Myeloablative doses of intravenous busulfan in combination with fludarabine have been employed as conditioning before hematopoietic cell allografts with reduced treatment-related toxicity and mortality. In this report, we describe the early results of a targeted busulfan pharmacokinetic dosing strategy (tBuFlu) used in combination with fludarabine before either related or unrelated grafts We treated 61 pts with tBuFlu prior to allogeneic peripheral blood stem cell transplantation. The median patient age was 48 (range 22-68) years. Patient diagnoses included AML (13 de novo, 7 with prior MDS, and 7 treatment related), MDS (7 pts), MF (5), NHL (6 pts), ALL (6 pts), CML (5 pts), CLL (2), MM (2) and PNH (1). Five patients had received a prior autologous HCT. Donors were HLA-A, B, C, DRB1, DQB1 matched siblings (29), matched unrelated donors (22), or unrelated donors mismatched for one HLA antigen (6), homozygous mismatch (1), one HLA allele (2), or two HLA alleles (1). Fludarabine 40 mg/m2 was given intravenously daily for four days, with each infusion followed immediately by intravenous busulfan. The dose of busulfan for days 1 and 2 was 130 mg/m2. Pharmacokinetic analysis was performed after the first infusion of busulfan; in 59 pts, the goal was to adjust busulfan doses for days 3 and 4 to achieve an average targeted Css level of 800-1000 ng/ml. Levels were drawn incorrectly in 4 of these pts and doses were not changed. Thirty-five (59%) pts had their doses adjusted, increased in 27 and decreased in 8, while 20 pts had Css within the desired range without adjustment. Patients received tacrolimus and standard doses of methotrexate for GVHD prophylaxis, with the exception of five patients. Engraftment occurred in 58 (95%) pts. Thirty (64%) of 47 pts followed for at least 100 days experienced acute GVHD requiring treatment. Six pts have died of transplant-related complications and 7 pts have failed to achieve remission or have relapsed. Median follow-up is 174 days (range 26-448 days). The 100-day K-M estimate of survival for the whole cohort is 92%, and event-free survival 88%. The 100-day mortality in this study compares well with the 100-day mortality reported to the IBMTR for patients with AML, ALL, MDS, and CML transplanted from either HLA-matched siblings or unrelated donors. These preliminary results indicate that tBuFlu is a promising myeloablative regimen that can be utilized in older patients with low early treatment-related mortality. Myeloablative doses of intravenous busulfan in combination with fludarabine have been employed as conditioning before hematopoietic cell allografts with reduced treatment-related toxicity and mortality. In this report, we describe the early results of a targeted busulfan pharmacokinetic dosing strategy (tBuFlu) used in combination with fludarabine before either related or unrelated grafts We treated 61 pts with tBuFlu prior to allogeneic peripheral blood stem cell transplantation. The median patient age was 48 (range 22-68) years. Patient diagnoses included AML (13 de novo, 7 with prior MDS, and 7 treatment related), MDS (7 pts), MF (5), NHL (6 pts), ALL (6 pts), CML (5 pts), CLL (2), MM (2) and PNH (1). Five patients had received a prior autologous HCT. Donors were HLA-A, B, C, DRB1, DQB1 matched siblings (29), matched unrelated donors (22), or unrelated donors mismatched for one HLA antigen (6), homozygous mismatch (1), one HLA allele (2), or two HLA alleles (1). Fludarabine 40 mg/m2 was given intravenously daily for four days, with each infusion followed immediately by intravenous busulfan. The dose of busulfan for days 1 and 2 was 130 mg/m2. Pharmacokinetic analysis was performed after the first infusion of busulfan; in 59 pts, the goal was to adjust busulfan doses for days 3 and 4 to achieve an average targeted Css level of 800-1000 ng/ml. Levels were drawn incorrectly in 4 of these pts and doses were not changed. Thirty-five (59%) pts had their doses adjusted, increased in 27 and decreased in 8, while 20 pts had Css within the desired range without adjustment. Patients received tacrolimus and standard doses of methotrexate for GVHD prophylaxis, with the exception of five patients. Engraftment occurred in 58 (95%) pts. Thirty (64%) of 47 pts followed for at least 100 days experienced acute GVHD requiring treatment. Six pts have died of transplant-related complications and 7 pts have failed to achieve remission or have relapsed. Median follow-up is 174 days (range 26-448 days). The 100-day K-M estimate of survival for the whole cohort is 92%, and event-free survival 88%. The 100-day mortality in this study compares well with the 100-day mortality reported to the IBMTR for patients with AML, ALL, MDS, and CML transplanted from either HLA-matched siblings or unrelated donors. These preliminary results indicate that tBuFlu is a promising myeloablative regimen that can be utilized in older patients with low early treatment-related mortality.