High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL)

High risk is set at diagnosis by age ten or over or a white count of 50 x 10^9/L or more, by T-cell immunophenotype, by central nervous system or testicular disease, and by adverse genetics: hypodiploidy, KMT2A rearrangement, iAMP21, TCF3::HLF and BCR::ABL1-like signatures. It is revised after induction by measurable residual disease, so a standard-risk child with residual disease above 0.01 percent joins this group and a high-risk child who clears it may be spared the most intensive blocks. T-ALL makes up around 15 percent of childhood ALL, presents with high counts and mediastinal masses in adolescent boys, and the early T-cell precursor subtype is treated by residual disease response rather than by immunophenotype.

The augmented Berlin-Frankfurt-Münster regimen, tested by the Children's Cancer Group in the 1990s for slow early responders, is the backbone: four-drug induction adding an anthracycline, consolidation with cyclophosphamide, cytarabine, mercaptopurine and asparaginase, and two interim maintenance and delayed intensification blocks. AALL0232 found high-dose methotrexate with leucovorin rescue superior to escalating Capizzi methotrexate for high-risk B-ALL, and dexamethasone superior to prednisone in children under ten. AALL0434, the largest T-ALL trial ever run, showed the opposite for T-ALL, Capizzi methotrexate beating high-dose methotrexate, and added nelarabine for intermediate- and high-risk T-ALL: five-year disease-free survival 88.2 percent against 82.1 percent, now standard. AALL1231 then removed prophylactic cranial irradiation for all but the highest-risk T-ALL and showed that bortezomib helped T-lymphoblastic lymphoma but not T-ALL. Allogeneic transplant in first remission is reserved for induction failure, hypodiploidy and persistent residual disease at the end of consolidation.

Immunotherapy is moving from relapse into first-line high-risk therapy. E1910 in adults and AALL1731 in standard-risk children showed blinatumomab consolidation lowers relapse, AALL1732 is testing inotuzumab ozogamicin added to chemotherapy for high-risk B-ALL, and CD19 CAR T-cells are being tried as consolidation for children with persistent residual disease instead of transplant. T-ALL has no antibody target in routine use: nelarabine, venetoclax combinations and CD7-directed CAR T-cells are the candidates, and daratumumab against CD38 is being tested in relapsed T-ALL. Toxicity is the other frontier: asparaginase-related thrombosis and pancreatitis, osteonecrosis in adolescents, methotrexate neurotoxicity, and the late cardiac and cognitive costs that push every trial to remove a drug wherever residual disease allows.