title: Monitoring of minimal residual disease after allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial.
abstract: OBJECTIVE
  To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster Stem Cell Transplantation Group (ALL-BFM-SCT) conducted a prospective clinical trial.
  
  
  METHODS
  In the ALL-BFM-SCT 2003 trial, MRD was assessed in the bone marrow at days +30, +60, +90, +180, and +365 after transplantation in 113 patients with relapsed disease. Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD Group.
  
  
  RESULTS
  All patients showed a 3-year probability of event-free survival (pEFS) of 55%. The cumulative incidence rates of relapse and treatment-related mortality were 32% and 12%, respectively. The pEFS was 60% for patients who received their transplantations in second complete remission, 50% for patients in ≥ third complete remission, and 0% for patients not in remission (P = .015). At all time points, the level of MRD was inversely correlated with event-free survival (EFS; P < .004) and positively correlated with the cumulative incidence of relapse (P < .01). A multivariable Cox model was fitted for each time point, which showed that MRD ≥ 10(-4) leukemic cells was consistently correlated with inferior EFS (P < .003). The accuracy of MRD measurements in predicting relapse was investigated with time-dependent receiver operating curves at days +30, +60, +90, and +180. From day +60 onward, the discriminatory power of MRD detection to predict the probability of relapse after 1, 3, 6, and 9 months was more than 96%, more than 87%, more than 71%, and more than 61%, respectively.
  
  
  CONCLUSIONS
  MRD after transplantation was a reliable marker for predicting impending relapses and could thus serve as the basis for pre-emptive therapy.
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria. peter.bader@kgu.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Kreyenberg
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Arend
authors.initials: A
authors.lastname: von Stackelberg
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Emilia
authors.initials: E
authors.lastname: Salzmann-Manrique
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Roland
authors.initials: R
authors.lastname: Meisel
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Poetschger
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stachel
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Alten
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Andre
authors.initials: A
authors.lastname: Schrauder
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Ingo
authors.initials: I
authors.lastname: Müller
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Andre M
authors.initials: AM
authors.lastname: Willasch
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Klingebiel
authors.affiliation: Peter Bader, Hermann Kreyenberg, Emilia Salzmann-Manrique, Andre M. Willasch, and Thomas E. Klingebiel, University Hospital for Children and Adolescents, Frankfurt/Main; Arend von Stackelberg and Cornelia Eckert, Children's Hospital Charité, Berlin, Berlin; Roland Meisel, Heinrich-Heine-University, Düsseldorf; Daniel Stachel, University Hospital Erlangen, Erlangen; Martin Schrappe, Julia Alten, Andre Schrauder, Christian-Albrechts-University and Medical Center Schleswig-Holstein, Kiel; Ansgar Schulz, University Medical Center, Ulm; Peter Lang, University Children's Hospital, Tuebingen; Ingo Müller, University Medical Center Hamburg-Eppendorf, Hamburg; Michael H. Albert, University Children's Hospital, Munich, Germany; and Ulrike Poetschger and Christina Peters, St Anna Children's Hospital, Vienna, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Peters
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000401:mortality; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D015999:Multivariate Analysis; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012372:ROC Curve; D012008:Recurrence; D012074:Remission Induction; D012307:Risk Factors; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult