Prostate cancer radioligand therapy strongly promotes clonal hematopoiesis compared with chemotherapy
In a TheraP trial analysis, 177Lu-PSMA-617 drove far more treatment-emergent clonal hematopoiesis, especially PPM1D mutations, than cabazitaxel.
Summary
Clonal hematopoiesis (CH) is a blood-cell precursor state tied to higher risk of blood cancers, and radiation may worsen it. Researchers analyzed blood samples from TheraP, a randomized trial comparing 177Lu-PSMA-617 radioligand therapy with cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer. Baseline CH was common (77%) and similar between arms. By progression, new treatment-emergent CH appeared in 62% of patients given 177Lu-PSMA-617 versus 40% given cabazitaxel. The DNA damage response gene PPM1D made up 42% of the radioligand-emergent mutations. CH clones also expanded more often (71% vs. 30%), and growth rose with the number of treatment cycles. The authors conclude that 177Lu-PSMA-617 strongly promotes CH and support longitudinal monitoring for long-term blood-related complications as the therapy moves earlier in care.
Detailed Summary
Radioligand therapies are moving into earlier stages of prostate cancer care, so patients may live longer after exposure. That makes long-term safety important. Clonal hematopoiesis (CH), in which blood stem cell clones with somatic mutations expand, is a precursor state linked to hematologic neoplasms and may be worsened by radiation.
This post hoc correlative analysis used serial blood samples from TheraP (ANZUP 1603), a randomized phase II trial in docetaxel-refractory metastatic castration-resistant prostate cancer. Cell-free DNA and leukocyte DNA were sequenced with error-corrected deep targeted sequencing, calling CH mutations at a variant allele frequency of at least 0.25%. Of 178 patients with baseline samples, 107 (60 on 177Lu-PSMA-617, 47 on cabazitaxel) had paired baseline and progression samples.
Baseline CH was found in 77% of patients, with similar prevalence and gene distribution across arms. Treatment-emergent CH was more frequent after 177Lu-PSMA-617 (62% vs. 40%; P = 0.03), and 83% of all emergent mutations arose in that arm. PPM1D accounted for 42% of radioligand-emergent mutations; odds ratios versus cabazitaxel were 3.2 for any emergent CH and 5.4 for PPM1D. CH clones expanded more often with 177Lu-PSMA-617 (70.9% vs. 29.5%), and maximal CH VAF rose by 2.9% per treatment cycle.
The authors argue that longitudinal monitoring for hematologic sequelae should be considered as radioligand therapy is used earlier in the disease course. PPM1D-mutant CH is associated with prior cytotoxic exposure and therapy-related myeloid neoplasms, though this abstract does not report clinical outcomes.
Caveats: this was a post hoc analysis in a modest sample, with a limited paired subset. Follow-up for actual myeloid neoplasms was not described in the abstract, so clinical significance remains unproven. Only the abstract was available for this summary.
Key Findings
- Baseline clonal hematopoiesis was present in 77% (138/178) of mCRPC patients, with similar prevalence and genes across treatment arms.
- Treatment-emergent CH occurred in 62% after 177Lu-PSMA-617 versus 40% after cabazitaxel (P = 0.03).
- PPM1D made up 42% of 177Lu-PSMA-617-emergent mutations; odds ratio versus cabazitaxel was 5.4.
- CH clones expanded in 70.9% of radioligand patients versus 29.5% on chemotherapy (P = 7.5 × 10-5).
- Maximal CH VAF rose 2.9% per 177Lu-PSMA-617 cycle received (P = 0.002).
Methodology
Post hoc correlative analysis of TheraP (ANZUP 1603), a randomized phase II trial in docetaxel-refractory mCRPC. Cell-free and leukocyte DNA underwent error-corrected deep targeted sequencing, with CH called at VAF ≥0.25%. Emergent CH was defined as variants present at progression but undetected at baseline, in 107 patients with paired samples (60 radioligand, 47 cabazitaxel).
Study Limitations
This was a post hoc analysis with a relatively small paired-sample cohort, and the abstract reports no clinical outcomes such as myeloid neoplasms or cytopenias. Sequencing was targeted, and the 0.25% VAF threshold and the short follow-up interval (~27-29 weeks) may limit conclusions about long-term risk. Only the abstract was reviewed.
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