Safety and Efficacy of Fludarabine and PK-Targeted Intravenous Busulfan Before Allografting for Adult ALL

Remission consolidation with allogeneic blood or marrow transplantation improves survival of young patients with acute lymphoid leukemia (ALL), but the potential benefit of transplantation in older patients is offset by regimen toxicity and non-relapse mortality. Busulfan is not thought to be an effective drug for ALL, presumably because of intrinsic resistance of ALL to alkylating agents, or perhaps because of the large variability in busulfan pharmacokinetics and erratic drug exposure. Here we report results of treatment with a PK-targeted intravenous busulfan regimen in 25 adults with ALL. Patient age was 23–55 (median 40) years, 13 were treated in first complete remission, 10 in second remission, and 2 with resistant disease. Treatment was with 4 consecutive daily doses of fludarabine 40 mg/m2, followed by intravenous busulfan, administered on days 1 and 2 at 130–145 mg/m2 daily over 4 hours with PK-sampling and mass spectrometry assay. On days 3 and 4 busulfan dose was adjusted to target an average area under the concentration curve of 5300 ± 530 mMol∗min/L for each of the four days. Donors were siblings (14), or unrelated (11). Grafts were T-replete, filgrastim-mobilized hematopoietic blood cells. GVHD prophylaxis was tacrolimus plus methotrexate or mycophenolate mofetil. Mortality from all non-relapse causes was 4% at 100 days, and 8% at one year. The one-year overall survival (OS) was 66%, and relapse-free survival (RFS) was 62%, with a median follow-up of 1.3 years for live patients. For patients transplanted in CR1, one-year OS was 77% and RFS 70%; in CR2, OS and RFS were 58%; and with resistant disease, OS and RFS were 0%. OS was 56% in patients up to 40 years, and 67% in patients 41–55 years old, with disease status and stage similarly distributed in younger and older cohorts. With this treatment protocol, the one-year non-relapse mortality is identical to what is observed with non-transplant therapies. When compared to irradiation-containing regimens, fludarabine and PK-targeted busulfan appear much safer and similarly effective in controlling ALL, providing a treatment option for all adult patients with ALL. A multicenter study comparing this transplant protocol against post-remission chemotherapy for adult ALL is warranted.