Abstract: We studied a new combination of mitoxantrone, ara C and pentostatin (MAP) as non-myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (NST). 25 patients with high-risk hematological malignancies were enrolled in this phase I study. Median age was 51 years (26-62). The MAP regimen consists of mitoxantrone (40 mg m-2 on day -6), cytarabine (2 g m-2 on day -6,-5,-4) and pentostatin. Pentostatin was given from 6 to 13 mg m-2 over 2 or 3 days in a dose-escalating manner. 18 patients received HLA-matched sibling grafts, 7 patients received unrelated grafts. Median donor chimerism at 1 month was 76% for related NST, 98% at 3 months. Four of seven patients with unrelated NST had primary graft failure but all had autologous recovery, the other three had full donor chimerism. Day 100 mortality is 8%. Dose-limiting toxicity was not observed, but two patients enrolled at level 5 died of sepsis and severe GVHD, respectively. Level 4 (pentostatin 13 mg m-2 over 3 days) is safe and chosen as phase II regimen. With a median follow-up of 28 months (12-1122 days), the median duration of overall and disease-free survival are 15 and 12 months, respectively. The estimated disease-free and overall survival rates at 2 years are 37 and 40%, respectively. In conclusion, Level 4 of the MAP regimen is safe and chosen as phase II regimen for further clinical investigation.