Saturday June 11th session – CML Clinical 1
BCR ABL Fusion Transcript and outcome of CML CP in early CP treated with Imatinib: A Gimema CML WP analysis
The BCR ABL fusion gene characterizes CML. Different types of transcripts can be found because of the different genomic breakpoints and alternative splicing (where the DNA breaks and reattaches itself during the translocation process between chromosome 9 and 22). The most frequent transcripts are the e13a2 (b2a2) and the e14a2 (b3a2). Sometimes both transcripts can be present. However in the IM era we do not have much data that would be helpful for a prognostic value by determining the transcript type, especially in early CML CP. We have seen some studies that that have indicated that patients with a b2a2 transcript may be more sensitive to IM, yet two other larger studies say that patients with b3a2 transcripts may be more sensitive to IM. Which is it? There have been no systematic evaluations in large clinical trials. So, the Gimema group aimed to investigate the influence of the BCR ABL transcript type on responses and outcomes of early CP CML patients treated with IM. TO do this they chose to analyze 3 clinical trials in their group, clin. Trials gov. NCT00514488 and NCT00510926 and an observational trial CML/023. Response monitoring for these trials was tracked with the conventional standards of cytogenetic examination (bone marrow) and Q PCR (on peripheral blood). Definitions of the responses are as follows: MMR was defined as BCR ABL/ABL ratio <0.1% (IS) failures were defined as per the revised ELN criteria, events were defined as failure or treatment discontinuation for any reason. All calculations for these analyses were based on the intention to treat (ITT) principle. A total of 559 consecutive patients in ECP CML (early chronic phase) were enrolled. Patients expressing rare transcripts such as e1a2 and e19a2 and patients with both transcripts b2a2 and b3a2 were excluded. That means that 493 patients of 559 were evaluable. (Note from C.A. Simoneau, that looks like about 66 (11.8%) were excluded for having rare breakpoint transcripts or both transcripts). 41% of the 493 patients had the b2a2 transcript and 59% of the 493 patients had the b3a2 transcripts. Aside from this the groups were comparable with regards to sex, age, hasford/sokal scores and clonal chromosomal abnormalities in the Ph+ cells. But there was a difference of the number of patients treated with 800 mg daily, which was 20% and 28% in patients with b2a2 and b3a2 respectively. The median observation time was 60 months. @ 12 months the observed CCgR rates were 75% and 79% respectively with no statistical significance between the groups for cumulative CCgR which was 89% and 88% respectively. Of interest however was that the time to MMR was significantly shorter for patients with the b3a2 transcript and the overall estimated probability of achieving MMR was significantly lower for patients with b2a2 transcripts. The probability of OS, PFS, FFS, and EFS was 86%, 91%, 82% and 90%, 70% and 76%, 58% and 70% in patients with the b2a2 and b3a2 transcripts, so we can see that patients who harbor the b2a2 transcripts scored lower in all of these categories. But how does that measure up to CCgR rates? Overall there was really no difference between the groups to achieve CCgR, but the overall estimated probability of MMR was significantly lower for patients with b2a2. The conclusion is that the b2a2 transcript is a prognostic factor in ECP CML patients treated with Imatinib. (Note from C.A. Simoneau, it would be interesting to have this analysis done with the newer treatments of Nilotinib and Dasatinib)