title: Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96.
abstract: OBJECTIVE
  This blinded prospective study was performed to optimise the risk assessment of children with a late isolated, combined or an early combined bone marrow (BM) relapse of precursor B-cell acute lymphoblastic leukaemia (ALL). The aim was to develop a reliable tool to identify patients with an intermediate risk relapse who are in need of haematopoietic stem cell transplantation (HSCT).
  
  
  METHODS
  Included were 80 children and adolescents with first intermediate risk BM relapse of ALL recruited in trial ALL-REZ BFM P95/96. We assessed the prognostic value of minimal residual disease (MRD) after induction therapy quantified by PCR using leukaemia clone-specific T-cell receptor/immunoglobulin gene rearrangements.
  
  
  RESULTS
  Molecular good responders (MRD < 10(-3), n=46) had a probability of event-free survival (pEFS) at 10 years of 76% standard error (SE) ± 6% and a cumulative incidence of second relapse (CIR) at 10 years of 21% SE ± 6%; pEFS of molecular poor responders (MRD ≥ 10(-3), n=34) at 10 years was 18% SE ± 7% and CIR 61% SE ± 9% (p<0.001). Cox regression analysis revealed MRD after induction to be the strongest independent prognostic parameter with a 6.6-fold increased risk (95% confidence interval 3.3-13.5, p<0.001) for molecular poor responders to suffer a subsequent adverse event compared to good responders.
  
  
  CONCLUSIONS
  In patients with intermediate risk BM relapse of ALL, low MRD after induction is associated with an excellent long-term prognosis with conventional chemo-/radiotherapy whereas patients with insufficient response have an extremely poor prognosis. Therefore, in the subsequent trial ALL-REZ BFM 2002, MRD is used to allocate molecular good responders to conventional post-induction therapy and molecular poor responders to allogeneic HSCT.
authors.affiliation: Department of Paediatric Oncology/Haematology, Charité Universitätsmedizin Berlin, Berlin, Germany. cornelia.eckert@charite.de
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.forename: Arend
authors.initials: A
authors.lastname: von Stackelberg
authors.forename: Karl
authors.initials: K
authors.lastname: Seeger
authors.forename: Tom W L
authors.initials: TW
authors.lastname: Groeneveld
authors.forename: Christina
authors.initials: C
authors.lastname: Peters
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Gabriele
authors.initials: G
authors.lastname: Escherich
authors.forename: Günter
authors.initials: G
authors.lastname: Henze
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001853:Bone Marrow / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D005260:Female; D015321:Gene Rearrangement; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D060828:Induction Chemotherapy / Q000379:methods; D008297:Male; D018365:Neoplasm, Residual / Q000175:diagnosis*; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D007136:Immunoglobulins; D011948:Receptors, Antigen, T-Cell