E14a2 and e14a2+e13a2 BCR-ABL Transcripts Are Associated with Earlier Cytogenetic and Molecular Response Rates in CML-CP Treated with Imatinib

Background: The prognostic significance of BCR-ABL1 transcripts in chronic myeloid leukemia (CML) is still controversial. Methods: All consecutive CML patients in chronic phase treated with Glivec between January 2010 and December 2011 and generic imatinib between January 2015 and February 2017 from 8 Brazilian centers were analyzed. BCR-ABL1 transcripts were evaluated by multiplex qualitative RT-PCR. Only patients with BCR-ABL transcripts e13a2 and/or e14a2 were included in this analysis. All patients started imatinib less than six months from diagnosis. Study data were collected and managed using REDCap electronic data capture tools. Demographic data were collected at diagnosis: age, gender, blood cell counts, Sokal, Hasford and EUTOS score, cytogenetics and BCR-ABL transcript type. The definition of the responses followed the European Leukemia Net 2013 criteria. Event-free survival (EFS) was measured from starting of treatment until loss of complete hematologic remission, loss of complete cytogenetic response (CCyR), loss of major (MMR), progression to accelerated (AP) or blast phase (BC), or death from any cause at any time after initial therapy. Overall survival (OS) was measured from starting of imatinib until last follow-up or date of death from any cause at any time. Progression-free survival (PFS) was measured from date of imatinib starting to transformation to AP or BC or deaths while on therapy. SPSS 21.0 software (IBM Corp., Armonk, NY, USA) was used for chi-square, t-test, ANOVA, when adequate, considering p-value <0.05 as significant.

Results

191 CML-CP patients treated with imatinib (121 Glivec and 70 generic imatinib) were analyzed. Patient's characteristics are described in Table 1. The median age of patients was 46 (18-89) years. Sokal score: 52.1% low; 33.8% intermediate and 14.1% high risk. BCR-ABL transcripts: 109 (57%) presented e14a2 transcripts, 74 (38.8%) e13a2 and 8 (4.2%) both transcripts. There was no difference between the groups concerning age, gender, Hasford, EUTOS scores, whereas white blood cell counts at diagnosis was higher in patients with e13a2 transcripts (P=0.009). Higher rates of CCyR at 6 months were observed in e14a2 and both transcripts group, compared to e13a2 (58.4%, 60% and 30%, respectively - P=0.003); e14a2 group had higher rates of BCR-ABL transcripts <10% measured by real-time quantitative polymerase chain reaction (RQ-PCR) at 3 months (82.9%, 85.7% and 59.3%; P=0.007) and BCR-ABL <1% at 6 months (78.4% e14a2; 61.7% e13a2 and 43% both transcripts; P=0.039). The groups presented similar OS (89 %, 87% and 83%, P=0.49) and PFS (88%, 84% and 71%, P=0.08). EFS was inferior in the e13a2 group (45% vs. 65% e14a2 vs. 54% both transcripts; P=0.02).

Conclusion: Patients with BCR-ABL transcripts e14a2 presented higher rates of CCyR at 6 months and higher rates of optimal molecular response at 3 and 6 months when compared to e13a2 transcripts, but there was no difference in overall and progression-free survival by 5 years.