AI Article Synopsis

  • Acute myeloid leukemia (AML) with NPM1 mutations is prevalent but challenging to treat, especially in elderly and unfit patients who can't tolerate intensive therapies.
  • Dactinomycin, a low-cost chemotherapy, shows promise in inducing complete responses in relapsed/refractory NPM1-mutated AML based on a pilot study, highlighting its safety and efficacy.
  • The drug's effectiveness may be linked to its ability to create nucleolar stress, which appears to particularly affect cells with NPM1 mutations, indicating a need for further large-scale research.

Article Abstract

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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410589PMC
http://dx.doi.org/10.1038/s41375-021-01192-7DOI Listing

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Article Synopsis
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  • Dactinomycin, a low-cost chemotherapy, shows promise in inducing complete responses in relapsed/refractory NPM1-mutated AML based on a pilot study, highlighting its safety and efficacy.
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September 2020

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