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 beta-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/beta-actin decrease was > or =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 x 10(-2):10(-4)). In relapsed ALL, TEL-AML1/beta-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/beta-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.
Seeger
K
K
Department of Pediatric Oncology/Hematology, Otto-Heubner-Centrum Berlin, Germany. karl.seeger@charite.de
Kreuzer
K A
KA
Lass
U
U
Taube
T
T
Buchwald
D
D
Eckert
C
C
Körner
G
G
Schmidt
C A
CA
Henze
G
G
D000199:Actins / Q000235:genetics; D002138:Calibration; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit; D005260:Female; D005453:Fluorescence; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D016896:Treatment Outcome; D000097764:ETS Translocation Variant 6 Protein
D000199:Actins; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein