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

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).

Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights

“…In patients who received imatinib (frontline, after or in combination with IFN-α; Table 3 ), most studies concluded for higher and earlier molecular response rates in favor of e14a2 compared to e13a2 [ 90 , 93 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. Regarding the possible role of the transcript type on the long-term outcomes investigated in some of these studies, there was no evidence of a significant impact in the majority of cases [ 90 , 91 , 92 , 94 , 102 , 105 ].…”

Prospective monitoring of chronic myeloid leukemia patients from the time of TKI discontinuation: the fate of peripheral blood CD26+ leukemia stem cells

“…The immune system also appears to have a predictive role in higher TFR success since it has been suggested that higher levels of NK cells may be able to eradicate Leukemia Stem Cells (LSCs) and potentiate adaptive immune responses (Hughes and Yong, 2017;Ureshino et al, 2017;Irani et al, 2020;Hsieh et al, 2021). Some studies focused attention on the type of BCR::ABL1 transcript, hypothesizing that the e13a2 transcript has higher risks of molecular relapse compared to e14a2 (Claudiani et al, 2017;Chen et al, 2022). Instead, in terms of prognostic scores, a low-risk Sokal score has better progressionfree survival (PFS) and overall survival (OS), with high TFR rate, while the ELTS score could not be predictive of TFR success.…”

Fine‐tuning of frontline tyrosine kinase inhibitor (TKI) therapy in chronic‐phase chronic myeloid leukemia: The choice of the right TKI for the right patient

“…15,16 It was also shown that rates of MMR in patients with e14a2 transcripts treated with imatinib were comparable to those of patients receiving 2G-TKIs. 17 So, in addition to other factors including age, comorbidities, and risk scores, transcript type might also influence the selection of frontline TKI therapy, and patients with e14a2 transcripts could reduce risk stratification to a certain extent 16 and thereby receive effective imatinib therapy with relatively less toxicity, whereas choosing 2G-TKIs might be a convenient approach in patients with CML with the e13a2 transcript. 15 Another important issue in the decision of convenient medication is affordability, particularly in patients in whom treatment may continue throughout their lifetime.…”

“…It was also shown that rates of MMR in patients with e14a2 transcripts treated with imatinib were comparable to those of patients receiving 2G‐TKIs 17 . So, in addition to other factors including age, comorbidities, and risk scores, transcript type might also influence the selection of frontline TKI therapy, and patients with e14a2 transcripts could reduce risk stratification to a certain extent 16 and thereby receive effective imatinib therapy with relatively less toxicity, whereas choosing 2G‐TKIs might be a convenient approach in patients with CML with the e13a2 transcript 15 …”

“…Although not mentioned in this study, 8 BCR::ABL1 transcript variants in patients with CML may affect TKI responses and long‐term outcomes that might play a role in TKI selection. Studies revealed that the presence of e14a2 at diagnosis is relevant, with higher molecular response rates including DMR when compared to those with e13a2, and expression of e14a2 might even have a positive impact on successful TFR 15,16 . It was also shown that rates of MMR in patients with e14a2 transcripts treated with imatinib were comparable to those of patients receiving 2G‐TKIs 17 .…”