Favorable outcome of chronic myeloid leukemia co‐expressing e13a2 and e14a2 transcripts, treated with nilotinib

Abstract

Chronic myeloid leukemia (CML) is characterized by a reciprocal translocation between the long arms of chromosome 9 and chromosome 22 leading to the formation of a fusion hybrid gene (BCR-ABL1) [t(9;22)(q34;q1.1)]. The BCR-ABL1 fusion gene includes the 5 0-end of the BCR gene (breakpoint cluster region) and the 3'-end of the ABL1 gene. Although the BCR and ABL1 genomic breakpoints are highly variable, the recombination usually involves the fusion of intron 13 or 14 of the BCR with a 140-kb region of ABL1 between exons 1b and 2. Regardless of the breakpoint location on the ABL1 gene, in 90% of cases, mRNA splicing gives rise to a major BCR-ABL1 transcripts with e13a2 (also known as b2a2) or e14a2 junctions (also known as b3a2). Both transcripts result in the expression of a 210-kDa BCR-ABL1 protein with a constitutively activated tyrosine kinase activity. 1 The coexpression of both transcripts, e13a2 and e14a2, may also be found. A recent international overview showed that the proportion of cases co-expressing e13a2 and e14a2 at diagnosis ranged between 1.1% and 26.9%. 2 The correlation between the transcript type, their coexpression, and the outcomes in CML patients has been rarely investigated, particularly with the first-generation tyrosine kinase inhibitor (TKI) imatinib. 3,4 So far, no data have been reported on the clinical outcome of CML patients co-expressing e13a2 and e14a2, and treated frontline with second-generation TKI at the frontline. The primary objective of this study was to evaluate the cumulative incidence of deep molecular response (DMR) in CML patients co-expressing

Impact of BCR-ABL1 Transcript Type on Outcome in Chronic Myeloid Leukemia Patients Treated With Tyrosine Kinase Inhibitors: A Pairwise and Bayesian Network Meta-Analysis

“…Among the 16 studies, 16 investigated the outcome differences between the e13a2 and e14a2 groups, and 8 the differences between the three groups (e13a2 vs e14a2 vs both) ( 9 , 12 – 15 , 19 , 22 , 31 ). The detailed characteristics of the studies and patients are given in Table 1 .…”

“…A total of 8 studies involving 2,880 patients were included in this part. Of these, DMR is defined as MR 4 in 4 studies (10,12,15,19), MR 4.5 in 3 studies (13,16,18), and MR 4 /MR 4.5 in 1 study (11). Compared to e13a2, the patients with e14a2 transcripts had a favorable effect on DMR at 6, 12, 18 and 60 months, with an OR of 2.13 (95% CI: 1.19-3.80, I 2 = 35.83%, 7 studies), 2.00 (95% CI: 1.36-2.95, I 2 = 44.64%, 8 studies), 1.84 (95% CI: 1.40-2.41, I 2 = 35.45%, 8 studies) and 2.21 (95% CI: 1.71-2.87, I 2 = 42.62%, 8 studies), respectively (Figure 4).…”

“…Event-free survival (EFS) was demonstrated to be the same in two studies ( 16 , 18 ), but to be significantly better in e14a2 patients in four studies ( 13 , 15 , 20 , 21 ). Progression-free survival (PFS) was demonstrated to be the same in three studies ( 11 , 12 , 19 ), but to be significantly better in e14a2 patients in two studies ( 13 , 15 ). Overall survival (OS) was demonstrated to be the same in seven studies ( 12 , 13 , 16 , 19 – 22 ), but to be significantly different in two ( 11 , 15 ).…”

“…Progression-free survival (PFS) was demonstrated to be the same in three studies (11,12,19), but to be significantly better in e14a2 patients in two studies (13,15). Overall survival (OS) was demonstrated to be the same in seven studies (12,13,16,(19)(20)(21)(22), but to be significantly different in two (11,15). To our knowledge, no meta-analysis has been conducted to summarize the conflicting evidence.…”

“…Six studies reported that e14a2 was a better predictor of deep molecular response (DMR) (10,12,13,15,16,18). However, Mulas et al (19) and Marce et al (11) showed that the transcript types did not affect DMR. In addition to molecular response, survival was also a major subject of debate.…”