Curing using the minimal – Strategies for treatment reduction in childhood acute lymphoblastic leukemia

Childhood acute lymphoblastic leukemia (ALL) in the contemporary era of intensive chemotherapy is highly curable, but is associated with a plethora of toxicities, with persistent disparities in survival outcomes globally especially in low-middle income countries (LMIC). Because of limited supportive care in LMIC, treatment-related morbidity and mortality may be a more critical treatment factor than relapse. Therefore, the next frontier in childhood ALL is to cure low-risk ALL with as minimal therapy as possible. Here, we discuss how to identify the subset of low-risk patients for whom this is possible, along with the components of deintensification strategies across several regimens in recent clinical trials for low-risk ALL. In treating low-risk childhood ALL, the key is accurately identifying this curable subset. NCI standard-risk criteria at diagnosis (age 1–10 years, WBC < 50,000/uL) remains an effective cornerstone of stratification. Other favorable features such as identifying low risk genetics (ETV6::RUNX1, hyperdiploidy), early peripheral blood and bone marrow responses, and simplified flow MRD at the end of induction can be added depending on resources to enhance stratification. A reduced intensity induction particularly through anthracycline-free induction, allows early marrow recovery and reduces the need for intensive supportive care. Other key effective deintensification strategies in low-toxicity protocols include: replacing high-dose with low-dose escalating methotrexate; judicious or even omission of anthracyclines throughout therapy; non-augmentation of consolidation therapy; reducing or even omitting delayed intensification; decreasing thiopurine or methotrexate doses during maintenance; and lowering intensity of steroid pulses during maintenance. Future directions include potential implementation of immunotherapy upfront to low-risk ALL, which may allow for even further reducing toxic chemotherapy or treatment duration. Overall, the first effective step in achieving global ALL cure is to focus on curing low-risk ALL through as minimal therapy as possible.