Hematologic Consequences of Radiopharmaceutical Therapy: From Clonal Hematopoiesis to Therapy-Related Myeloid Neoplasms

Radiopharmaceutical therapy (RPT) uses radionuclides linked to targeting ligands to bind tumor-associated receptors or antigens and deliver ionizing radiation to malignant cells. Approved agents include [¹⁷⁷Lu]Lu-DOTATATE for gastroenteropancreatic neuroendocrine tumors, [¹⁷⁷Lu]Lu-PSMA-617 for metastatic castration-resistant prostate cancer, and ²²³Ra-dichloride for bone-predominant metastatic castration-resistant prostate cancer. Accumulating evidence suggests that RPT may impose genotoxic stress on the hematopoietic system, resulting in prolonged cytopenias and, in some patients, therapy-related myeloid neoplasms (tMNs). This review synthesizes evidence regarding hematologic toxicities associated with [¹⁷⁷Lu]Lu-based RPT, emphasizing mechanisms of marrow injury, limitations of dose-only frameworks, host susceptibility factors, and emerging strategies for risk stratification, monitoring, and mitigation. We propose an integrated radiogenomic framework in which hematologic toxicity and tMN risk after RPT may arise from interactions among prior genotoxic exposure, heterogeneous red marrow radiation delivery, host genomic susceptibility—including clonal hematopoiesis and germline predisposition—and baseline marrow reserve. As RPT moves into earlier lines of therapy and populations with a longer expected survival, anticipating hematologic consequences will be essential for safe and precise clinical implementation.