/71; 18%) recipients. Multivariate analysis identified recipients of marrow grafts and those without preceding chemotherapy at highest risk for graft rejection (p=0.006 for each). The t½ of mycophenolic acid, the active metabolite of MMF, was 3 hours, and its binding to IMPDH II rapidly reversible. This led to the hypothesis that exclusive use of PBSC grafts and TID dosing of MMF might result in higher engraftment and lower acute GVHD rates. The current protocol (MMF TID) was identical to the original one (MMF BID) except that all pts received PBSC and were given MMF TID. The protocol’s primary goal was to achieve graft rejection <10% and <20% for pts with and without prior chemotherapy, respectively, and its secondary goal to reduce the incidence of acute GVHD. Pts with malignant diseases (n=103), matched with their donors for HLA-A, -B, -C antigens and -DRB1 and -DQB1 alleles, were entered on study. Median donor T cell chimerism at day 28 was 92% compared to 75% for 71 PBSC recipients given MMF BID on the prior protocol (p=0.02). When BID and TID MMF pts were considered together, donor T cell chimerism <50% was highly predictive for graft rejection (p<0.0001). The durable engraftment rate for pts given MMF TID versus BID was 95% (98/103) compared to 82%, respectively (p=0.004). For pts with and without prior chemotherapy given MMF TID versus BID, rejection rates were 3% compared to 10% (p=0.08) and 17% compared to 53% (p=0.05), respectively. Cumulative probabilities of grades II, III and IV acute and chronic extensive GVHD were 39%, 10%, 2%, and 45%, respectively, and were similar to rates in BID MMF pts, suggesting further improvements in GVHD prevention are needed. For the 103 pts given MMF TID, 1-year overall survival, progression-free survival, relapse/progression, and non-relapse mortality were 64%, 54%, 27%, and 19%, respectively. Kaplan-Meier 1-year survivals were as follows: acute leukemia (n=24) 79%, B cell malignancies (n=47: CLL, n=13; Hodgkin disease, n=8; NHL, n=27) 63%, multiple myeloma (n=11) 55%, CML (n=5) 100%, MDS/myeloproliferative syndromes (MPS) (n=12) 50%, and RCC 50%. Kaplan-Meier 1-year progression free survivals were as follows: acute leukemia 71%, B cell malignancies 61%, multiple myeloma 46%, CML 60%, MDS/MPS 33%, and RCC 25%. The use of unrelated donor PBSC grafts and administration of MMF TID after nonmyeloablative conditioning significantly improved donor T cell chimerism and engraftment rates over the preceding protocol. However, further improvements in immunosuppression after HCT are needed to reduce acute GVHD rates.