E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy

Abstract

E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy Treatment-free remission (TFR) is a new therapy goal for patients with chronic phase chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs), with approximately 40% sustaining deep molecular responses after stopping treatment.1-3 However, it is difficult to predict precisely who will achieve TFR and the subject remains controversial.3 We present data from 64 patients who stopped TKI therapy. Data show a significant association between the type of BCR-ABL1 transcript and age on the probability of TFR.Subjects were in 1 st chronic phase and had a deep molecular response (≥MR4 on the International Scale) for one year or more before stopping TKI therapy, equivalent to the eligibility criteria of the Euro-Ski trial. 4Molecular response level was calculated by standard criteria 5 and molecular relapse defined as loss of MR3. Time to molecular relapse was measured from the date of TKI discontinuation to the first of 2 or more consecutive quantitative real-time polymerase chain reaction (qRT-PCR) assessments confirming less than MR3.Treatment-free remission was defined as the interval between the date of stopping TKI therapy and the date of molecular relapse or, if this did not happen, the date of last contact. Continuous variables were dichotomized to assess prognostic values for TFR using the median value. Sensitivity analysis was performed for these variables excluding outlier values. To explore the impact of age, we interrogated cut-off points at the median age (51 years) and at ages 40 and 60 years. P<0.05 (two-tailed) was considered significant. Potential predictive variables for TFR were analyzed in univariate analysis using the KaplanMeier method. Only statistically significant variables were included in multivariate analysis using a Cox proportional hazard regression model. Subject-, disease-and therapy-related variables before stopping TKI therapy are shown in Table 1. Median follow up from stopping TKI therapy was 26 months (range 6-121 months). Forty-one subjects [64%; 95% confidence interval (CI): 53, 75%)] stopped TKI because of intolerance, 7 (11%; 95%CI: 5, 19%) in order to conceive, and 16 (25%; 95%CI: 14, 36%) were elected to stop treatment on achieving a sustained deep response. At the time of discontinuing TKI, 32 subjects (50%; 95%CI: 38, 63%) were receiving imatinib and 32 (50%; 95%CI: 38, 63%), dasatinib or nilotinib. The frequency of patients with e13a2 (42%) or e14a2 transcripts (58%) is similar to that reported within the European LeukemiaNet (ELN) registry, at 45% and 55%, respectively. 6Thirty-seven subjects (58%; 95%CI: 45, 70%) remain in molecular remission at a median of 26 months (range 7-64 months) after stopping TKI therapy. The 3-year actuarial probability of TFR is 53% (95%CI: 38, 66%). Twenty-seven subjects (42%; 95%CI: 30, 55%) had a molecular relapse at a median of four months (range 1...

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

“…According to these data and to a recently reported, retrospective study of selected patients, 28 the transcript type should be added to the list of prognostic factors that have been associated with a higher risk of TFR failure. 29 It is noteworthy that neither age, nor Sokal risk score, nor the duration of TKI therapy or of DMR significantly influenced the risk of DMR loss in our series.…”

The impact of BCR‐ABL1 transcript type on tyrosine kinase inhibitor responses and outcomes in patients with chronic myeloid leukemia

“…Thirteen patients received upfront 2GTKI treatment. After TKI discontinuation, 37 patients (58%) sustained molecular remission at a median of 26 months, and patients with the e13a2 transcript demonstrated inferior results compared with the e14a2 group (45% vs 70%) . The 3‐year probability of TFR was 53% for the entire cohort, and this percentage was higher for patients with the e14a2 transcript compared with those with the e13a2 transcript (66% vs 38%, respectively).…”

“…In a recent study, Claudiani et al analyzed 37 patients with the e14a2 transcript and 27 patients with the e13a2 transcript who achieved and maintained MR 4 or MR 4.5 for at least 12 months and then discontinued TKI therapy. Thirty‐two patients received imatinib, 17 patients were treated with nilotinib, and the remaining 15 patients were receiving dasatinib at the time of TKI cessation.…”

“…The incidence rates of the BCR‐ABL1 transcript types gathered from the full‐text articles are given in Table . Of 26 articles, 22 (85%) showed a higher incidence of the e14a2 transcript whereas only 4 articles demonstrated a higher incidence of the e13a2 transcript.…”

“…The 3‐year probability of TFR was 53% for the entire cohort, and this percentage was higher for patients with the e14a2 transcript compared with those with the e13a2 transcript (66% vs 38%, respectively). Having the e14a2 transcript and being aged ≥40 years at the time of diagnosis were marked as positive predictors of TFR ( P = .016 for the e14a2 vs e13a2 transcript and P = .003 for age ≥40 years vs age <40 years) …”