{"entity":{"id":"all-paediatric-relapsed","kind":"cancer","name":"Relapsed and refractory acute lymphoblastic leukaemia in children","aka":["Relapsed childhood ALL","Refractory paediatric B-ALL","Second-line childhood ALL"],"tldr":"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.\n\nBlinatumomab, 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.\n\nSequencing 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Tisagenlecleucel","links":[{"label":"Wikipedia: Tisagenlecleucel","url":"https://en.wikipedia.org/wiki/Tisagenlecleucel"},{"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-high-risk","all-infant"],"cancers":[],"sections":[],"technologies":["car-t","t-cell-engager","adc","allogeneic-hsct"],"targets":["cd19","cd22","cd3"],"drugs":[],"companies":[],"institutions":["childrens-oncology-group"],"pathways":[],"terms":["crs","icans","mrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-eliana-tisagenlecleucel-nejm-2018"],"journals":[],"dependsOn":[],"notes":[],"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"],"standardOfCare":[{"setting":"First relapse: reinduction","approach":"Mitoxantrone-based reinduction (UKALLR3) with vincristine, dexamethasone, asparaginase and intrathecal therapy; MRD after the block sets the path.","refs":["mitoxantrone","vincristine","dexamethasone","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":"First relapse, high or intermediate risk: consolidation","approach":"Blinatumomab in place of chemotherapy blocks (AALL1331, IntReALL), then allogeneic transplant in MRD-negative remission.","refs":["blinatumomab","allogeneic-hsct","cd19","t-cell-engager"],"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":"Second or later relapse, or refractory disease","approach":"Tisagenlecleucel (ELIANA) or inotuzumab ozogamicin, with transplant after inotuzumab and after CAR T-cells in selected children.","refs":["tisagenlecleucel","eliana","inotuzumab-ozogamicin","car-t","crs","icans","allogeneic-hsct"],"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":"Relapsed T-cell ALL","approach":"Nelarabine with cyclophosphamide and etoposide, then allogeneic transplant; venetoclax combinations and CD7 CAR T-cells in trials.","refs":["nelarabine","cyclophosphamide","etoposide","allogeneic-hsct","venetoclax"],"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":"Relapsed KMT2A-rearranged ALL","approach":"Revumenib (approved from the age of one) alone or in trials with chemotherapy, as a bridge to transplant.","refs":["revumenib","augment-101","allogeneic-hsct"],"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":["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."],"history":[{"year":2010,"title":"UKALLR3: mitoxantrone reinduction nearly doubles progression-free survival in relapsed childhood ALL","refs":["mitoxantrone"]},{"year":2014,"title":"Blinatumomab approved for relapsed or refractory B-ALL in adults","refs":["blinatumomab"]},{"year":2017,"title":"Tisagenlecleucel approved: the first CAR T-cell therapy for any cancer, for children and young adults with relapsed B-ALL","refs":["tisagenlecleucel","eliana"]},{"year":2018,"title":"ELIANA published: 81 percent remission in 75 heavily pretreated children","refs":["paper-eliana-tisagenlecleucel-nejm-2018","eliana"]},{"year":2021,"title":"AALL1331 and IntReALL: blinatumomab beats chemotherapy in first relapse","refs":["blinatumomab"]},{"year":2024,"title":"Inotuzumab ozogamicin approved for children with relapsed or refractory CD22-positive B-ALL","refs":["inotuzumab-ozogamicin"]}],"pipeline":["tisagenlecleucel","blinatumomab","inotuzumab-ozogamicin","obecabtagene-autoleucel","felix","revumenib","ngs-mrd-clonoseq","car-t","venetoclax"],"openProblems":["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."],"parent":"all-leukemia"},"route":"/cancers/all-paediatric-relapsed/","neighbours":{"cancer":[{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","route":"/cancers/all-leukemia/"},{"id":"all-paediatric-high-risk","kind":"cancer","name":"High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL)","route":"/cancers/all-paediatric-high-risk/"},{"id":"all-infant","kind":"cancer","name":"Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year)","route":"/cancers/all-infant/"},{"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":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/"},{"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":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"}],"target":[{"id":"cd19","kind":"target","name":"CD19","route":"/targets/cd19/"},{"id":"cd22","kind":"target","name":"CD22","route":"/targets/cd22/"},{"id":"cd3","kind":"target","name":"CD3","route":"/targets/cd3/"}],"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":"crs","kind":"term","name":"Cytokine release syndrome (CRS)","route":"/terms/crs/"},{"id":"icans","kind":"term","name":"ICANS (neurotoxicity)","route":"/terms/icans/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"}],"paper":[{"id":"paper-eliana-tisagenlecleucel-nejm-2018","kind":"paper","name":"ELIANA: the global trial that made tisagenlecleucel the first approved CAR-T therapy for children and young adults with relapsed ALL","route":"/key-papers/paper-eliana-tisagenlecleucel-nejm-2018/"}],"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":"cyclophosphamide","kind":"drug","name":"Cyclophosphamide","route":"/drugs/cyclophosphamide/"},{"id":"dexamethasone","kind":"drug","name":"Dexamethasone","route":"/drugs/dexamethasone/"},{"id":"etoposide","kind":"drug","name":"Etoposide","route":"/drugs/etoposide/"},{"id":"inotuzumab-ozogamicin","kind":"drug","name":"Inotuzumab ozogamicin","route":"/drugs/inotuzumab-ozogamicin/"},{"id":"methotrexate","kind":"drug","name":"Methotrexate","route":"/drugs/methotrexate/"},{"id":"mitoxantrone","kind":"drug","name":"Mitoxantrone","route":"/drugs/mitoxantrone/"},{"id":"nelarabine","kind":"drug","name":"Nelarabine","route":"/drugs/nelarabine/"},{"id":"obecabtagene-autoleucel","kind":"drug","name":"Obecabtagene autoleucel","route":"/drugs/obecabtagene-autoleucel/"},{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"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":"nct05667506","kind":"trial","name":"A Study of CNCT19 Treatment in Children and Adolescent r/r ALL Patients(Pediatric)","route":"/trials/nct05667506/"},{"id":"nct05334823","kind":"trial","name":"A Study of pCAR-19B in the Treatment of CD19-positive Relapsed/Refractory B-ALL in Children and Adolescents","route":"/trials/nct05334823/"},{"id":"nct07134088","kind":"trial","name":"A Study of Subcutaneous Blinatumomab in Children With R/R and and MRD+ B-Cell Precursor Acute Lymphoblastic Leukemia","route":"/trials/nct07134088/"},{"id":"nct05748171","kind":"trial","name":"A Study to Learn More About the Study Medicine Called Inotuzumab Ozogamicin (InO) in Children (1 to <18 Years) With First Relapse ALL","route":"/trials/nct05748171/"},{"id":"augment-101","kind":"trial","name":"AUGMENT-101","route":"/trials/augment-101/"},{"id":"eliana","kind":"trial","name":"ELIANA","route":"/trials/eliana/"},{"id":"felix","kind":"trial","name":"FELIX","route":"/trials/felix/"},{"id":"nct07387926","kind":"trial","name":"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)","route":"/trials/nct07387926/"},{"id":"nct03934372","kind":"trial","name":"Safety and Efficacy of Ponatinib for Treatment of Pediatric Recurrent or Refractory Leukemias, Lymphomas or Solid Tumors","route":"/trials/nct03934372/"}]}}