title: Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.
abstract: BACKGROUND
  Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification.
  
  
  METHODS
  Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119.
  
  
  RESULTS
  Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%).
  
  
  CONCLUSIONS
  Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy.
  
  
  BACKGROUND
  Medical Research Council and Leukaemia and Lymphoma Research.
authors: Sheffield Children's Hospital, Sheffield, UK. ajay.vora@sch.nhs.uk
authors: Ajay
authors: A
authors: Vora
authors: Nick
authors: N
authors: Goulden
authors: Rachel
authors: R
authors: Wade
authors: Chris
authors: C
authors: Mitchell
authors: Jeremy
authors: J
authors: Hancock
authors: Rachael
authors: R
authors: Hough
authors: Clare
authors: C
authors: Rowntree
authors: Sue
authors: S
authors: Richards
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001215:Asparaginase / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D003561:Cytarabine / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D007494:Ireland; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D018365:Neoplasm, Residual / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D012008:Recurrence; D012307:Risk Factors; D016896:Treatment Outcome; D006113:United Kingdom; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D003561:Cytarabine; D014750:Vincristine; D003520:Cyclophosphamide; D001215:Asparaginase; D008727:Methotrexate