PT  - JOURNAL ARTICLE
AU  - Parlani, Maria
AU  - Boccalatte, Francesco
AU  - Yeaton, Anna
AU  - Wang, Feng
AU  - Zhang, Jianhua
AU  - Aifantis, Iannis
AU  - Dondossola, Eleonora
TI  - <sup>223</sup>Ra Induces Transient Functional Bone Marrow Toxicity
AID  - 10.2967/jnumed.121.263310
DP  - 2022 Oct 01
TA  - Journal of Nuclear Medicine
PG  - 1544--1550
VI  - 63
IP  - 10
4099  - http://jnm.snmjournals.org/content/63/10/1544.short
4100  - http://jnm.snmjournals.org/content/63/10/1544.full
SO  - J Nucl Med2022 Oct 01; 63
AB  - 223Ra is a bone-seeking, α-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 223Ra hematologic safety showed a significantly increased rate of neutropenia and thrombocytopenia in patients, hinting at myelosuppression as a side effect. Methods: In this study, we investigated the consequences of 223Ra treatment on bone marrow biology by combining flow cytometry, single-cell RNA sequencing, three-dimensional multiphoton microscopy and bone marrow transplantation analyses. Results: 223Ra accumulated in bones and induced zonal radiation damage confined to the bone interface, followed by replacement of the impaired areas with adipocyte infiltration, as monitored by 3-dimensional multiphoton microscopy ex vivo. Flow cytometry and single-cell transcriptomic analyses on bone marrow hematopoietic populations revealed transient, nonspecific 223Ra-mediated cytotoxicity on resident populations, including stem, progenitor, and mature leukocytes. This toxicity was paralleled by a significant decrease in white blood cells and platelets in peripheral blood—an effect that was overcome within 40 d after treatment. 223Ra exposure did not impair full hematopoietic reconstitution, suggesting that bone marrow function is not permanently hampered. Conclusion: Our results provide a comprehensive explanation of 223Ra reversible effects on bone marrow cells and exclude long-term myelotoxicity, supporting safety for patients.