Abstract
In this study we utilized a large animal model to identify a dose of intravenous busulfan that can cause reversible myelosuppression. Nine baboons (Papio anubis) were treated with IV busulfan at 6.4 (Group A), 8 (Group B), or 9.6 mg/kg (Group C). Peripheral blood counts were measured up to 90 days after treatment and serial bone marrow samples were obtained to analyze CD34+ cell content and colony forming units. Overall, the highest grade of peripheral blood cytopenia was observed 15 days after treatment in all three groups (n = 3/group). In particular, we observed a notable reduction of neutrophil and platelet counts in the blood and the number of marrow CD34+ cells and colony forming units. In contrast, the effect of busulfan on hemoglobin levels was mild. Baboons who received the highest dose of busulfan showed only a 25–35% recovery of marrow CD34+ cells and colony forming units after 90 days of busulfan administration. However, all three groups of animals showed a full recovery of peripheral blood counts and normal marrow cellularity and tri-lineage hematopoiesis after treatment. Notably, all three doses of busulfan were tolerated well without significant extra-medullary toxicity. These results validate the hierarchy of blood cells likely targeted by busulfan, and based on these findings, clinical trials using myelotoxic but not myeloablative doses of intravenous busulfan will be designed for patients with myeloid malignancies.
Highlights
Busulfan is an alkylating agent with myelosuppressive effects which exhibits a prominent effect on subsets of hematopoietic progenitor cells defined by lineage commitment and differentiation stage as well as non-cycling cells [1]
Increasing doses of IV busulfan at 6.4, 8.0, and 9.6 mg/ kg were administered to three groups of animals (Fig 1) to assess the level of peripheral blood cytopenia caused by these treatments and the time to full hematologic recovery
Effects of busulfan administration on lymphocytes was analyzed by monitoring bone marrow (BM) CD3 + T-lymphocyte counts by flow cytometry prior to and following therapy
Summary
Busulfan is an alkylating agent with myelosuppressive effects which exhibits a prominent effect on subsets of hematopoietic progenitor cells defined by lineage commitment and differentiation stage as well as non-cycling cells [1]. Busulfan was first used at low doses in the treatment. IV busulfan in baboon collection, analysis and interpretation of data; writing of the paper, and or decision to submit for publication
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