The e13a2 BCR‐ABL transcript negatively affects sustained deep molecular response and the achievement of treatment‐free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors

Abstract

Background Stopping tyrosine kinase inhibitor (TKI) treatment has become a realistic and safe objective for patients who have chronic myeloid leukemia (CML). Both a sustained deep molecular response (sDMR) and the lack of a molecular recurrence after TKI discontinuation are required to reach a durable treatment‐free remission (TFR). Methods The potential predictive role of BCR‐ABL transcripts in attaining an sDMR and a TFR was analyzed in a strictly consecutive, unselected series of 194 patients who were diagnosed and treated with TKIs at the authors’ center. Results Of 173 fully evaluable patients, 67 (38.7%) had the e13a2 transcript, and 106 (61.3%) had the e14a2 transcript. Complete cytogenetic and major molecular remissions were not affected, whereas the achievement of both a DMR (P = .008) and an sDMR (P = .004) was favored significantly in patients who had the e14a2 transcript. After a median of 68 months, the sDMR rate was 39.6% in those with the e14a2 transcript and 19.4% in those with the e13a2 transcript. In addition to transcript type, both the early achievement of a molecular response and starting treatment with a second‐generation TKI positively affected the attainment of an sDMR in multivariate analysis. The use of a second‐generation TKI as frontline treatment increased the sDMR rate in both transcript types. However, in patients who had the e13a2 transcript, the probability of attaining an sDMR was 37% after 60 months and did not increase further despite continuing therapy. Among 51 of 60 patients who attained an sDMR after discontinuing TKIs, 24 experienced a molecular relapse, but all regained molecular remission after resuming TKI treatment. Again, transcript type influenced TFR maintenance (P = .005), because only 2 patients (3%) with the e13a2 transcript enjoyed a durable TFR compared with 25 (23.5%) of those with the e14a2 transcript. Conclusions The e13a2 transcript hinders the achievement of deep responses and the possibility of stopping TKI treatment in patients with CML.

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when and for whom?

“…44 In one study by D'Adda et al, the rates of a sustained DMR and maintaining TFR were 39.6% versus 19.4% and 61% versus 22% for patients with e14a2 versus e13a2 transcripts, respectively. 45 • Depth of response is also emerging as an important factor in predicting successful TFR. In the DESTINY trial, 2 in which patients with BCR-ABL1 <0.1% were enrolled, a dose de-escalation phase was included.…”

Tyrosine Kinase Inhibitor Therapy Discontinuation for Patients with Chronic Myeloid Leukaemia in Clinical Practice

“…There is some evidence that RFS after stopping TKI may be better in patients with the e14a2 form of BCR-ABL1 transcript than in those with the e13a2 form [45,46], though this finding is not universal. It is unclear whether this is real or due to a PCR artefact whereby a given level of e13a2 burden may appear higher than for e14a2, thus disproportionately lowering any relapse threshold in e13a2 patients.…”

Patient-Initiated Discontinuation of Tyrosine Kinase Inhibitor for Chronic Myeloid Leukemia

“…Interest has focussed on the influence of the BCR-ABL1 transcript type on response to first-line TKI with the patients expressing e14a2 transcripts having superior molecular responses to those harboring e13a2 transcripts; however, the impact on overall survival remains unclear [23,24]. is theory has been extrapolated to those patients attempting TFR with one recent study suggesting that the e14a2 BCR-ABL1 transcript, as expressed in the above case, favourably impacts on sustained TFR upon TKI discontinuation [25]. 2 Case Reports in Hematology e initial molecular response to TKI in this case was slow and would be considered as a warning under current European LeukemiaNet guidelines, yet this did not prevent the patient achieving a subsequent TFR [26].…”