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Comparative Study
. 2009 Oct;94(10):1362-7.
doi: 10.3324/haematol.2009.009134. Epub 2009 Aug 27.

Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

Claire M Lucas  1 , Robert J Harris, Athina Giannoudis, Andrea Davies, Katy Knight, Sarah J Watmough, Lihui Wang, Richard E Clark
Affiliations
Comparative Study

Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

Claire M Lucas et al. Haematologica. 2009 Oct.

Abstract

Background: Chronic myeloid leukemia is characterized by a reciprocal translocation between chromosomes 9 and 22, creating the fusion gene BCR-ABL. The clinical significance of the type of BCR-ABL transcript in newly diagnosed patients in chronic phase treated with imatinib 400 mg from initial diagnosis remains unknown.

Design and methods: We analyzed the clinical outcome of 78 newly diagnosed chronic phase patients, aged 16 or over, treated with imatinib 400 mg. Of these, 71 expressed either e13a2 or e14a2 transcripts. BCR-ABL transcripts were assayed by quantitative real-time polymerase chain reaction.

Results: After 12 months of treatment, 54% of the e14a2 patients had achieved a complete cytogenetic response, compared to 25% of the e13a2 patients (p=0.01). Kaplan-Meier analysis of the time to achieve complete cytogenetic response revealed that e14a2 patients had more rapid response rates, compared to e13a2 patients (p=0.006). e14a2 patients had a higher event-free survival rate in the first 12 months of treatment, although overall survival did not differ significantly between the patients with the two types of transcript. Human organic cation transporter protein 1 mRNA levels did not differ between the patients with the two types of transcript. The pre-treatment pCrKL/CrKL ratio (a surrogate marker of BCR-ABL tyrosine kinase activity) was higher in patients with e13a2 transcripts than in those with e14a2 (p=0.017).

Conclusions: Patients expressing the e14a2 transcript type have a higher rate and more rapid complete cytogenetic responses than e13a2-expressing patients, which may be due to higher BCR-ABL tyrosine kinase activity. Knowledge of the transcript type may yield additional prognostic information, although this requires testing on larger datasets.

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Figures

Figure 1.
Figure 1.
Kaplan Meier plots. (A) Kaplan Meier estimate of time to achieve CCRe for patients with the e13a2 and e14a2 BCR-ABL transcripts, demonstrating a slower response for e13a2 patients (p=0.006). (B) Overall survival stratified by BCR-ABL transcript type and (C) event-free survival; no statistically significant differences were observed (SPSS statistical package Mantel-Cox log-rank test).
Figure 2.
Figure 2.
pCrKL/CrKL ratio for patients with the e13a2 and e14a2 transcripts pCrKL/CrKL ratio was measured in 28 newly diagnosed chronic CML patients prior to treatment as a surrogate marker for BCR-ABL tyrosine kinase activity, the pCrKL/CrKL ratio was higher in e13a2 patients than in e14a2 patients.
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Comment in

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