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

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.
Competing Interests: Elizabeth A. GriffithsHonoraria: NovartisConsulting or Advisory Role: Alexion Pharmaceuticals, Takeda, Taiho Oncology, Novartis, Genentech, Celgene/Bristol Myers Squibb, AbbVie, Otsuka US, CTI BioPharma Corp, PicnicHealthResearch Funding: Genentech (Inst), Celgene (Inst), Apellis Pharmaceuticals (Inst), Astex Pharmaceuticals (Inst), Celldex (Inst), Bristol Myers Squibb/CelgeneOpen Payments Link: https://openpaymentsdata.cms.gov/physician/134906 Mark G. FaberStock and Other Ownership Interests: AstraZeneca/MedImmune/Spirogen Eti SinhaEmployment: Foundation MedicineStock and Other Ownership Interests: Roche/Genentech Duane C. HassaneEmployment: TempusStock and Other Ownership Interests: TempusResearch Funding: Daiichi SankyoPatents, Royalties, Other Intellectual Property: ddPCR assessment of minimal residual disease via NPM1 mutations, risk prediction for acute myeloid leukemia David Neil HayesLeadership: GeneCentricStock and Other Ownership Interests: GeneCentricConsulting or Advisory Role: GeneCentric, Merck, Turnstone BioPatents, Royalties, Other Intellectual Property: I hold several diagnostic patents or pending patents in the area of solid tumor diagnostics Monica L. GuzmanConsulting or Advisory Role: SeqRx, Bridge MedicinesResearch Funding: Cellectis (Inst), Bridge Medicines (Inst), Daiichi Sankyo/UCB Japan (Inst) Renuka IyerConsulting or Advisory Role: Lexicon, Novartis, Eisai, Merck, Bayer, Advanced Accelerator Applications, Exelixis, Sun pharma, QED therapeutics, Ipsen, Sandoz, TerSera, AstraZenecaResearch Funding: Genentech/Roche (Inst), Ipsen (Inst), Lilly (Inst), Merck (Inst), Taiho Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Cleveland BioLabs (Inst), Novartis (Inst) Eunice S. WangConsulting or Advisory Role: AbbVie, Pfizer, Jazz Pharmaceuticals, Astellas Pharma, Stemline Therapeutics, Kite/Gilead, MacroGenics, PTC Therapeutics, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Novartis, Genentech, TakedaSpeakers' Bureau: Stemline Therapeutics, Pfizer, Dava Oncology Swapna ThotaHonoraria: Blueprint Medicines, Incyte, Adelson Medical Research FoundationSpeakers' Bureau: IncyteNo other potential conflicts of interest were reported.