title: Detectable minimal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute lymphoblastic leukemia.
abstract: BACKGROUND
  The level of minimal residual disease (MRD) prior to allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be an independent prognostic factor for outcome of pediatric patients with high-risk acute lymphoblastic leukemia (ALL). Retrospective studies which used (semi-) quantitation of clone-specific immunoglobulin/T-cell receptor (Ig/TCR) rearrangements have documented the feasibility and practicality of this technique. This approach has also been disputed due to the occurrence of clonal evolution and generally high MRD levels prior to HSCT.
  
  
  METHODS
  In our prospective study, MRD before and after HSCT was monitored using quantitative real-time PCR in a cohort of 36 children with ALL consecutively transplanted in our center between VIII/2000 and VII/2004.
  
  
  RESULTS
  In 25 of 36 patients, MRD level prior HSCT was assessed. Seventeen patients were classified as MRD-negative and eight were MRD-positive up to 9 x 10(-2). In MRD-positive subgroup, seven events (six relapses) occurred post-transplant in striking contrast to only one relapse in MRD-negative subgroup (event-free survival (EFS) log-rank P < 0.0001). MRD proved to be the only significant prognostic factor in a multivariate analysis (P < 0.0001). Adoptive immunotherapy including donor lymphocyte infusions in patients with adverse dynamics of MRD after HSCT had only limited and/or temporary effect. Clonal evolution did not present a problem precluding MRD monitoring in any of patients suffering a post-transplant relapse.
  
  
  CONCLUSIONS
  We show that MRD quantitation using clonal Ig/TCR rearrangements successfully assesses the risk in pediatric ALL patients undergoing allogeneic HSCT. As our ability to treat detectable MRD levels after HSCT is very limited, alternative strategies for MRD-positive patients prior HSCT are necessary.
authors.affiliation: CLIP-Childhood Leukemia Investigation Prague, Prague, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Sramkova
authors.forename: Katerina
authors.initials: K
authors.lastname: Muzikova
authors.forename: Eva
authors.initials: E
authors.lastname: Fronkova
authors.forename: Ondrej
authors.initials: O
authors.lastname: Krejci
authors.forename: Petr
authors.initials: P
authors.lastname: Sedlacek
authors.forename: Renata
authors.initials: R
authors.lastname: Formankova
authors.forename: Ester
authors.initials: E
authors.lastname: Mejstrikova
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000401:mortality; D007223:Infant; D017710:Lymphocyte Transfusion / Q000401:mortality; D008297:Male; D008991:Monitoring, Physiologic; D018365:Neoplasm, Residual / Q000235:genetics / Q000401:mortality*; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000401:mortality* / Q000628:therapy; D011237:Predictive Value of Tests; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome