Favorable outcome in patients with chronic myeloid leukemia co-expressing E13A2 transcript treated frontline with nilotinib

Background: 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-ABL). The p210kda protein is most frequently encoded. Depending on alternative splicing, different transcripts have been described, such as e13a2, e14a2. Approximately 10-15% of patients carry both transcripts at diagnosis. So far, no data have been reported on the clinical outcome of CML patients co-expressing e13a2 and e14a2, and treated with second generation tyrosine kinase inhibitors (TKI). Aims: The primary objective of this study was to evaluate the cumulative incidence of deep molecular response (MR4) in CML patients co-expressing at diagnosis e13a2 and e14a2 treated frontline with nilotinib, and to compare it with patients carrying a single transcript. Progression-free survival (PFS) represented a secondary endpoint. Methods: We evaluated a consecutive series of CML patient in chronic phase treated frontline with nilotinib 300 mg bid between July 2007 and July 2017 in 19 Italian centers. Only patients co-expressing e13a2 and e14a2 were considered. MR4 or more were considered as deep molecular responses (DMR) and MR3 as a major molecular response. PFS was defined as the time elapsed between the start of nilotinib and one of the following events: death, resistance to treatment or change of TKI due to loss of molecular response. Results: A total of 183 patients were recruited. The median follow-up was 44 months (range 2-64). One hundred and two patients (56%) were male. The mean age at diagnosis was 50 years (18-81). Overall, 51 patients (28%) expressed the e13a14 transcript, 108 patients (59%) expressed e14a2 and 24 (13%) expressed both transcripts. Patients co-expressing both transcripts had a significantly higher incidence of DMR compared to patients carrying the e14a2 and e13a2 transcript alone: 100% vs 80.3±5% and 80.7±6.6%, respectively, p = 0.037 (Fig. 1). In multivariate analysis, considering as independent variables gender, age, transcript type and Sokal risk, only co-expression was significantly associated with a DMR (p = 0.008, HR = 1.94 95% CI = 1.18-3.19). The 60-month overall survival (OS) was 98.8±0.8% and the 60-month PFS was 97.8±1%. No significant differences in OS and PFS were found between patients harboring the different transcripts (e13a2 vs e14a2 vs both). Summary/Conclusion: Our results underline the importance of a precise identification of the BCR-ABL transcript at the time of CML diagnosis. Co-expression of e13a2 and e14a2 might have an important impact in the achievement of a DMR in patients treated with nilotinib frontline and could become an additional criterion of TKI choice, particularly at a time when treatment-free remission is becoming an increasing treatment endpoint. Further studies are needed on this CML subgroup.