Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML.

Aged Antibiotics, Antineoplastic / therapeutic use Cell Nucleolus / drug effects Dactinomycin / therapeutic use Drug Resistance, Neoplasm Female Follow-Up Studies Humans Leukemia, Myeloid, Acute / drug therapy Male Middle Aged Mutation Neoplasm Recurrence, Local / drug therapy Nuclear Proteins / genetics Nucleophosmin Pilot Projects Prognosis Remission Induction Salvage Therapy

Journal

Leukemia

ISSN: 1476-5551

Titre abrégé: Leukemia

Pays: England

ID NLM: 8704895

Informations de publication

Date de publication:
09 2021

Historique:

received: 30 09 2020

accepted: 08 02 2021

revised: 19 01 2021

pubmed: 4 3 2021

medline: 6 10 2021

entrez: 3 3 2021

Statut: ppublish

Résumé

Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies.

Identifiants

DOI: 10.1038/s41375-021-01192-7 PMID: 33654209 PMC: PMC8410589

pubmed: 33654209

doi: 10.1038/s41375-021-01192-7

pii: 10.1038/s41375-021-01192-7

pmc: PMC8410589

doi:

Substances chimiques

Antibiotics, Antineoplastic 0

NPM1 protein, human 0

Nuclear Proteins 0

Nucleophosmin 117896-08-9

Dactinomycin 1CC1JFE158

Types de publication

Clinical Trial, Phase II Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

2552-2562

Informations de copyright

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