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.
Highlights
The NPM1 gene encodes for a multifunctional nucleolar chaperone [1, 2], that continuously shuttles between nucleus and cytoplasm [3, 4]
One patient (UPN004), who was colonized by a multiresistant Klebsiella pneumoniae, died early during induction 1 due to a septic shock caused by the same microorganism and was not considered evaluable for toxicity or response rate
We report the results of the first phase 2 trial evaluating the safety and efficacy of dactinomycin in r/r NPM1mutated acute myeloid leukemia (AML)
Summary
The NPM1 gene encodes for a multifunctional nucleolar chaperone [1, 2], that continuously shuttles between nucleus and cytoplasm [3, 4]. NPM1 mutations are usually heterozygous insertions in the last exon of the gene [5, 6] that cause the loss of the nucleolar localization signal and generation of a novel nuclear export signal [7, 8]. These changes result in aberrant delocalization of the NPM1 mutant in the nucleoplasm and in the cytoplasm that is, in turn, responsible for leukemogenesis through a yet unclear mechanism [9]. Criteria for the diagnosis, risk stratification and monitoring of measurable residual disease
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