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

• Published in: PloS one Vol. 13; no. 11; p. e0206980
• Main Authors: Mahmud, Nadim, Khanal, Amit, Taioli, Simona, Koca, Emre, Gaitonde, Sujata, Petro, Benjamin, Sweiss, Karen, Halliday, Lisa, Wang, Xinhe, Patel, Pritesh, Rondelli, Damiano
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.11.2018; Public Library of Science (PLoS)
• Subjects: Ablation (Surgery); Administration, Intravenous; Animal models; Animals; Baboons; Biology and life sciences; Blood; Blood Cell Count; Blood cells; Bone marrow; Bone Marrow - drug effects; Busulfan; Busulfan - administration & dosage; Cancer therapies; CD34 antigen; Chemotherapy; Clinical trials; Colonies; Dosage and administration; Drug dosages; Drug Evaluation, Preclinical; Female; Glycosylated hemoglobin; Health sciences; Hematology; Hematopoiesis; Hematopoiesis - drug effects; Hemoglobin; Hemoglobins; Intravenous administration; Laboratory animals; Leukemia; Leukocyte Count; Medical research; Medicine; Medicine and Health Sciences; Models, Animal; Myeloablative Agonists - administration & dosage; Myelosuppression; Oncology; Papio; Peripheral blood; Pharmacy; Primates; Recovery; Stem cells; Stem Cells - metabolism; Studies; Toxicity; Transplants & implants; United States > US; Illinois; Chicago Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0206980

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.