Prostate cancer radioligand therapy strongly promotes clonal hematopoiesis compared with chemotherapy

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.