{"entity":{"id":"all-paediatric-high-risk","kind":"cancer","name":"High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL)","aka":["NCI high-risk B-ALL","Very high-risk childhood ALL","Childhood T-cell ALL","T-ALL in children"],"tldr":"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.\n\nThe 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.\n\nImmunotherapy 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia","links":[{"label":"Wikipedia: Acute lymphoblastic leukaemia","url":"https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia"},{"label":"NCI PDQ: Childhood ALL Treatment","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}],"tags":["subtype-page","paediatric"],"related":["all-paediatric-standard-risk","all-paediatric-ph-positive","all-ph-like","all-paediatric-relapsed"],"cancers":[],"sections":[],"technologies":["flow-cytometry-mrd","allogeneic-hsct","cytotoxic-chemotherapy"],"targets":["cd19","cd22","cd38"],"drugs":[],"companies":[],"institutions":["childrens-oncology-group"],"pathways":[],"terms":["mrd","efs","b-all-cytogenetic-risk","ph-like-all"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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)"],"standardOfCare":[{"setting":"Induction (four weeks)","approach":"Four-drug induction: vincristine, dexamethasone or prednisone, daunorubicin and pegylated asparaginase with intrathecal methotrexate; MRD at day 29.","refs":["vincristine","dexamethasone","prednisone","daunorubicin","asparaginase","methotrexate","flow-cytometry-mrd"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Consolidation and interim maintenance, high-risk B-ALL","approach":"Augmented BFM consolidation with cyclophosphamide, cytarabine, mercaptopurine and asparaginase; high-dose methotrexate with leucovorin rescue (AALL0232); blinatumomab or inotuzumab ozogamicin added in current trials.","refs":["cyclophosphamide","cytarabine","mercaptopurine","asparaginase","methotrexate","leucovorin","blinatumomab","inotuzumab-ozogamicin"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"T-cell ALL","approach":"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).","refs":["nelarabine","methotrexate","asparaginase","prophylactic-cranial-irradiation"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Delayed intensification and maintenance","approach":"Two delayed intensification blocks with vincristine, dexamethasone, doxorubicin, cyclophosphamide, cytarabine and thioguanine; maintenance with mercaptopurine, methotrexate and vincristine-steroid pulses.","refs":["vincristine","dexamethasone","doxorubicin","cyclophosphamide","cytarabine","thioguanine","mercaptopurine","methotrexate"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}},{"setting":"Very high risk: induction failure, hypodiploidy, persistent residual disease","approach":"Blinatumomab to clear residual disease, then allogeneic transplant in first remission; CD19 CAR T-cells as consolidation in trials.","refs":["allogeneic-hsct","blinatumomab","tisagenlecleucel","flow-cytometry-mrd","ngs-mrd-clonoseq"],"guideline":{"version":"NCI PDQ: Childhood Acute Lymphoblastic Leukemia Treatment (health professional version)","url":"https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq"}}],"stateOfArt":["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."],"history":[{"year":1998,"title":"Children's Cancer Group: augmented BFM therapy improves outcome for slow early responders","refs":[]},{"year":2016,"title":"AALL0232: high-dose methotrexate beats Capizzi methotrexate in high-risk B-ALL","refs":["methotrexate","leucovorin"]},{"year":2020,"title":"AALL0434: nelarabine improves disease-free survival in T-ALL","refs":["nelarabine"]},{"year":2022,"title":"AALL1231 removes prophylactic cranial irradiation for most T-ALL; bortezomib helps T-lymphoblastic lymphoma only","refs":["prophylactic-cranial-irradiation","bortezomib"]},{"year":2024,"title":"Blinatumomab approved for consolidation of newly diagnosed CD19-positive B-ALL","refs":["blinatumomab","e1910"]}],"pipeline":["inotuzumab-ozogamicin","blinatumomab","tisagenlecleucel","venetoclax","ngs-mrd-clonoseq","allogeneic-hsct"],"openProblems":["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."],"parent":"all-leukemia"},"route":"/cancers/all-paediatric-high-risk/","neighbours":{"cancer":[{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","route":"/cancers/all-leukemia/"},{"id":"all-ph-like","kind":"cancer","name":"Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL)","route":"/cancers/all-ph-like/"},{"id":"all-paediatric-ph-positive","kind":"cancer","name":"Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL)","route":"/cancers/all-paediatric-ph-positive/"},{"id":"all-paediatric-relapsed","kind":"cancer","name":"Relapsed and refractory acute lymphoblastic leukaemia in children","route":"/cancers/all-paediatric-relapsed/"},{"id":"all-paediatric-standard-risk","kind":"cancer","name":"Standard-risk B-cell acute lymphoblastic leukaemia in children","route":"/cancers/all-paediatric-standard-risk/"}],"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"flow-cytometry-mrd","kind":"technology","name":"Multiparameter flow cytometry MRD","route":"/technologies/flow-cytometry-mrd/"},{"id":"ngs-mrd-clonoseq","kind":"technology","name":"NGS-based MRD (clonoSEQ and molecular MRD)","route":"/technologies/ngs-mrd-clonoseq/"},{"id":"prophylactic-cranial-irradiation","kind":"technology","name":"Prophylactic cranial irradiation vs MRI surveillance","route":"/technologies/prophylactic-cranial-irradiation/"}],"target":[{"id":"cd19","kind":"target","name":"CD19","route":"/targets/cd19/"},{"id":"cd22","kind":"target","name":"CD22","route":"/targets/cd22/"},{"id":"cd38","kind":"target","name":"CD38","route":"/targets/cd38/"}],"institution":[{"id":"childrens-oncology-group","kind":"institution","name":"Children's Oncology Group (COG)","route":"/institutions/childrens-oncology-group/"}],"term":[{"id":"b-all-cytogenetic-risk","kind":"term","name":"B-ALL risk groups (NCI criteria, ETV6::RUNX1, hyperdiploidy, hypodiploidy, iAMP21, IKZF1, CNS status)","route":"/terms/b-all-cytogenetic-risk/"},{"id":"efs","kind":"term","name":"Event-free / disease-free survival (EFS, DFS, iDFS, RFS)","route":"/terms/efs/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"},{"id":"ph-like-all","kind":"term","name":"Ph-like (BCR::ABL1-like) acute lymphoblastic leukaemia","route":"/terms/ph-like-all/"}],"drug":[{"id":"asparaginase","kind":"drug","name":"Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)","route":"/drugs/asparaginase/"},{"id":"blinatumomab","kind":"drug","name":"Blinatumomab","route":"/drugs/blinatumomab/"},{"id":"bortezomib","kind":"drug","name":"Bortezomib","route":"/drugs/bortezomib/"},{"id":"cyclophosphamide","kind":"drug","name":"Cyclophosphamide","route":"/drugs/cyclophosphamide/"},{"id":"cytarabine","kind":"drug","name":"Cytarabine","route":"/drugs/cytarabine/"},{"id":"daunorubicin","kind":"drug","name":"Daunorubicin","route":"/drugs/daunorubicin/"},{"id":"dexamethasone","kind":"drug","name":"Dexamethasone","route":"/drugs/dexamethasone/"},{"id":"doxorubicin","kind":"drug","name":"Doxorubicin","route":"/drugs/doxorubicin/"},{"id":"inotuzumab-ozogamicin","kind":"drug","name":"Inotuzumab ozogamicin","route":"/drugs/inotuzumab-ozogamicin/"},{"id":"leucovorin","kind":"drug","name":"Leucovorin (folinic acid)","route":"/drugs/leucovorin/"},{"id":"mercaptopurine","kind":"drug","name":"Mercaptopurine","route":"/drugs/mercaptopurine/"},{"id":"methotrexate","kind":"drug","name":"Methotrexate","route":"/drugs/methotrexate/"},{"id":"nelarabine","kind":"drug","name":"Nelarabine","route":"/drugs/nelarabine/"},{"id":"prednisone","kind":"drug","name":"Prednisone","route":"/drugs/prednisone/"},{"id":"thioguanine","kind":"drug","name":"Thioguanine","route":"/drugs/thioguanine/"},{"id":"tisagenlecleucel","kind":"drug","name":"Tisagenlecleucel","route":"/drugs/tisagenlecleucel/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"},{"id":"vincristine","kind":"drug","name":"Vincristine","route":"/drugs/vincristine/"}],"trial":[{"id":"e1910","kind":"trial","name":"ECOG-ACRIN E1910","route":"/trials/e1910/"},{"id":"nct03876769","kind":"trial","name":"Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients","route":"/trials/nct03876769/"}]}}