223 Ra Induces Transient Functional Bone Marrow Toxicity

The Journal of Nuclear Medicine

article

Eleonora Dondossola¹  Maria Parlani¹  Francesco Boccalatte²  Anna Yeaton²  Feng Wang³  Jianhua Zhang³  Iannis Aifantis² 

[1] Genitourinary Medical Oncology Department and David H. Koch Center for Applied Research of Genitourinary Cancers, University of Texas M.D. Anderson Cancer Center;Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine;Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center

关键词: 223Ra;    myelotoxicity;    bone marrow;   

DOI  :  10.2967/jnumed.121.263310

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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.

【 授权许可】

CC BY