Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin

Bridget K. Marcellino, Noushin Farnoud, Bruno Cassinat, Min Lu, Emanuelle Verger, Erin McGovern, Minal Patel, Juan Medina-Martinez, Max Fine Levine, Juanes E. Arango Ossa, Yangyu Zhou, Heidi Kosiorek, Meenakshi Mehrotra, Jane Houldsworth, Amylou Dueck, Michael Rossi, John Mascarenhas, Jean Jacques Kiladjian, Raajit K. Rampal, Ronald Hoffman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Activation of the P53 pathway through inhibition of MDM2 using nutlins has shown clinical promise in the treatment of solid tumors and hematologic malignancies. There is concern, however, that nutlin therapy might stimulate the emergence or expansion of TP53-mutated subclones. We recently published the results of a phase 1 trial of idasanutlin in patients with polycythemia vera (PV) that revealed tolerability and clinical activity. Here, we present data indicating that idasanutlin therapy is associated with expansion of TP53 mutant subclones. End-of-study sequencing of patients found that 5 patients in this trial harbored 12 TP53 mutations; however, only 1 patient had been previously identified as having a TP53 mutation at baseline. To identify the origin of these mutations, further analysis of raw sequencing data of baseline samples was performed and revealed that a subset of these mutations was present at baseline and expanded during treatment with idasanutlin. Follow-up samples were obtained from 4 of 5 patients in this cohort, and we observed that after cessation of idasanutlin, the variant allele frequency (VAF) of 8 of 9 TP53 mutations decreased. Furthermore, disease progression to myelofibrosis or myeloproliferative neoplasm blast phase was not observed in any of these patients after 19- to 32-month observation. These data suggest that idasanutlin treatment may promote transient TP53 mutant clonal expansion. A larger study geared toward high-resolution detection of low VAF mutations is required to explore whether patients acquire de novo TP53 mutations after idasanutlin therapy.

Original languageEnglish (US)
Pages (from-to)5735-5744
Number of pages10
JournalBlood Advances
Volume4
Issue number22
DOIs
StatePublished - Nov 24 2020

ASJC Scopus subject areas

  • Hematology

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