3–4% of paediatric acute lymphoblastic leukaemias are Philadelphia chromosome-positive (Ph+ ALL) and thus express oncogenic BCR–ABL1 kinase that is sensitive to imatinib. Accordingly, imatinib has greatly improved the outcomes of children with Ph+ ALL, but resistance and relapse is common. Now, a phase III trial has revealed that superior outcomes can be achieved with the second-generation BCR–ABL1 inhibitor dasatinib.

In this trial, children with Ph+ ALL were randomly assigned to receive dasatinib (n = 92) or imatinib (n = 97) during frontline induction, consolidation and continuation chemotherapy. Randomization was stopped after a planned interim analysis showed a significant improvement in event-free survival (EFS), the primary end point. At 4 years, EFS was 71.0% with dasatinib and 48.9% with imatinib (HR 2.36, 95% CI 1.27–4.40; P = 0.007). Moreover, 4-year overall survival was 88.4% and 69.2%, respectively (HR 2.26, 95% CI 1.02–4.99; P = 0.04). Notably, the 4-year risk of isolated central nervous system (CNS) relapse was lower with dasatinib (2.7% versus 8.4%; P = 0.06).

In previous studies of imatinib, EFS was ~60% at 5 years, but almost all patients received prophylactic cranial irradiation (PCI) and most underwent allogeneic stem cell transplantation, both of which can have serious and long-term adverse effects. In the current trial, no patient received PCI and only four underwent transplantation.

Both treatments were well tolerated and had a similar profile of toxicities, most commonly infections, pancreatitis and seizures. Five fatal infections occurred in each group, but were not directly attributed to dasatinib or imatinib treatment.

Together, these findings suggest that the ability of dasatinib to penetrate the CNS and to inhibit mutant forms of BCR–ABL1 that are resistant to imatinib enables improved outcomes, without excess toxicity and whilst avoiding interventions with potentially deleterious effects, which is important in paediatric patients.