ArticleBlood advances2020
Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin.
Article in Blood advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 27 citations in OpenAlex.
- ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis.Blood advances · 2025Trial
- The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study.Blood advances · 2022Trial
- Clonal hematopoiesis and its progression to myeloid neoplasms: insights into risk, biology, and therapeutic strategies.Haematologica · 2026Review
- Unraveling the role ofHemaSphere · 2026Review
- Advances in polycythemia vera treatment with targeted therapies and clinical trials.Discover oncology · 2025Review
- MDM2 inhibition is associated with the emergence of TP53-altered clonal hematopoiesis.NPJ precision oncology · 2025Article
- Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.Cancer medicine · 2024Article
- Translating p53-based therapies for cancer into the clinic.Nature reviews. Cancer · 2024Review
- Pharmacological reactivation of p53 in the era of precision anticancer medicine.Nature reviews. Clinical oncology · 2024Review
- Evolving landscape of JAK inhibition in myelofibrosis: monotherapy and combinations.Hematology. American Society of Hematology. Education Program · 2023Article
- Targeted Therapy for MPNs: Going Beyond JAK Inhibitors.Current hematologic malignancy reports · 2023Review
- Review
- Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial.Blood · 2023Article
- Acute Myeloid Leukemia Following Myeloproliferative Neoplasms: A Review of What We Know, What We Do Not Know, and Emerging Treatment Strategies.Journal of hematology · 2022Review
- Advances in Risk Stratification and Treatment of Polycythemia Vera and Essential Thrombocythemia.Current hematologic malignancy reports · 2022Review
- Single-cell analysis reveals selection of TP53-mutated clones after MDM2 inhibition.Blood advances · 2022Article
- GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers.Communications biology · 2022Article
- Combined Drug Targeting of p53-dependent and -independent Pathways Depletes Myelofibrosis Hematopoietic Stem/Progenitor Cells.Leukemia · 2022Article
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- Review
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Authors and funding
20 authors at 7 institutions in 2 countries.
Funding
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.
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