# Relapsed and refractory acute lymphoblastic leukaemia in children

Source: https://onco.cc/cancers/all-paediatric-relapsed/  
OnCo record `all-paediatric-relapsed` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When childhood leukaemia comes back, chemotherapy alone cures fewer than half. Three immune treatments changed this: blinatumomab, which links the child's T-cells to leukaemia cells and beat chemotherapy in two trials; tisagenlecleucel, the first approved CAR T-cell therapy, which put over eight in ten pretreated children into remission; and the antibody-drug conjugate inotuzumab ozogamicin.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Relapsed childhood ALL; Refractory paediatric B-ALL; Second-line childhood ALL
- Tags: subtype-page; paediatric
- Group: paediatric
- Burden: About one child in ten with acute lymphoblastic leukaemia relapses, and relapsed ALL remains one of the leading causes of cancer death in children.
- Subtypes: Late marrow relapse of B-ALL (36 months or more from diagnosis; chemotherapy with or without immunotherapy); Early or very early marrow relapse of B-ALL (immunotherapy then allogeneic transplant); Isolated central nervous system or testicular relapse; Primary refractory B-ALL (induction failure); Second or later relapse, or relapse after transplant (CAR T-cells); Relapsed T-cell ALL (nelarabine-based salvage and transplant)
- Biomarkers: Time from diagnosis and from end of treatment; Site of relapse (marrow, CNS, testis, combined); MRD after reinduction by flow cytometry and next-generation sequencing; CD19 and CD22 expression on blasts; KMT2A rearrangement (lineage switch risk); Prior exposure to blinatumomab or CAR T-cells

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/all-paediatric-relapsed/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/all-paediatric-relapsed/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/all-paediatric-relapsed/#what-it-is [6 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/all-paediatric-relapsed/#finding-it [6 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/all-paediatric-relapsed/#treating-it [5 settings, 5 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/all-paediatric-relapsed/#evidence [13 trials, 4 key papers, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/all-paediatric-relapsed/#science [6 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/all-paediatric-relapsed/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/all-paediatric-relapsed/#living-with-it [23 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/all-paediatric-relapsed/coming/ [14 medicines, 11 trials, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/all-paediatric-relapsed/data/ [69 connected records]

## Standard of care

- First relapse: reinduction: Mitoxantrone-based reinduction (UKALLR3) with vincristine, dexamethasone, asparaginase and intrathecal therapy; MRD after the block sets the path. ([Mitoxantrone](https://onco.cc/drugs/mitoxantrone/), [Vincristine](https://onco.cc/drugs/vincristine/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)](https://onco.cc/drugs/asparaginase/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Multiparameter flow cytometry MRD](https://onco.cc/technologies/flow-cytometry-mrd/), [ALL R3 (UKALLR3)](https://onco.cc/trials/ukallr3/))
- First relapse, high or intermediate risk: consolidation: Blinatumomab in place of chemotherapy blocks (AALL1331, IntReALL), then allogeneic transplant in MRD-negative remission. ([Blinatumomab](https://onco.cc/drugs/blinatumomab/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [CD19](https://onco.cc/targets/cd19/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/), [AALL1331](https://onco.cc/trials/aall1331/), [IntReALL SR 2010](https://onco.cc/trials/intreall-sr-2010/))
- Second or later relapse, or refractory disease: Tisagenlecleucel (ELIANA) or inotuzumab ozogamicin, with transplant after inotuzumab and after CAR T-cells in selected children. ([Tisagenlecleucel](https://onco.cc/drugs/tisagenlecleucel/), [ELIANA](https://onco.cc/trials/eliana/), [Inotuzumab ozogamicin](https://onco.cc/drugs/inotuzumab-ozogamicin/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Cytokine release syndrome (CRS)](https://onco.cc/terms/crs/), [ICANS (neurotoxicity)](https://onco.cc/terms/icans/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/))
- Relapsed T-cell ALL: Nelarabine with cyclophosphamide and etoposide, then allogeneic transplant; venetoclax combinations and CD7 CAR T-cells in trials. ([Nelarabine](https://onco.cc/drugs/nelarabine/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Etoposide](https://onco.cc/drugs/etoposide/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Venetoclax](https://onco.cc/drugs/venetoclax/))
- Relapsed KMT2A-rearranged ALL: Revumenib (approved from the age of one) alone or in trials with chemotherapy, as a bridge to transplant. ([Revumenib](https://onco.cc/drugs/revumenib/), [AUGMENT-101](https://onco.cc/trials/augment-101/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/))

## State of the art

- Blinatumomab replaced chemotherapy consolidation in high- and intermediate-risk first relapse after two randomised trials in 2021.
- Tisagenlecleucel, the first approved CAR T-cell therapy, produces durable remissions in a substantial minority of children with multiply relapsed disease.
- Inotuzumab ozogamicin is approved for children, adding a CD22 option when CD19 is lost.

## Open problems

- CD19-negative relapse and lineage switch after CD19-directed therapy.
- Which children need transplant after a CAR T-cell remission.
- Relapsed T-ALL has no approved immunotherapy, and CAR T-cell access is limited to a handful of countries.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Tisagenlecleucel
- Wikipedia: Tisagenlecleucel: https://en.wikipedia.org/wiki/Tisagenlecleucel
- NCI PDQ: Childhood ALL Treatment: https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq

## Connected records

- cancers: [Acute lymphoblastic leukaemia](https://onco.cc/cancers/all-leukemia/), [High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL)](https://onco.cc/cancers/all-paediatric-high-risk/), [Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year)](https://onco.cc/cancers/all-infant/), [Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL)](https://onco.cc/cancers/all-ph-like/), [Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL)](https://onco.cc/cancers/all-paediatric-ph-positive/), [Standard-risk B-cell acute lymphoblastic leukaemia in children](https://onco.cc/cancers/all-paediatric-standard-risk/)
- technologies: [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Multiparameter flow cytometry MRD](https://onco.cc/technologies/flow-cytometry-mrd/), [NGS-based MRD (clonoSEQ and molecular MRD)](https://onco.cc/technologies/ngs-mrd-clonoseq/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/)
- targets: [CD19](https://onco.cc/targets/cd19/), [CD22](https://onco.cc/targets/cd22/), [CD3](https://onco.cc/targets/cd3/)
- companies: [Children's Oncology Group (COG)](https://onco.cc/companies/childrens-oncology-group/)
- terms: [B-ALL risk groups (NCI criteria, ETV6::RUNX1, hyperdiploidy, hypodiploidy, iAMP21, IKZF1, CNS status)](https://onco.cc/terms/b-all-cytogenetic-risk/), [Cytokine release syndrome (CRS)](https://onco.cc/terms/crs/), [ICANS (neurotoxicity)](https://onco.cc/terms/icans/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/)
- key papers: [AALL1331: blinatumomab added to chemotherapy in low-risk first relapse of childhood B-ALL](https://onco.cc/key-papers/paper-aall1331-low-risk-hogan-jco-2023/), [AALL1331: blinatumomab versus chemotherapy consolidation in high- and intermediate-risk first relapse of childhood B-ALL](https://onco.cc/key-papers/paper-aall1331-brown-jama-2021/), [ALL R3: mitoxantrone versus idarubicin in first relapse of childhood acute lymphoblastic leukaemia](https://onco.cc/key-papers/paper-all-r3-mitoxantrone-relapsed-childhood-all-parker-lancet-2010/), [ELIANA: the global trial that made tisagenlecleucel the first approved CAR-T therapy for children and young adults with relapsed ALL](https://onco.cc/key-papers/paper-eliana-tisagenlecleucel-nejm-2018/)
- drugs: [Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)](https://onco.cc/drugs/asparaginase/), [Blinatumomab](https://onco.cc/drugs/blinatumomab/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Etoposide](https://onco.cc/drugs/etoposide/), [Inotuzumab ozogamicin](https://onco.cc/drugs/inotuzumab-ozogamicin/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Mitoxantrone](https://onco.cc/drugs/mitoxantrone/), [Nelarabine](https://onco.cc/drugs/nelarabine/), [Obecabtagene autoleucel](https://onco.cc/drugs/obecabtagene-autoleucel/), [Revumenib](https://onco.cc/drugs/revumenib/), [Tisagenlecleucel](https://onco.cc/drugs/tisagenlecleucel/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [Vincristine](https://onco.cc/drugs/vincristine/)
- trials: [A Study of CNCT19 Treatment in Children and Adolescent r/r ALL Patients(Pediatric)](https://onco.cc/trials/nct05667506/), [A Study of pCAR-19B in the Treatment of CD19-positive Relapsed/Refractory B-ALL in Children and Adolescents](https://onco.cc/trials/nct05334823/), [A Study of Subcutaneous Blinatumomab in Children With R/R and and MRD+ B-Cell Precursor Acute Lymphoblastic Leukemia](https://onco.cc/trials/nct07134088/), [A Study to Learn More About the Study Medicine Called Inotuzumab Ozogamicin (InO) in Children (1 to <18 Years) With First Relapse ALL](https://onco.cc/trials/nct05748171/), [AALL1331](https://onco.cc/trials/aall1331/), [ALL R3 (UKALLR3)](https://onco.cc/trials/ukallr3/), [AUGMENT-101](https://onco.cc/trials/augment-101/), [ELIANA](https://onco.cc/trials/eliana/), [FELIX](https://onco.cc/trials/felix/), [IntReALL SR 2010](https://onco.cc/trials/intreall-sr-2010/), [Safety and Efficacy of Asciminib in Pediatrics and Young Adults With Relapse/Refractory (r/r) Philadelphia Positive (Ph+) or ABL-class Ph-like Acute Lymphoblastic Leukemia (ALL)](https://onco.cc/trials/nct07387926/), [Safety and Efficacy of Ponatinib for Treatment of Pediatric Recurrent or Refractory Leukemias, Lymphomas or Solid Tumors](https://onco.cc/trials/nct03934372/), [Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma](https://onco.cc/trials/nct01700946/)
- biomarkers: [CD19 expression (CD19-positive)](https://onco.cc/biomarkers/cd19-expression/), [CD22 expression (CD22-positive)](https://onco.cc/biomarkers/cd22-expression/)

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JSON: https://onco.cc/api/v1/entities/all-paediatric-relapsed.json