title: Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial.
abstract: BACKGROUND
  No randomised study has shown whether stratification of treatment by minimal residual disease (MRD) response improves outcome in children and young people with acute lymphoblastic leukaemia (ALL). We assessed whether children and young people with clinical standard and intermediate-risk ALL who have persistent MRD at the end of induction therapy benefit from augmented post-remission therapy.
  
  
  METHODS
  Between Oct 1, 2003, and June 30, 2011, we enrolled eligible patients aged 1-24 years and initially categorised them into clinical standard-risk, intermediate-risk, and high-risk groups on the basis of a combination of National Cancer Institute criteria, cytogenetics, and early morphological response to induction therapy. Clinical standard-risk and intermediate-risk patients with MRD of 0·01% or higher at day 29 of induction (MRD high risk) were randomly assigned (1:1) to standard therapy (treatment regimens A and B) or augmented post-remission therapy (regimen C). Compared with standard therapy, the augmented treatment regimen (regimen C) included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous methotrexate without folinic acid rescue during interim maintenance courses. Computer randomisation was used for treatment allocation and was balanced for sex, age (<10 years vs ≥10 years), and white blood cell count at diagnosis (<50 × 10(9)/L vs ≥50 × 10(9)/L) by minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcomes were event-free survival and overall survival. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07355119.
  
  
  RESULTS
  533 MRD high-risk patients were randomly assigned to receive standard (n=266) or augmented (n=267) post-remission therapy. After a median follow-up of 70 months (IQR 52-91), 5-year event-free survival was better in the augmented treatment group (89·6% [95% CI 85·9-93·3]) than in the standard group (82·8% [78·1-87·5]; odds ratio [OR] 0·61 [95% CI 0·39-0·98], p=0·04). Overall survival at 5 years was numerically, but not significantly, higher in the augmented treatment group (92·9% [95% CI 89·8-96·0]) than in the standard therapy group (88·9% [85·0-92·8]; OR 0·67 [95% CI 0·38-1·17], p=0·16). More adverse events occurred in the augmented treatment group than in the standard group (asparaginase-related hypersensitivity in 18 [6·7%] in the augmented group vs two [0·8%] in the standard group and asparaginase-related pancreatitis in eight [3·0%] vs one [0·4%]; intravenous methotrexate-related mucositis in 11 [4·1%] vs three [1·1%] and methotrexate-related stomatitis in 48 [18·0%] vs 12 [4·5%]).
  
  
  CONCLUSIONS
  Our findings suggest that children and young people with acute lymphoblastic leukaemia and 0·01% or more MRD at the end of remission induction therapy could benefit from augmented post-remission therapy. However, the asparaginase and intravenous methotrexate used in the augmented treatment regimen is associated with more adverse events than is the standard post-remission treatment regimen.
  
  
  BACKGROUND
  Medical Research Council and Leukaemia and Lymphoma Research.
authors.affiliation: Sheffield Children's Hospital, Sheffield, UK. Electronic address: ajay.vora@sch.nhs.uk.
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
authors.affiliation: Great Ormond Street Hospital, London, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Goulden
authors.affiliation: John Radcliffe Hospital, Oxford, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Mitchell
authors.affiliation: North Bristol NHS Trust, Bristol, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hancock
authors.affiliation: University College Hospital, London, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Hough
authors.affiliation: University Hospital of Wales, Cardiff, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Rowntree
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle, UK.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: Clinical Trial Service Unit, University of Oxford, Oxford, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Wade
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D060830:Consolidation Chemotherapy / Q000009:adverse effects / Q000379:methods*; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004342:Drug Hypersensitivity / Q000209:etiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D052016:Mucositis / Q000139:chemically induced; D018365:Neoplasm, Residual; D010195:Pancreatitis / Q000139:chemically induced; D011092:Polyethylene Glycols / Q000008:administration & dosage; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012074:Remission Induction; D018570:Risk Assessment; D013280:Stomatitis / Q000139:chemically induced; D015996:Survival Rate; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D003561:Cytarabine; D011092:Polyethylene Glycols; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D015122:Mercaptopurine; D001215:Asparaginase; D008727:Methotrexate