In conclusion, it remains to be established whether: (i) dactinomycin could be used at lower doses with lower toxicity and similar efficacy; (ii) dactinomycin may represent an option for NPM1-mutated AML patients unfit or older than 75 years refractory to or relapsed after venetoclax-based regimens; and (iii) combination of dactinomycin with newer agents (e.g., HMAs, venetoclax, FLT3 inhibitors) may yield better results, particularly in NPM1-mutated patients carrying FLT3-ITD. This evidence concerns the gene FLT3 and acute myeloid leukemia.