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

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

## TL;DR

High-risk childhood leukaemia means a child aged ten or over, a very high white cell count, T-cell disease, spread to the brain or testes, or adverse genetics, and it is treated with longer and more intensive chemotherapy. Most children are still cured; the T-cell form gained the drug nelarabine after the AALL0434 trial, and cranial radiotherapy has been dropped for almost everyone.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: NCI high-risk B-ALL; Very high-risk childhood ALL; Childhood T-cell ALL; T-ALL in children
- Tags: subtype-page; paediatric
- Group: paediatric
- Burden: About a third of children with B-cell ALL are high risk by age or white count, and T-cell ALL adds about 15 percent of childhood ALL; together they account for most of the relapses and deaths in a disease that is otherwise usually cured.
- Subtypes: High-risk B-ALL by age or white count (NCI high risk: aged 10 or over, or white count 50 x 10^9/L or more); B-ALL with adverse genetics (hypodiploidy, KMT2A rearrangement, iAMP21, TCF3::HLF); B-ALL with end-induction or end-consolidation residual disease (very high risk); T-cell ALL (about 15 percent of childhood ALL; nelarabine added for intermediate and high risk); Early T-cell precursor ALL (treated by residual disease response); ALL with CNS or testicular involvement at diagnosis
- Biomarkers: Age and white cell count (NCI criteria); Immunophenotype (CD19, CD22, CD7, cytoplasmic CD3); Karyotype and FISH (hypodiploidy, KMT2A, iAMP21); BCR::ABL1 and BCR::ABL1-like screening; Flow cytometry MRD at day 29 and end of consolidation; CNS status (CNS1 to CNS3)

## Standard of care

- Induction (four weeks): Four-drug induction: vincristine, dexamethasone or prednisone, daunorubicin and pegylated asparaginase with intrathecal methotrexate; MRD at day 29. ([Vincristine](https://onco.cc/drugs/vincristine/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Prednisone](https://onco.cc/drugs/prednisone/), [Daunorubicin](https://onco.cc/drugs/daunorubicin/), [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/))
- Consolidation and interim maintenance, high-risk B-ALL: Augmented BFM consolidation with cyclophosphamide, cytarabine, mercaptopurine and asparaginase; high-dose methotrexate with leucovorin rescue (AALL0232); blinatumomab or inotuzumab ozogamicin added in current trials. ([Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Cytarabine](https://onco.cc/drugs/cytarabine/), [Mercaptopurine](https://onco.cc/drugs/mercaptopurine/), [Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)](https://onco.cc/drugs/asparaginase/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Leucovorin (folinic acid)](https://onco.cc/drugs/leucovorin/), [Blinatumomab](https://onco.cc/drugs/blinatumomab/), [Inotuzumab ozogamicin](https://onco.cc/drugs/inotuzumab-ozogamicin/))
- T-cell ALL: Augmented BFM with Capizzi escalating methotrexate and nelarabine courses for intermediate- and high-risk disease (AALL0434); cranial irradiation only for CNS3 or the highest risk (AALL1231). ([Nelarabine](https://onco.cc/drugs/nelarabine/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)](https://onco.cc/drugs/asparaginase/), [Prophylactic cranial irradiation vs MRI surveillance](https://onco.cc/technologies/prophylactic-cranial-irradiation/))
- Delayed intensification and maintenance: Two delayed intensification blocks with vincristine, dexamethasone, doxorubicin, cyclophosphamide, cytarabine and thioguanine; maintenance with mercaptopurine, methotrexate and vincristine-steroid pulses. ([Vincristine](https://onco.cc/drugs/vincristine/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Cytarabine](https://onco.cc/drugs/cytarabine/), [Thioguanine](https://onco.cc/drugs/thioguanine/), [Mercaptopurine](https://onco.cc/drugs/mercaptopurine/), [Methotrexate](https://onco.cc/drugs/methotrexate/))
- Very high risk: induction failure, hypodiploidy, persistent residual disease: Blinatumomab to clear residual disease, then allogeneic transplant in first remission; CD19 CAR T-cells as consolidation in trials. ([Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Blinatumomab](https://onco.cc/drugs/blinatumomab/), [Tisagenlecleucel](https://onco.cc/drugs/tisagenlecleucel/), [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/))

## State of the art

- Nelarabine is standard for intermediate- and high-risk T-ALL after AALL0434 raised five-year disease-free survival to 88 percent.
- Prophylactic cranial irradiation has been dropped for almost all children after AALL1231, with intrathecal therapy taking its place.
- Blinatumomab and inotuzumab ozogamicin are being folded into first-line high-risk B-ALL therapy, and transplant is confined to persistent residual disease.

## Open problems

- No antibody or cell therapy target in routine use for T-ALL.
- Which high-risk children still need transplant once immunotherapy clears residual disease.
- Asparaginase toxicity and osteonecrosis in adolescents receiving the most intensive regimens.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia
- Wikipedia: Acute lymphoblastic leukaemia: https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia
- 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/), [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/), [Relapsed and refractory acute lymphoblastic leukaemia in children](https://onco.cc/cancers/all-paediatric-relapsed/), [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/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [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/), [Prophylactic cranial irradiation vs MRI surveillance](https://onco.cc/technologies/prophylactic-cranial-irradiation/)
- targets: [CD19](https://onco.cc/targets/cd19/), [CD22](https://onco.cc/targets/cd22/), [CD38](https://onco.cc/targets/cd38/)
- institutions: [Children's Oncology Group (COG)](https://onco.cc/institutions/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/), [Event-free / disease-free survival (EFS, DFS, iDFS, RFS)](https://onco.cc/terms/efs/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/), [Ph-like (BCR::ABL1-like) acute lymphoblastic leukaemia](https://onco.cc/terms/ph-like-all/)
- drugs: [Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)](https://onco.cc/drugs/asparaginase/), [Blinatumomab](https://onco.cc/drugs/blinatumomab/), [Bortezomib](https://onco.cc/drugs/bortezomib/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Cytarabine](https://onco.cc/drugs/cytarabine/), [Daunorubicin](https://onco.cc/drugs/daunorubicin/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Inotuzumab ozogamicin](https://onco.cc/drugs/inotuzumab-ozogamicin/), [Leucovorin (folinic acid)](https://onco.cc/drugs/leucovorin/), [Mercaptopurine](https://onco.cc/drugs/mercaptopurine/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Nelarabine](https://onco.cc/drugs/nelarabine/), [Prednisone](https://onco.cc/drugs/prednisone/), [Thioguanine](https://onco.cc/drugs/thioguanine/), [Tisagenlecleucel](https://onco.cc/drugs/tisagenlecleucel/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [Vincristine](https://onco.cc/drugs/vincristine/)
- trials: [ECOG-ACRIN E1910](https://onco.cc/trials/e1910/), [Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients](https://onco.cc/trials/nct03876769/)

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