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Molecular Quantification of Response to Therapy and Remission Status in TEL-AML1-Positive Childhood ALL by Real-Time Reverse Transcription Polymerase Chain Reaction¹

Department of Pediatric Oncology/Hematology, Otto-Heubner-Centrum [K. S., T. T., D. B., C. E., G. K., G. H.], and Department of Internal Medicine, Hematology/Oncology [K-A. K., U. L., C-A. S.], Charité Medical Center, Campus Virchow, Humboldt-University at Berlin, Berlin, Germany 13353

Although TEL-AML1 positivity [translocation t(12;21)(p13;q22)], detected in 20–25% of initial childhood acute lymphoblastic leukemia (ALL), has been associated with an excellent prognosis, its positive predictive value is insufficient for appropriate treatment stratification considering reported prevalence in relapsed ALL (3–28%). Molecular quantification of response to therapy by PCR-based methods has been shown to improve risk assessment. Here, we report on the sensitive quantification of leukemia-specific TEL-AML1 fusion transcript levels normalized to ß-actin expression (sensitivity threshholds, 10^-5) by a novel real-time reverse transcription-PCR (RQ-RT-PCR) based on fluorescent TaqMan technique providing early and rapid evidence on the treatment efficacy of children with initial or relapsed TEL-AML1⁺ ALL enrolled in frontline or relapse trials of the Berlin-Frankfurt-Münster (BFM)-Study Group. In initial ALL, TEL-AML1/ß-actin decrease was 10⁵-fold in 50% of patients after induction therapy (day 33) and stayed TEL-AML1-negative throughout therapy, which suggested high sensitivity of leukemic cells to antineoplastic therapy. The remaining patients were still TEL-AML1⁺ before reintensification (ratios, 0.7 x 10^-2:10^-4). In relapsed ALL, TEL-AML1/ß-actin decrease was generally less pronounced at corresponding time points, and conversion to TEL-AML1 negativity was observed in 40% of patients. Most notably, subsequent relapses occurred only among molecular poor responders, whereas all early responders remain in their second complete remission. In conclusion, real-time quantification of TEL-AML1/ß-actin kinetics distinguishes distinct molecular response groups, and provides indications capable of directing therapeutic interventions for patients with TEL-AML1⁺ ALL. Before considering modification of therapy, results should be interpreted cautiously taking into account the long duration of remission associated with TEL-AML1⁺ ALL.

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