Originally published as JCO Early Release 10.1200/JCO.2008.17.6065 on December 8 2008

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Prognostic Value of Minimal Residual Disease Quantification Before Allogeneic Stem-Cell Transplantation in Relapsed Childhood Acute Lymphoblastic Leukemia: The ALL-REZ BFM Study Group

Peter Bader, Hermann Kreyenberg, Günter H.R. Henze, Cornelia Eckert, Miriam Reising, Andre Willasch, Andrea Barth, Arndt Borkhardt, Christina Peters, Rupert Handgretinger, Karl-Walter Sykora, Wolfgang Holter, Hartmut Kabisch, Thomas Klingebiel, Arend von Stackelberg

From the Children's Hospital of the J.W. Goethe University, Frankfurt; Charité, Pediatric Oncology/Hematology, Berlin; University Medical Center, Pediatric Oncology/Hematology, Düsseldorf; University Children's Hospital Tübingen, Tübingen; Medizinische Hochschule Hannover, Hannover; University Children's Hospital, Erlangen, Erlangen; University Children's Hospital Hamburg, Hamburg, Germany; and St Anna Kinderspital, Pediatric Oncology/Hematology, Vienna, Austria

Corresponding author: Peter Bader, MD, University Children's Hospital, Division for Stem Cell Transplantation, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany; e-mail: peter.bader{at}kgu.de

Purpose Minimal residual disease (MRD) before allogeneic stem-cell transplantation was shown to predict outcome in children with relapsed acute lymphoblastic leukemia (ALL) in retrospective analysis. To verify this, the Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group conducted a prospective trial.

Patients and Methods Between March 1999 and July 2005, 91 children with relapsed ALL treated according to the ALL-REZ BFM 96 or 2002 protocols and receiving stem-cell transplantation in second remission were enrolled. MRD quantification was performed by real-time polymerase chain reaction using T-cell receptor and immunoglobulin gene rearrangements.

Results Probability of event-free survival (pEFS) and cumulative incidence of relapse (CIR) in 45 patients with MRD 10^–4 leukemic cells was 0.27 and 0.57 compared with 0.60 and 0.13 in 46 patients with MRD less than 10^–4 leukemic cells (EFS, P = .004; CIR, P < .001). Intermediate-risk patients (strategic group S1) with MRD 10^–4 leukemic cells (n = 14) had a pEFS of 0.20 and CIR of 0.73, whereas patients with MRD less than 10^–4 leukemic cells (n = 21) had a pEFS of 0.68 and CIR of 0.09 (EFS, P = .020; CIR, P < .001). High-risk patients (S3/4, third complete remission) who received transplantation with an MRD load of less than 10^–4 leukemic cells (n = 25) showed a pEFS and CRI of 0.53 and 0.18, respectively. In contrast, pEFS and CRI were 0.30 and 0.50 in patients who received transplantation with an MRD load of 10^–4 leukemic cells. Multivariate Cox regression analysis revealed MRD as the only independent parameter predictive for EFS (P = .006).

Conclusion MRD is an important predictor for post-transplantation outcome. As a result, new strategies with modified stem-cell transplantation procedures will be evaluated in ALL-BFM trials.

published online ahead of print at www.jco.org on December 8, 2008

Supported by the Wilhelm Sander Stiftung, München, Germany (P.B.) and the Deutsche Kinderkrebsstiftung, Bonn, Germany (Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster Study Group).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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