Introduction. Chronic myeloid leukemia (CML) is characterised by a reciprocal translocation between the long arms of chromosome 9 and chromosome 22 leading to formation of a fusion hybrid gene (BCR-ABL). The p210kda protein is the most frequently encoded. Depending on alternative splicing, different transcripts have been described, such as e13a2, e14a2. Interestingly, around 10-15% of CML patients are carriers of both transcripts at diagnosis. To now, no data on clinical outcome of CML patients co-expressing e13a2 and e14a2, and treated with second generation Tyrosine Kinase Inhibitor (TKI) have been reported. Objectives. The primary objective was to evaluate the cumulative incidence of deep molecular response (MR4) in CML patients co-expressing at diagnosis e13a2 and e14a2, in comparison with patients carrying a single transcript. Secondary aim was to evaluate the progression free survival (PFS). Methods. We evaluated consecutive CML patient in chronic phase, treated frontline with Nilotinib 300 mg bid, between July 2007 and July 2017 in 19 Italian centres. Only patients with e13a2, e14a2 and their co-expression were considered. Deep molecular response (DMR) was defined as achieving MR4 or deeper; MR3 was considered a major molecular response. PFS was defined as the time elapsed between start of nilotinib and one of following events: death, resistance to treatment or change 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 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 with e14a2 and e13a2 expression alone (100% vs 80.3±5% and 80.7±6.6% respectively, p=0.037), figure 1. In multivariate analysis, considering as independent variables sex, age, transcript type and Sokal risk, only co-expression was confirmed significantly associated with DMR (p=0.008, HR=1.94 95% CI=1.18-3.19). Overall, the 60-month overall survival (OS) was 98.8±0.8% and the 60-month PFS was 97.8±1%. No significant differences were found between OS and PFS according to different transcripts (e13a2 vs e14a2 vs both). Conclusions. Our results suggest the importance of a properly identification of BCR-ABL transcript at CML diagnosis. Co-expression of e13a2 and e14a2 might have an important role in the achievement of DMR in patients treated with nilotinib frontline and could become an additional criterion to address TKI choice for the patient, also in prospective of a treatment free remission strategy (TFR). Further studies are needed on this CML subgroup.
Favorable outcome of chronic myeloid leukemia co-expressing e13a2 and e14a2 transcripts, treated with nilotinib
Bonifacio, Massimiliano;Scaffidi, Luigi;
2020-01-01
Abstract
Introduction. Chronic myeloid leukemia (CML) is characterised by a reciprocal translocation between the long arms of chromosome 9 and chromosome 22 leading to formation of a fusion hybrid gene (BCR-ABL). The p210kda protein is the most frequently encoded. Depending on alternative splicing, different transcripts have been described, such as e13a2, e14a2. Interestingly, around 10-15% of CML patients are carriers of both transcripts at diagnosis. To now, no data on clinical outcome of CML patients co-expressing e13a2 and e14a2, and treated with second generation Tyrosine Kinase Inhibitor (TKI) have been reported. Objectives. The primary objective was to evaluate the cumulative incidence of deep molecular response (MR4) in CML patients co-expressing at diagnosis e13a2 and e14a2, in comparison with patients carrying a single transcript. Secondary aim was to evaluate the progression free survival (PFS). Methods. We evaluated consecutive CML patient in chronic phase, treated frontline with Nilotinib 300 mg bid, between July 2007 and July 2017 in 19 Italian centres. Only patients with e13a2, e14a2 and their co-expression were considered. Deep molecular response (DMR) was defined as achieving MR4 or deeper; MR3 was considered a major molecular response. PFS was defined as the time elapsed between start of nilotinib and one of following events: death, resistance to treatment or change 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 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 with e14a2 and e13a2 expression alone (100% vs 80.3±5% and 80.7±6.6% respectively, p=0.037), figure 1. In multivariate analysis, considering as independent variables sex, age, transcript type and Sokal risk, only co-expression was confirmed significantly associated with DMR (p=0.008, HR=1.94 95% CI=1.18-3.19). Overall, the 60-month overall survival (OS) was 98.8±0.8% and the 60-month PFS was 97.8±1%. No significant differences were found between OS and PFS according to different transcripts (e13a2 vs e14a2 vs both). Conclusions. Our results suggest the importance of a properly identification of BCR-ABL transcript at CML diagnosis. Co-expression of e13a2 and e14a2 might have an important role in the achievement of DMR in patients treated with nilotinib frontline and could become an additional criterion to address TKI choice for the patient, also in prospective of a treatment free remission strategy (TFR). Further studies are needed on this CML subgroup.
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