Abstract
PurposeTo evaluate the impact of BCR-ABL1 transcript type on outcome in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs).MethodsPubMed, Embase and Cochrane library were systematically searched for relevant studies. Outcomes assessed were: major molecular response (MMR) at 6, 12, 18 and 60 months, deep molecular response (DMR) at 6, 12, 18 and 60 months, event-free survival (EFS), progression-free survival (PFS), overall survival (OS) and treatment-free remission (TFR). Odds ratios (ORs) and hazard ratios (HRs) were estimated and pooled using a random effect model.ResultsA total of 16 retrospective cohort studies involving 5,411 patients were included in this study. Compared with e13a2 transcripts, there was a statistically significant advantage for patients with e14a2 (alone or with co-expressed e13a2) in terms of MMR and DMR at 6, 12 and 18 months. This benefit was sustained up to 5 years for patients with e14a2 transcripts (OR 1.60, 1.23-2.07 and 2.21, 1.71-2.87, respectively), but not for patients with both transcripts. The expression of e14a2 also improved EFS (HR 0.71, 0.53-0.94) and OS (HR 0.76, 0.57-1.00) throughout treatment period. Importantly, having e14a2 transcripts were associated with a higher rate of TFR (OR 2.94, 1.70-5.08) in CML patients attempting TKI discontinuation. Bayesian network meta-analysis showed that e14a2 had the highest probability to be the most favorable transcript type for all outcomes, followed by both and e13a2.ConclusionsThe expression of e14a2 had a positive impact on MMR, DMR, EFS, OS and TFR. We suggest that in the future, the e14a2 transcript can be added to the list of prognostic factors to guide clinical decisions in treating CML.Systematic Review Registration[https://www.crd.york.ac.uk/PROSPERO/#myprospero], identifier PROSPERO (CRD42021288440).
Highlights
A reciprocal translocation between chromosomes 9 and 22 results in the fusion gene BCR-ABL1, which is the genetic hallmark of chronic myeloid leukemia (CML) [1, 2]
Having e14a2 transcripts were associated with a higher rate of treatment-free remission (TFR) in CML patients attempting tyrosine kinase inhibitors (TKIs) discontinuation
Our meta-analysis indicated that the deep molecular response (DMR) at 60 months was still higher in the e14a2 arm, suggesting 121% more patients expressing e14a2 transcripts qualified for entering TFR phase compared to those expressing e13a2 transcripts
Summary
A reciprocal translocation between chromosomes 9 and 22 results in the fusion gene BCR-ABL1, which is the genetic hallmark of chronic myeloid leukemia (CML) [1, 2]. The co-expression of both transcripts (e14a2 and e13a2) can be found in approximately 5-10% of patients Both transcripts are translated into constitutively active proteins of 210 kDa which serve as targets for tyrosine kinase inhibitors (TKIs). One possible hypothesis for the causes of resistance to TKIs could be due to the different protein tyrosine kinases (i.e., e13a2 and e14a2) that differ from one another by 75 base pairs. This structural difference may be related to the rates of transcription and translation, and the affinity of protein tyrosine kinases to TKIs, which may affect the response to TKI treatment [8]. Transcript type could be used to guide clinical decisions in treating CML, especially at a time when treatment-free remission (TFR) is becoming the ultimate goal of therapy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
