Recent research from the TheraP trial indicates that 177Lu-PSMA-617 radioligand therapy significantly promotes clonal hematopoiesis (CH) in patients with metastatic castration-resistant prostate cancer (mCRPC). While this therapy offers improved survival outcomes, it also appears to drive the emergence and expansion of potentially harmful blood cell mutations. Therefore, clinicians must now consider the long-term hematological impact as this treatment moves into earlier stages of prostate cancer care.

Impact of 177Lu-PSMA-617 Radioligand Therapy on Hematopoiesis

The study compared 177Lu-PSMA-617 with cabazitaxel chemotherapy to assess their effects on blood cell DNA. Results showed that treatment-emergent CH occurred in 62% of patients receiving the radioligand therapy. In contrast, only 40% of those on cabazitaxel developed new mutations. Furthermore, the radioligand therapy accounted for 83% of all emergent mutations researchers detected during the trial. These findings suggest a strong link between internal radiation exposure and DNA damage in hematopoietic stem cells.

A primary concern for oncologists is the specific expansion of the PPM1D gene. This DNA damage response gene accounted for 42% of mutations emerging after the radioligand therapy. Patients receiving 177Lu-PSMA-617 had a 5.4-fold higher risk of developing PPM1D mutations than those on standard chemotherapy. Additionally, existing CH clones expanded more frequently and with greater magnitude following several radioligand cycles.

Clinical Monitoring and Long-term Risks

The expansion of these clones correlates directly with the number of therapy cycles patients received. Specifically, the variant allele frequency (VAF) increased by approximately 2.9% per treatment cycle. Consequently, longitudinal monitoring for long-term hematological sequelae is now essential. As 177Lu-PSMA-617 becomes a standard for mCRPC, physicians must track patients for potential hematological malignancies related to this clonal expansion.

Frequently Asked Questions

What is Clonal Hematopoiesis (CH)?

CH is a precursor state where a single hematopoietic stem cell develops a somatic mutation. This mutation gives the cell a competitive advantage, allowing it to expand into a large clone. It is associated with an increased risk of blood cancers and cardiovascular disease.

Why does 177Lu-PSMA-617 increase CH mutations?

The therapy delivers targeted radiation directly to cancer cells, but it also exposes the bone marrow to radiation. This stress can cause DNA damage and selectively promotes the expansion of clones with specific mutations, like PPM1D, which help cells survive radiation-induced injury.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or a professional relationship. Always seek the advice of a qualified healthcare provider regarding any medical condition. Refer to the latest local and national guidelines for clinical practice.

References

Munzur AD et al. Clonal hematopoiesis after 177Lu-PSMA-617 radioligand therapy in prostate cancer. Clin Cancer Res. 2026 Feb 06. doi: 10.1158/1078-0432.CCR-25-4001. PMID: 41649873.

Hofman MS et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021 Feb 27;397(10276):797-804.

Munzur AD et al. Clonal hematopoiesis (CH) in participants with mCRPC receiving 177Lu-PSMA-617 or cabazitaxel: An exploratory post-hoc analysis of TheraP. J Clin Oncol. 2025;43(15_suppl):5020.