EvidenceAcute lymphoblastic leukaemia

AALL1731 brings immunotherapy into the front-line treatment of the commonest childhood cancer, in the group of children where most relapses were occurring despite good initial risk. Blinatumomab was approved for this use in 2024 and paediatric protocols worldwide are being amended. Whether it can allow less chemotherapy, and its effect on very low-risk children, are the next questions.

A lower-middle-income country can design, manufacture, trial and approve an autologous CAR-T therapy. Response rates are in the range of first-generation Western products in similar mixed populations, at a price an order of magnitude lower, which reopens the question of what CAR-T should cost everywhere.

E1910 changed the standard of care for adult B-ALL: immunotherapy is now part of front-line consolidation even for patients with no detectable leukaemia, because MRD-negative by flow cytometry does not mean cured. It also demonstrated that a T-cell engager can improve overall survival in a curative setting. Chemotherapy-light or chemotherapy-free regimens built on blinatumomab and inotuzumab are the next step.

Blinatumomab belongs in the treatment of low-risk marrow relapse in children; isolated extramedullary relapse needs new approaches.

Revumenib proved that a transcriptional dependency, rather than a kinase, can be drugged in leukaemia, opening treatment for two genetic subgroups that together cover roughly a third of AML plus most infant ALL. It is now approved and is being combined with venetoclax-azacitidine and intensive chemotherapy in front-line trials. Single-agent remissions are often short without transplant.

Prophylactic cranial radiotherapy can be limited to central nervous system involvement and the highest-risk patients in childhood T-ALL, and bortezomib is a reasonable addition for T-lymphoblastic lymphoma.

Blinatumomab consolidation is a safer bridge to transplant for children with higher-risk relapsed B-ALL and improved survival; it is the basis for using blinatumomab in place of chemotherapy blocks after relapse.

The UCART19 report was the first clinical evidence that a universal, pre-manufactured CAR-T made from a donor can work, avoiding the weeks of autologous manufacturing and the problem of patients whose own T cells are too damaged. It set the template for later allogeneic programmes (including cemacabtagene autoleucel in the ALPHA studies) and for in vivo CAR generation. Short persistence and the need for deep lymphodepletion remain the central weaknesses.

ELIANA turned CAR-T from a single-centre experiment into a licensed product and created the regulatory and logistical template every later cell therapy has followed. For children with refractory leukaemia it offers a chance of durable remission without transplant. The trial also exposed the gaps: manufacturing failures, patients dying while waiting, and roughly half relapsing within a few years.

Continuous imatinib from induction lets many children with Philadelphia-positive ALL avoid transplant, but the intensive BFM backbone is toxic; later trials reduced chemotherapy intensity under tyrosine kinase inhibitor cover.

Paediatric-inspired protocols are the reference for younger adults with ALL, but their intensity is not tolerated from about age 55, which is where reduced-intensity and antibody-based approaches take over.

INO-VATE made inotuzumab a standard salvage therapy for adult ALL and a common route to transplant, and, with the TOWER trial of blinatumomab, moved adult ALL from chemotherapy-only salvage to immunotherapy. Both drugs have since been pulled into front-line regimens. The liver toxicity signal shaped how transplant conditioning is chosen after inotuzumab.

This paper is the proof-of-concept for a living drug: a single infusion of a patient's own engineered T cells could eradicate leukaemia that had survived chemotherapy, transplant and antibody therapy. It defined cytokine release syndrome and its antidote, tocilizumab, and revealed antigen-loss relapse. It led directly to the first approved gene-modified cell therapy three years later.

Mitoxantrone-based reinduction became the reference treatment for relapsed childhood ALL and the control arm of later international relapse trials.