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.

A Clinical Guide to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Neuroendocrine Tumor Patients

“…Additionally, there is a relevant long-term risk of 2% for the development of myelodysplastic syndrome (MDS) and 1% for acute myeloid leukemia (AML) after PRRT [ 27 , 29 , 91 ]. Little is known about the pathophysiology of persistent hematological toxicity, but a role for clonal hematopoiesis has been postulated [ 92 ]. Known risk factors for severe hematological toxicity include decreased renal function, pre-existent cytopenias, extensive tumor mass, age over 70, extensive bone metastases and pre-treatment with myelotoxic chemotherapy [ 91 , 93 , 94 ].…”

Neuroendocrine Tumors and Peptide Receptor Radionuclide Therapy: When Is the Right Time?

“…74,75 Early work suggests that clonal hematopoiesis may relate to the development of cytopenias and potentially secondary myeloid neoplasms. 73,76 In patients with advanced NET, the median survival is measured in years, with a subset of patients living decades, and, therefore, the risk of secondary bone marrow malignancies can be the biggest concern.…”

Ageing and cancer: a research gap to fill

“…Clonal mutations in the DNA damage response genes TP53, PPM1D and CHEK2 are most specifically associated with these therapy-related myeloid neoplasms. Among treatment modalities, radiation and cytotoxic therapies (mostly topoisomerase II inhibitors and platinum agents) are again strongly associated with clonal hematopoiesis evolution, an event that is not observed when targeted therapies and immunotherapeutic agents are used [126,127]. In the near future, screening for clonal hematopoiesis may form part of risk stratification before cancer treatment, leading to the adaptation of a therapeutic strategy.…”