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

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 β -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-Munster (BFM)-Study Group. In initial ALL, TEL-AML1/β -actin decrease was ≥10 5 -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 × 10 −2 :10 −4 ). In relapsed ALL, TEL-AML1/β -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 /β -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.