Relapsed and refractory acute lymphoblastic leukaemia in children

Relapse is classified by time from diagnosis, site and response. Early relapse, within 18 months of diagnosis or within six months of finishing treatment, is much harder to cure than late relapse; isolated extramedullary relapse in the central nervous system or testis does better than marrow relapse; and residual disease after the first reinduction block sorts children into those who can be cured with chemotherapy alone and those who need transplant. T-cell ALL relapse carries the worst prognosis. The UK ALLR3 trial in 2010 showed that mitoxantrone in reinduction beat idarubicin, three-year progression-free survival 64.6 percent against 35.9 percent, and mitoxantrone-based reinduction with allogeneic transplant for high-risk relapse became the international standard.

Blinatumomab, a CD19 and CD3 bispecific T-cell engager, was tested against chemotherapy in two randomised trials of first relapse published together in 2021. In COG AALL1331, children with high- and intermediate-risk relapse given blinatumomab instead of two chemotherapy blocks before transplant had two-year disease-free survival of 54.4 percent against 39.0 percent and overall survival of 71.3 percent against 58.4 percent, with more reaching transplant in remission and fewer deaths from infection. In the European IntReALL trial, high-risk first relapse treated with one blinatumomab cycle instead of a third consolidation block had events in 31 percent against 57 percent and residual-disease remission in 90 percent against 54 percent. Tisagenlecleucel, an autologous CD19 CAR T-cell product, produced an overall remission rate of 81 percent within three months in 75 children and young adults with second or later relapse or refractory disease in ELIANA, with event-free survival of 50 percent and overall survival of 76 percent at twelve months; it was approved in August 2017, the first CAR T-cell therapy for any cancer, and long-term follow-up shows durable remissions in a substantial minority without transplant. Inotuzumab ozogamicin, a CD22 antibody-drug conjugate, gave complete remissions in most children in the ITCC-059 and COG AALL1621 studies and was approved for children from the age of one in March 2024.

Sequencing is now the question: antigen loss (CD19-negative relapse after blinatumomab or CAR T-cells, CD22 loss after inotuzumab), lineage switch in KMT2A-rearranged disease and T-cell exhaustion each shape the next choice, and whether to consolidate a CAR T-cell remission with transplant depends on prior therapy and residual disease by next-generation sequencing. Trials are testing blinatumomab and CAR T-cells earlier, in low-risk first relapse and in first-line high-risk therapy, dual CD19 and CD22 CAR T-cells, allogeneic off-the-shelf CAR T-cells, and menin inhibitors for KMT2A-rearranged relapse. Relapsed T-ALL still depends on nelarabine and transplant, with CD7 CAR T-cells and venetoclax combinations in early trials, and access to CAR T-cells outside a handful of countries is the widest gap of all.