RT Journal Article
SR Electronic
T1 Radium 223 induces transient functional bone marrow toxicity
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP jnumed.121.263310
DO 10.2967/jnumed.121.263310
A1 Maria Parlani
A1 Francesco Boccalatte
A1 Anna Yeaton
A1 Feng Wang
A1 Jianhua Zhang
A1 Iannis Aifantis
A1 Eleonora Dondossola
YR 2022
UL http://jnm.snmjournals.org/content/early/2022/02/17/jnumed.121.263310.abstract
AB Radium 223 (Ra223) is a bone-seeking, alpha-particle-emitting radionuclide approved for the treatment of patients with metastatic prostate cancer and is currently being tested in a variety of clinical trials for primary and metastatic cancers to bone. Clinical evaluation of Ra223 hematologic safety showed a significantly increased rate of neutropenia and thrombocytopenia in patients, hinting at myelosuppression as a side effect. In this study we investigate the consequences of Ra223 treatment on bone marrow biology. Ra223 accumulated in bones and induced zonal radiation damage confined at the bone interface, followed by replacement of the impaired areas with adipocyte infiltration, as monitored by three-dimensional multiphoton microscopy, ex vivo. Flow cytometry and single cell transcriptomic analyses on bone marrow hematopoietic populations revealed transient, non-specific Ra223-mediated cytotoxicity on resident populations, including stem, progenitor and mature leukocytes. This was paralleled by a significant decrease of white blood cells and platelets in peripheral blood, which was overcome within 40 days post-treatment. Ra223 exposure did not impair full hematopoietic reconstitution, suggesting that the bone marrow function is not permanently hampered. Our results provide a comprehensive explanation of Ra223 reversible effects on bone marrow cells and exclude long-term myelotoxicity, supporting its safety for patients.