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Residual Disease Monitoring in Childhood Acute Myeloid Leukemia by Multiparameter Flow Cytometry: The MRD-AML-BFM Study Group

Claudia Langebrake, Ursula Creutzig, Michael Dworzak, Ondrej Hrusak, Ester Mejstrikova, Frank Griesinger, Martin Zimmermann, Dirk Reinhardt

From the Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover; Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster; Germany; Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria; Department of Immunology/Pediatric Hematology/Oncology, Charles University, Prague, Czech Republic; and the Department of Hematology and Oncology, University of Goettingen, Goettingen, Germany

Address reprint requests to Claudia Langebrake, PhD, Department of Pediatric Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; e-mail: langebrake.claudia{at}mh-hannover.de

PURPOSE: Monitoring of residual disease (RD) by flow cytometry in childhood acute myeloid leukemia (AML) may predict outcome. However, the optimal time points for investigation, the best antibody combinations, and most importantly, the clinical impact of RD analysis remain unclear.

PATIENTS AND METHODS: Five hundred forty-two specimens of 150 children enrolled in the AML-Berlin-Frankfurt-Muenster (BFM) 98 study were analyzed by four-color immunophenotyping at up to four predefined time points during treatment. For each of the 12 leukemia-associated immunophenotypes and time points, a threshold level based on a previous retrospective analysis of another cohort of children with AML and on control bone marrows was determined.

RESULTS: Regarding all four time points, there is a statistically significant difference in the 3-year event-free survival (EFS) in those children presenting with immunologically detectable blasts at 3 or more time points. The levels at bone marrow puncture (BMP) 1 and BMP2 turned out to have the most significant predictive value for 3-year-EFS: 71% ± 6% versus 48% ± 9%, P_Log-Rank = .029 and 70% ± 6% versus 50% ± 7%, P_Log-Rank = .033), resulting in a more than two-fold risk of relapse. In a multivariate analysis, using a combined risk classification based on morphologically determined blasts at BMP1 and BMP2, French-American-British classification, and cytogenetics, the influence of immunologically determined RD was no longer statistically significant.

CONCLUSION: RD monitoring before second induction has the same predictive value as examining levels at four different time points during intensive chemotherapy. Compared with commonly defined risk factors in the AML-BFM studies, flow cytometry does not provide additional information for outcome prediction, but may be helpful to evaluate the remission status at day 28.

Supported by grants from the Leukemia and Lymphoma Society (LLS 6180-02), Competence Network Pediatric Oncology and Haematology (KPOH, 01GI9963/2), and the José Carreras Foundation (SP 01/04).

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

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