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

Acute myeloid leukemia (AML) with mutatedNPM1accounts for one-third of newly diagnosed AML. Despite recentadvances, treatment of relapsed/refractoryNPM1-mutated AML remains challenging, with the majority of patientseventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainlybecause they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is alow-cost chemotherapeutic agent, which has been anecdotally reported to induce remission inNPM1-mutated patients,although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot studyinvestigating the safety and efficacy of single-agent dactinomycin in relapsed/refractoryNPM1-mutated adult AML patients,demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence thatthe 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 thatNPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish thatdactinomycin is a potential therapeutic alternative in relapsed/refractoryNPM1-mutated AML that deserves furtherinvestigation in larger clinical studies.