Targeted Intravenous Busulfan Combined with Fludarabine (tBuFlu) as Conditioning Prior to Allogeneic Peripheral Blood Stem Cell Transplant: Early Results of Low Treatment Related Mortality.
Authors: Field Teresa , Perkins Janelle , Alsina Melissa , Ayala Ernesto , Fancher Karen , Janssen William , Perez Lia , Sullivan Daniel , Tate Cheryl , Anasetti Claudio 
Published: April 2020

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 43 pts with tBuFlu prior to allogeneic peripheral blood stem cell transplantation. The median patient age was 48 (range 22–67) years. Patient diagnoses included AML (8 de novo, 6 with prior MDS, and 2 treatment related), MDS (6 pts), MF (5), NHL (5 pts), ALL (4 pts), CML (3 pts), CLL (2), MM (1) and PNH (1). Three patients had received a prior autologous HCT. Donors were HLA-A, B, C, DRB1, DQB1 matched siblings (24), matched unrelated donors (13), or unrelated donors mismatched for one HLA antigen (3), 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 41 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. Twenty-five (61%) pts had their doses adjusted, increased by 42% (± 28%) in 18 and decreased by 27% (± 14%) in 7, while 12 pts had Css within the desired range without adjustment. Patients received tacrolimus and standard doses of methotrexate for GVHD prophylaxis, with the exception of three patients treated with tacrolimus and mycophenolate mofetil or cyclosporine and prednisone. Engraftment occurred in 41 (95%) pts. Median day to ANC &gt; 500/uL was 16 days, range (range 12–28); median day to platelet count &gt; 20,000/uL untransfused was 18 days (range 8–45). Thirteen (52%) of 25 pts followed for at least 100 days experienced acute GVHD requiring treatment. Two pts have died of transplant-related complications (aplasia and suspected fungal pneumonitis), and 4 pts have failed to achieve remission or have relapsed. Median follow-up is 115 days (range 17–361 days). The 100-day K-M estimate of survival for the whole cohort is 94%, and event-free survival 86%. 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. We plan to escalate the busulfan dose based on targeted Css to explore a potential dose-response relationship and improve control of malignancy.