Molecular quantification of response to therapy and remission status in TEL-AML1-positive childhood ALL by real-time reverse transcription polymerasechain reaction

Although TEL-AML1 positivity [translocation t(12;21)(p13;q22)], detected in 20-25% of initial childhood acute lymphoblastic leukemia (ALL), has been a ssociated with an excellent prognosis, its positive predictive value is ins ufficient for appropriate treatment stratification considering reported pre valence in relapsed ALL (3-28%), Molecular quantification of response to th erapy by PCR-based methods has been shown to improve risk assessment. Here, we report on the sensitive quantification of leukemia-specific TEL-AML1 fu sion transcript levels normalized to beta -actin expression (sensitivity th reshholds, 10(-5)) by a novel real-time reverse transcription-PCR (RQ-RT-PC R) based on fluorescent TaqMan technique providing early and rapid evidence on the treatment efficacy of children with initial or relapsed TEL-AM1(+) ALL enrolled in frontline or relapse trials of the Berlin-Frankfurt-Munster (BFM)-Study Group, In initial ALL, TEL-AML1/beta -actin decrease was great er than or equal to 10(5)-fold in 50% of patients after induction therapy ( day 33) and stayed TEL-AML1-negative throughout therapy, which suggested hi gh sensitivity of leukemic cells to antineoplastic therapy. The remaining p atients were still TEL-AML1(+) before reintensification (ratios, 0.7 x 10(- 2):10(-4)). In relapsed ALL, TEL-AML2/beta -actin decrease was generally le ss pronounced at corresponding time points, and conversion to TEL-AMl1 nega tivity was observed in 40% of patients. Most notably, subsequent relapses o ccurred only among molecular poor responders, whereas all early responders remain in their second complete remission. In conclusion, real-time quantif ication of TEL AML1/beta -actin kinetics distinguishes distinct molecular r esponse groups, and provides indications capable of directing therapeutic i nterventions for patients with TEL-AML1(+) ALL. Before considering modifica tion of therapy, results should be interpreted cautiously taking into accou nt the long duration of remission associated with TEL-AML1(+) ALL.