Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL)

The t(9;22) translocation fuses BCR to ABL1 and makes a constitutively active tyrosine kinase; in ALL the fusion is usually the p190 form. Before kinase inhibitors, Ph-positive childhood ALL had the worst outcome of any subtype, with event-free survival around a quarter to a third on chemotherapy alone, and allogeneic transplant from a matched sibling in first remission was standard. Imatinib, approved for chronic myeloid leukaemia in 2001, was taken into childhood ALL by the Children's Oncology Group in AALL0031: given continuously with intensive chemotherapy, it produced a three-year event-free survival of 80 percent in the highest-exposure cohort against about 35 percent in historical controls, and no advantage for transplant over chemotherapy plus imatinib. The European EsPhALL trials confirmed that continuous imatinib beat intermittent dosing, and imatinib was approved for children with newly diagnosed Ph-positive ALL in 2013.

Dasatinib is more potent and crosses into the cerebrospinal fluid. AALL0622 combined it with the AALL0031 backbone and dropped cranial irradiation without excess central nervous system relapse; CA180-372, the registration trial, gave three-year event-free survival of 65.5 percent and overall survival of 91.5 percent with dasatinib and EsPhALL chemotherapy, and dasatinib was approved for children with Ph-positive ALL in December 2018. The Chinese Children's Cancer Group randomised 189 children directly between imatinib and dasatinib on the CCCG-ALL-2015 backbone: four-year event-free survival 71.0 percent with dasatinib against 48.9 percent with imatinib, overall survival 88.4 percent against 69.2 percent, and fewer central nervous system relapses. Transplant is now reserved for children with a poor residual disease response or persistent disease after consolidation.

The adult field has moved to ponatinib, a third-generation inhibitor that covers the T315I gatekeeper mutation, to chemotherapy-free induction with a kinase inhibitor plus blinatumomab (D-ALBA, PhALLCON), and to transplant-free treatment guided by molecular residual disease. Whether the same applies in children is the question for EsPhALL2017/COG AALL1631, which stratifies by residual disease and tests reduced-intensity chemotherapy with imatinib for good responders, and for trials adding blinatumomab. Resistance through ABL1 kinase domain mutations, kinase inhibitor effects on growing bones and the heart, and how long to continue the inhibitor after chemotherapy ends are unsettled.