Refractory/Relapsed AML in Children and Evolution of Novel Therapies

Intensive chemotherapy induces complete remission in the vast majority of children with acute myeloid leukemia (AML). Nevertheless, primary refractory disease (RefD) and relapse remain the most frequent causes of treatment failure and constitute significant obstacles to permanent cure. Evolution and expansion of highly malignant subclones and persistence of leukemic stem cells inherently resistant to conventional therapies are considered key mechanisms of RefD and relapse. Optimization of supportive care and stem cell procedures as well as treatment guidelines established through an international study protocol have collectively improved long-term survival after primary RefD and relapse during the last decades to approximately 40%. However, RefD and relapse refractory to induction attempts, relapse within 1 year of diagnosis, or high-risk genetic aberrations portend a dismal prognosis and emphasize the urgent need for innovative new therapies targeting leukemia-specific pathways with limited off-tumor effects. International collaborations such as the Pediatric Acute Leukemia/European Pediatric Acute Leukemia (PedAL/EUPAL) and ACCELERATE initiatives aim to identify and prioritize the most promising targeted therapies suitable for testing in pediatric AML populations. Incorporation of new therapies to replace or supplement conventional therapy elements may improve outcome after RefD and relapse and diminish long-term side effects in children with AML.