The e13a2 BCR-ABL1 Fusion Transcript Is a Candidate Adverse Prognostic Factor In Chronic Myeloid Leukemia Patients Treated Frontline With Imatinib Mesylate

The e13a2 and the e14a2 are the most frequent BCR-ABL1 transcripts in chronic myeloid leukemia (CML) patients. The aim of the present study was to assess the prognostic value of the e13a2 (b2a2) or the e14a2 (b3a2) fusion transcripts on the long-term outcome of early chronic phase (ECP) CML patients treated frontline with imatinib mesylate (IM). Few studies, mostly based on a small number of patients or with a relatively short observation, have been published, particularly in ECP setting. Due to partially conflicting data, the transcript type is not actually considered an established baseline prognostic factor. To our knowledge, this is the first long-term analysis conducted in the context of large prospective studies.

A retrospective analysis of 3 GIMEMA CML WP prospective clinical studies (NCT00514488, NCT00510926, observational study CML/023) was performed. All the 559 enrolled patients were analyzed. A qualitative RT-PCR for BCR-ABL1 transcript was routinely performed at enrollment. Patients expressing rare transcripts or with both e13a2-e14a2 transcripts were excluded: 493 out of 559 patients were included, 203 (41%) with e13a2 transcript and 290 with e14a2 transcript (59%). Definitions. Major molecular response (MMR): BCR-ABL1^IS ratio <0.1%. Deep molecular response (MR^4.0): detectable disease ≤ 0.01% BCR-ABL1^IS or undetectable disease with ≥10,000 ABL1 transcripts. Progression: transformation to accelerated or blastic phase. Failure: according to 2013 ELN recommendations. Event: failure or permanent discontinuation for any reasons. All the deaths, at any time and for any reasons, were included.

The median follow-up was 76 months; 95% of the patients had at least a 5-year observation. The 2 groups were comparable for demographic and hematologic characteristics, except for the proportion of male patients, that was higher in the e13a2 group (p = 0.05), and for the baseline percentages of eosinophils, that was lower in the e13a2 group (p = 0.009). The Sokal, Hasford and EUTOS risk score distributions and the proportion of patients with CCA in Ph+ cells were comparable. The complete cytogenetic response (CCyR) rate at 12 month was not significantly different (75% and 79% in e13a2 e14a2 patients, respectively, p=0.274), but the MMR rate at 18 months and the MR^4.0 at 36 months were significantly lower in e13a2 patients (52% and 67%, p = 0.001; 20% and 30%, p = 0.013, respectively). As far as the rapidity of response, the time to MMR and the time to MR⁴ were significantly slower for patients with e13a2 transcript (12 and 6 months; 54 and 37 months, respectively), with an inferior overall estimated probability of MMR (85% and 92%, p < 0.001) and MR⁴ (57% and 71%, p = 0.002). The overall survival (83% and 86%, p = 0.023), the progression-free survival (81% and 86%, p = 0.007), the failure-free survival (54% and 71%, p < 0.001) and the event-free survival (46% and 61%, p = 0.003) were significantly lower in patients with e13a2 transcript (figure 1). In a multivariate analysis (Cox model), the transcript type retained its prognostic significance, when adjusted for other relevant variables. Analyzing separately the patients treated with IM 400 mg (n = 371; e13a2 and e14a2 transcript: 208 and 163 patients, respectively) or IM 800 mg (n = 122; e13a2 and e14a2 transcript: 82 and 40 patients, respectively), all the above mentioned response and outcome differences were confirmed, with one exception: in the high-dose IM group the overall survival probability was inferior for the e13a2 patients, but, probably due to the small number of patients, the difference was not statistically significant (83% and 86%, p = 0.268).

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A long-term analysis in a large cohort of CML patients suggests that the e13a2 transcript is an adverse prognostic factor in ECP CML patients treated frontline with IM. An independent evaluation is required for confirmation.

University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo.

Castagnetti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Abruzzese:BMS, Novartis: Consultancy.