Researchers have found that a particular BCR-ABL transcript variant called e13a2 in chronic myeloid leukemia (CML) reduces the achievement of a deep molecular response to tyrosine kinase inhibitor (TKI) treatment and the probability of remaining in remission after treatment cessation.

BCR-ABL variants, which incorporate the Philadelphia chromosome, can differ depending on where exactly chromosome 22 and chromosome 9 are fused together. Those with the e13a2 transcript have BCR exon 13 fused to ABL exon 2, whereas those with e14a2 have BCR exon 14 fused to ABL exon 2, resulting in a marginally longer transcript.

Several previous studies have described how the e13a2 transcript (b2a2) confers a worse prognosis compared with the e14a2 (b3a2) transcript, but a new study published in Cancer investigated the effect of transcript variant on the probability of achieving a sustained deep molecular response (sDMR).1

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The researchers evaluated 173 people with CML, finding that 39% had the e13a2 BCR-ABL transcript and 61% had the e14a2 transcript. At 60 months following treatment initiation with TKIs, a sDMR was achieved by 48% of CML patients with e14a2, but only 22% of patients with e13a2.

“We demonstrate a significant negative influence of e13a2 transcript on sustained deep molecular response,which is a fundamental prerequisite for discontinuation of TKI treatment,” said Mirko Farina, MD, resident in hematology at the University of Brescia, Italy, and first author of the paper.

After the early significant successes of TKI therapy in managing CML, many patients in remission now want to come off TKIs entirely. The criteria for any attempt to suspend treatment is currently 2 years of a DMR, defined as when BCR-ABL transcripts are present at a level of less than 10-4 in peripheral blood samples.2 

Among 60 patients in the study who achieved as DMR, 51 decided to suspend their TKI treatment. After 12 months off TKI therapy, 61% of CML patients with the e14a2 transcript were still in treatment-free remission, but only 22% of those with the e13a2 transcript were.

“The probability of achievement of a clinical response and stopping TKI treatment was significantly influenced by the type of BCR-ABL transcript, and different transcripts can influence the achievement of deep molecular response,” said Dr Farina.