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.
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.
Authors: Catherine C Coombs; Ahmet Zehir; Sean M Devlin; Ashwin Kishtagari; Aijazuddin Syed; Philip Jonsson; David M Hyman; David B Solit; Mark E Robson; José Baselga; Maria E Arcila; Marc Ladanyi; Martin S Tallman; Ross L Levine; Michael F Berger Journal: Cell Stem Cell Date: 2017-08-10 Impact factor: 24.633
Authors: Lisa Bodei; Mark Kidd; Giovanni Paganelli; Chiara M Grana; Ignat Drozdov; Marta Cremonesi; Christopher Lepensky; Dik J Kwekkeboom; Richard P Baum; Eric P Krenning; Irvin M Modlin Journal: Eur J Nucl Med Mol Imaging Date: 2014-10-02 Impact factor: 9.236
Authors: R Coleman Lindsley; Wael Saber; Brenton G Mar; Robert Redd; Tao Wang; Michael D Haagenson; Peter V Grauman; Zhen-Huan Hu; Stephen R Spellman; Stephanie J Lee; Michael R Verneris; Katharine Hsu; Katharina Fleischhauer; Corey Cutler; Joseph H Antin; Donna Neuberg; Benjamin L Ebert Journal: N Engl J Med Date: 2017-02-09 Impact factor: 91.245
Authors: Terrence N Wong; Giridharan Ramsingh; Andrew L Young; Christopher A Miller; Waseem Touma; John S Welch; Tamara L Lamprecht; Dong Shen; Jasreet Hundal; Robert S Fulton; Sharon Heath; Jack D Baty; Jeffery M Klco; Li Ding; Elaine R Mardis; Peter Westervelt; John F DiPersio; Matthew J Walter; Timothy A Graubert; Timothy J Ley; Todd Druley; Daniel C Link; Richard K Wilson Journal: Nature Date: 2014-12-08 Impact factor: 49.962