Demographic and baseline disease characteristics were collected at baseline. 30 Only patients with BCR-ABL transcripts e13a2 (previously b2a2), e14a2 (previously b3a2), and coexpressed e13a2 (b2a2) with e14a2 (b3a2) were included in the analyses. Response criteria were as previously described. Real-time polymerase chain reaction was generally assessed every 3 months for the first year and then every 6 months. Eligibility criteria, follow-up, and response assessment were similar for all trials: cytogenetic analysis every 3 months for the first year, then every 6 months for the next 2 to 3 years, and then every 1 to 2 years.
Patients were treated on protocols approved by the institutional review board, and informed consent was obtained in accordance with the Declaration of Helsinki. 6, 9-13 More rarely, other variants such as e14a3 (b3a3) 14 and e8a2 transcripts 15 are described.Īll patients with chronic phase CML enrolled in consecutive or parallel clinical trials at The MD Anderson Cancer Center using TKI as front-line therapy from Jto Septemwere included in this analysis. Less frequently, the break in BCR occurs between exons 1 and 2, generating the e1a2 transcript, which codes for a 190-kDa protein, or between exons 19 and 20, generating the e19a2 transcript that codes for a 230-kDa protein. In some patients, both transcripts can be coexpressed: e13a2 (b2a2) with e14a2 (b3a2).
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These breakpoints result in various BCR-ABL rearrangements, most commonly the e13a2 (b2a2) and e14a2 (b3a2), which code for a 210-kDa protein: p210. 6-8 The breakpoint in the ABL1 gene is usually located between exons a1 and a2. 4, 5 The breakpoints in the BCR gene on chromosome 22 most commonly occur between exons e12 (b2) and e13 (b3) or between e13 (b3) and e14 (b4), in the major breakpoint cluster region (M-BCR), generating 2 slightly different chimeric transcripts. 1-3 This balanced reciprocal translocation results in the formation of the BCR-ABL1 oncogene, which is translated into a protein with constitutive tyrosine kinase activity, possibly the most effectively therapeutically targeted oncoprotein. The Philadelphia (Ph) chromosome resulting from the balanced reciprocal translocation between chromosomes 9 and 22 t(9 22)(q34 q11.2) is the cytogenetic hallmark of chronic myeloid leukemia (CML). Compared to e13a2 transcripts, patients with e14a2 (alone or with coexpressed e13a2) achieved earlier and deeper responses, predicted for optimal European Leukemia Net (ELN) responses (at 3, 6, and 12 months) and predicted for longer event-free and transformation-free survival. 043 e14a2) and transformation-free survival ( P =. The type of transcript also predicted for improved probability of event-free ( P =. In multivariate analysis, e14a2 and both predicted for optimal responses at 3, 6, and 12 months.
Median (international scale) levels of transcripts e13a2, e14a2, and both at 3 months were 0.2004, 0.056, and 0.0612 and at 6 months were 0.091, 0.0109, and 0.0130, respectively. The proportion of patients with e13a2, e14a2, and both achieving complete cytogenetic response at 3 and 6 months was 59%, 67%, and 63% and 73%, 81%, and 82%, respectively, whereas major molecular response rates were 27%, 49%, and 50% at 3 months, 42%, 67%, and 70% at 6 months, and 55%, 83%, and 76% at 12 months, respectively. Two hundred patients expressed e13a2 (42%), 196 (41%) expressed e14a2, and 85 (18%) expressed both transcripts. This study involved 481 patients with chronic phase CML expressing various BCR-ABL transcripts. The impact of the type of transcript on response and survival after initial treatment with different tyrosine kinase inhibitors is unknown. The most common breakpoint cluster region gene-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) transcripts in chronic myeloid leukemia (CML) are e13a2 (b2a2) and e14a2 (b3a2).