Mutant PPM1D- and TP53-Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy

Abstract

Purpose: Hematologic toxic effects of peptide receptor radionuclide therapy (PRRT) can be permanent. Patients with underlying clonal hematopoiesis (CH) may be more inclined to develop hematologic toxicity after PRRT. However, this association remains understudied.

Materials and methods: We evaluated pre- and post-PRRT blood samples of patients with neuroendocrine tumors. After initial screening, 13 cases of interest were selected. Serial blood samples were obtained on 4 of 13 patients. Genomic DNA was analyzed using a 100-gene panel. A variant allele frequency cutoff of 1% was used to call CH.

Result: Sixty-two percent of patients had CH at baseline. Persistent cytopenias were noted in 64% (7 of 11) of the patients. Serial sample analysis demonstrated that PRRT exposure resulted in clonal expansion of mutant DNA damage response genes (TP53, CHEK2, and PPM1D) and accompanying cytopenias in 75% (3 of 4) of the patients. One patient who had a normal baseline hemogram and developed persistent cytopenias after PRRT exposure showed expansion of mutant PPM1D (variant allele frequency increased to 20% after exposure from < 1% at baseline). In the other two patients, expansion of mutant TP53, CHEK2, and PPM1D clones was also noted along with cytopenia development.

Conclusion: The shifts in hematopoietic clonal dynamics in our study were accompanied by emergence and persistence of cytopenias. These cytopenias likely represent premalignant state, as PPM1D-, CHEK2-, and TP53-mutant clones by themselves carry a high risk for transformation to therapy-related myeloid neoplasms. Future studies should consider CH screening and longitudinal monitoring as a key risk mitigation strategy for patients with neuroendocrine tumors receiving PRRT.

FIG 1.

Oncoprint for patients with neuroendocrine tumors along with clinical and laboratory parameters. VAF, variant allele frequency.

FIG 2.

The clonal trajectories of mutation events. Serial analysis of patients exposed to PRRT. DNA specimens from four patient cases (patients 10, 2, 4, and 5) exposed to PRRT and serial samples after PRRT exposure were analyzed at serial time points. (A) Line graphs indicate change in VAF per year and change in blood parameters as a result of change in VAF, eg, in patient 5, with increasing PPM1D clone (in purple), there was a notable change in HgB, WBC, and platelet count (all decreased; the y-axis in (A) depicts changes in blood parameters over time). Different colors indicate different gene mutations. (B) Different colors indicate different patients and depict change in VAFs over time. Seen in example of patient 5 (purple), dramatic changes in VAF were noted over time. In the Data Supplement, additional associated changes in blood parameters are depicted, which highlight the considerable drop in all three blood parameters, particularly patient 5. HgB, hemoglobin; PRRT, peptide receptor radionuclide therapy; VAF, variant allele frequency. PRRT exposure leads to mutant TP53, CHEK2, and PPM1D expansion in blood, contributing to prolonged cytopenias.

FIG 3.

Dynamic model of clonal evolution and PRRT-induced carcinogenesis. The image was generated using BioRender. PRRT, peptide receptor radionuclide therapy.