BCR-ABL FUSION TRANSCRIPT AND OUTCOME OF CHRONIC MYELOID LEUKEMIA PATIENTS IN EARLY CHRONIC PHASE TREATED WITH IMATINIB: A GIMEMA CML WP ANALYSIS

Chronic myeloid leukemia (CML) is characterized by the BCR-ABL fusion gene. Different types of BCR-ABL transcripts can be found, due to different genomic breakpoints and alternative splicing. The most frequent transcripts are the e13a2 (b2a2) and the e14a2 (b3a2). Occasionally, both transcripts may be present. In the imainib (IM) era, few data about the prognostic significance of the transcript type are available, particularly in the setting of early chronic phase (ECP): one study suggested that patients with the b2a2 transcript may be more sensitive to IM (de Lemos et al. Genet Mol Res 2005), while two larger studies suggested that patients with b3a2 transcript may have better responses to IM (Vega-Ruiz et al. ASH 2007; Lucas et al. Haematologica 2009). No systematic evaluations in large prospective clinical trials have been performed. Aims. To investigate the influence of the BCR-ABL transcript type on the responses and the outcome of ECP CML treated with IM. Methods. Analysis of 3 concurrent clinical trials of the GIMEMA CML WP (Clin Trials Gov. NCT00514488, NCT00510926 and observational trial CML/023). Response monitoring: conventional cytogenetic examination (bone marrow) and QPCR (peripheral blood). Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio <0.1% (International Scale); failures: revised European LeukemiaNet criteria (Baccarani et al. J Clin Oncol 2009); events: failure or treatment discontinuation for any reason. All the calculations have been made according to the intention-to-treat principle. Results. 55Patients expressing rare transcript types (e1a2 and e19a2) and patients with both b2a2 and b3a2 transcripts were excluded: 493 out of 559 patients were evaluable, 203 (41%) with b2a2 transcript and 290 with b3a2 transcript (59%). The 2 groups were comparable (no significant differences in sex, age, Sokal/Hasford score distribution, clonal chromosomal abnormalities in Ph+ cells), except for the proportion of patients treated with IM 800 mg/daily: 20% and 28% (p=0.034) in patients with b2a2 and b3a2, respectively. The median observation time was 60 months. In patients with b2a2 and b3a2 transcript, the observed 12-months CCgR rates were 75% and 79%, respectively, with a cumulative CCgR incidence of 89% and 88%, respectively (no significant differences). The time to MMR was significantly shorter for patients with b3a2 transcript and the overall estimated probability of MMR was significantly lower for patients with b2a2 transcript (85% vs 90%, p<0.001, fig.1). The probability of Overall Survival (OS), Progression- Free Survival (PFS), Failure-Free Survival (FFS) and Event-Free Survival (EFS) was 86% and 91% (p=0.064), 82% and 90% (p=0.027), 70% and 76% (p=0.095), 58% and 70% (p=0.027) in patients with b2a2 and b3a2 transcript, respectively (fig. 1). Summary/Conclusions. In patients with b2a2 and b3a2 transcript the CCgR rates were comparable, but the overall estimated probability of MMR was significantly lower for patients with b2a2 transcript. OS, PFS, FFS, and EFS were uniformly lower in patients with b2a2 transcript (PFS and EFS: p< 0.05).The b2a2 transcript is a candidate adverse prognostic factor in ECP CML patients treated with IM frontline.