Preclinical IV busulfan dose-finding study to induce reversible myeloablation in a non-human primate model

PLoS One. 2018 Nov 29;13(11):e0206980. doi: 10.1371/journal.pone.0206980. eCollection 2018.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Animals
  • Blood Cell Count
  • Bone Marrow / drug effects
  • Busulfan / administration & dosage*
  • Drug Evaluation, Preclinical
  • Female
  • Hematopoiesis / drug effects*
  • Leukocyte Count
  • Models, Animal
  • Myeloablative Agonists / administration & dosage*
  • Papio
  • Primates
  • Stem Cells / metabolism

Substances

  • Myeloablative Agonists
  • Busulfan

Grants and funding

This study was supported by a research grant to DR and NM from Otsuka Pharmaceutical Co. Ltd, and by the Michael Reese Foundation grant to DR. As mentioned in the Materials and Methods section of the manuscript, IV busulfan was provided by Otsuka Pharmaceutical Development and Commercialization, Inc. (Princeton, NJ) for the study. We hereby declare that the funders had no role in the study design, collection, analysis and interpretation of data; writing of the paper, and or decision to submit for publication.