title: Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy?
abstract: OBJECTIVE
  We recently reported that children with acute leukemias who show increasing mixed chimerism (MC) after allogeneic stem-cell transplantation have a significantly enhanced risk of relapse. Here we present the results of a prospective multicenter study to investigate (1) whether relapse of acute lymphoblastic leukemia (ALL) can be determined in advance by serial analysis of chimerism, and (2) if outcome can be influenced by withdrawal of immunosuppression and/or by low-dose donor lymphocyte infusion when increasing MC is detected.
  
  
  METHODS
  Serial and quantitative analysis of chimerism was performed using a fluorescent-based short-tandem-repeat-polymerase chain reaction in 163 children with ALL.
  
  
  RESULTS
  One hundred one patients revealed complete chimerism (CC) or low-level MC (CC/low-level MC); increasing MC was found in 46 patients; and decreasing MC, in 16 patients. Relapse was significantly more frequent in patients with increasing MC (26 of 46) than in patients with CC/low-level MC (eight of 101) or in patients with decreasing MC (0 of 16; P <.0001). The probability of 3-year event-free survival (EFS) was 54% for all patients, 66% for patients with CC/low-level MC (n = 101), 66% for patients with decreasing MC (n = 16), and 23% for patients with increasing MC (n = 46; P <.0001). Of the 46 patients with increasing MC, 31 received immunotherapy. This group had a significantly higher 3-year EFS estimate (37%) than the 15 patients who did not receive immunotherapy (0%; P <.001).
  
  
  CONCLUSIONS
  Serial analysis of chimerism reliably identifies patients at highest risk to relapse. The 3-year EFS of patients with increasing MC without immunotherapy was 0%, by which overt relapse could be prevented in a considerable group of patients.
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital, and Department of Medical Biometry, University of Tübingen, Tuebingen, Germany. peter.bader@med.uni-tuebingen.de
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
authors.forename: Hermann
authors.initials: H
authors.lastname: Kreyenberg
authors.forename: Walter
authors.initials: W
authors.lastname: Hoelle
authors.forename: Gregor
authors.initials: G
authors.lastname: Dueckers
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kremens
authors.forename: Dagmar
authors.initials: D
authors.lastname: Dilloo
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Sykora
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Charlotte
authors.initials: C
authors.lastname: Niemeyer
authors.forename: Arend
authors.initials: A
authors.lastname: Von Stackelberg
authors.forename: Bernd
authors.initials: B
authors.lastname: Gruhn
authors.forename: Günter
authors.initials: G
authors.lastname: Henze
authors.forename: Johann
authors.initials: J
authors.lastname: Greil
authors.forename: Dietrich
authors.initials: D
authors.lastname: Niethammer
authors.forename: Klaus
authors.initials: K
authors.lastname: Dietz
authors.forename: James F
authors.initials: JF
authors.lastname: Beck
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
mesh_terms: D002648:Child; D002675:Child, Preschool; D002678:Chimera; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007167:Immunotherapy; D007223:Infant; D007231:Infant, Newborn; D017710:Lymphocyte Transfusion; D008297:Male; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents