Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML
Ilaria Gionfriddo, Lorenzo Brunetti, Federica Mezzasoma, Francesca Milano, Valeria Cardinali, Roberta Ranieri, Alessandra Venanzi, Sara Pierangeli, Calogero Vetro, Giulio Spinozzi, Erica Dorillo, Hsin-Chieh Wu, Caroline Berthier, Raffaella Ciurnelli, Melanie Griffin, Claire Jennings, Enrico Tiacci, Paolo Sportoletti, Franca Falzetti, Hugues de Thé, Gareth J. Veal, Maria Paola Martelli, Brunangelo Falini
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.