Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time quantitative reverse transcriptase-polymerase chain reaction study.
BACKGROUND
The translocation t(12;21)(p13;q22), which produces the TEL/AML1 fusion gene, is the most frequent chromosomal abnormality in patients with childhood acute lymphoblastic leukemia (ALL) and generally is associated with a favorable prognosis. Furthermore, real-time quantitative-polymerase chain reaction (RQ-PCR)-based detection of TEL/AML1 represents an accurate technique for the reproducible assessment of minimal residual disease (MRD).


METHODS
The authors employed RQ-reverse transcriptase-PCR (RQ-RT-PCR) technology to analyze MRD levels in 57 newly diagnosed patients with TEL/AML1 positive ALL in a prospective study.


RESULTS
On Day + 33, a particularly important time point in terms of outcome prediction based on MRD monitoring, 75% of patients reached negativity, 13% of patients were positive at very low levels (< 10(-4); i.e., 1 or more leukemic cell per 10(4) normal cells), and another 13% of patients were positive at the level of 10(-2) to 10(-4) cells. No patient showed MRD levels > or = 10(-2) cells at this time. The data demonstrate that patients with TEL/AML1 positive ALL had a better response to induction chemotherapy on Day + 33 compared with a group of unselected patients with ALL (P = 0.0001). However, four patients with TEL/AML1 positive ALL developed relapse disease. Remarkably, these children were positive for MRD on Day + 33 at a level between 10(-2) cells and 10(-4) (n = 3 patients) and at < 10(-4) (n = 1 patient). Kaplan-Meier analysis of disease free survival showed the statistical significance of this distribution (MRD positive vs. MRD negative; log-rank P = 0.0016).


CONCLUSIONS
The authors conclude that, although the TEL/AML1 positive leukemias generally are associated with a favorable outcome, MRD positivity assessed by RQ-RT-PCR analysis at the end of induction therapy represents a significantly negative prognostic feature.
Madzo
Jozef
J
Childhood Leukemia Investigation Prague, Prague, Czech Republic.
Zuna
Jan
J
Muzíková
Katerina
K
Kalinová
Markéta
M
Krejcí
Ondrej
O
Hrusák
Ondrej
O
Otová
Berta
B
Starý
Jan
J
Trka
Jan
J
D000293:Adolescent; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers / Q000737:chemistry; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018365:Neoplasm, Residual / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D016896:Treatment Outcome; D000097764:ETS Translocation Variant 6 Protein
D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein