BCR-ABL Transcript Type Predicts Response and Survival Among Patients with CML

The presence of one or both of the most common BCR-ABL transcripts in patients with chronic-phase chronic myeloid leukemia (CML), e13a2 and e14a2, is predictive of response to tyrosine kinase inhibitors (TKIs) and longer survival, according to results from a recent report in Blood.

“We have always considered the two variants of the typical BCR-ABL translocation as being equivalent in clinical features and outcome,” Preetesh Jain, MD, lead author of the study, told ASH Clinical News. “Our results suggest that the outcome may not be equal, with patients with e14a2 having a better probability of response.”

Dr. Jain and colleagues at the University of Texas MD Anderson Cancer Center in Houston, examined BCR-ABL transcripts in 487 patients with chronic-phase CML who were treated with TKIs between July 2000 and September 2013. Patients were treated with one of four different frontline TKI modalities:

  • Imatinib 400 mg daily (n=69)
  • Imatinib 800 mg daily (n=199)
  • Dasatinib 50 mg twice daily or 100 mg daily (n=105)
  • Nilotinib 400 mg twice daily (n=108)

The researchers measured event-free survival (EFS) from the start of treatment until any of the following events occurred: loss of complete hematologic remission, loss of major cytogenetic response, progression to accelerated or blast phase, or death from any cause.

Overall survival (OS) and transformation-free survival (TFS) were also measured. Cytogenetic analysis was conducted every three months for the first year, every six months for the subsequent two to three years, and every one to two years thereafter.

Nearly all patients (481 out of 487) expressed e13a2, e14a2, or both transcripts:

  • e13a2: 200 (42%)
  • e14a2: 196 (41%)
  • both transcripts: 85 (18%)

Baseline characteristics were similar among patients treated with the different TKI modalities, though patients with e13a2 had significantly lower platelets compared with those with e14a2 or both transcripts (p<0.001).

Twenty-one patients (4%) experienced disease evolution, and 14 patients (3%) died during the study follow-up. Of the patients whose disease evolved to accelerated phase or blast crisis CML, 15 expressed e13a2 (8% of all patients with this expression) and six expressed e14a2 (3% of all patients with this expression), while none of these patients expressed both transcripts (p=0.04).

Patients with e13a2 transcripts experienced lower rates of major molecular response (MMR) and complete cytogenetic response (CCyR) compared with patients who expressed e14a2 or both transcripts. The rates of response at three and six months are reported in TABLE.

In multivariate analyses, the expression of e14a2 or both transcripts were independent predictors of optimal responses, as well as longer EFS (p=0.043 for e14a2) and TFS (p=0.04 for both). They did not, however, predict for better OS.

“One possible explanation for inferior outcome for patients with e13a2 is the reported higher tyrosine kinase activity reflected by higher pCrKL levels with e13a2 transcripts,” Dr. Jain and co-authors explained, “which could result in a given TKI being able to more effectively suppress the kinase activity associated with the less active e14a2 transcripts.”

The type of TKI treatments patients received could also explain the differences in response and survival, the authors noted.

“Interestingly, there was a suggestion that treatment with imatinib 400 mg daily was associated with a lower probability of response only among patients with e13a2,” they reported. In addition, the rates of CCyR and MMR for patients with e14a2 or with co-expression of e13a2 and e14a2 treated with imatinib 400 mg daily was similar to that of patients treated with imatinib 800 mg, dasatinib, or nilotinib. “If these observations were to be confirmed in a prospective study, it would suggest that transcript type could be a tool to help select the TKI to be used for patients with newly diagnosed CML.”

For example, Dr. Jain explained, patients with e14a2 could be offered imatinib 400, whereas those with e13a2 may derive more benefit from the use of second-generation TKI as initial therapy. “The study results need to be validated prospectively, but this could provide an additional biomarker that can help guide therapy in different circumstances,” he added.

Limitations of the study include its retrospective, non-controlled design, as well as that the study cannot be generalized to different institutions.


Reference

Jain P, Kantarjian H, Patel KP, et al. Impact of BCR-ABL transcript type on response and survival in patients with chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood. 2016 January 4. [Epub ahead of print]

TABLE. Cytogenetic and Molecular Response Rates
e13a2 e14a2 Both e13a2/e14a2
Complete cytogenetic response
Three months 59% 67% 63%
Six months 73% 81% 82%
Major molecular response
Three months 27% 49% 50%
Six months 42% 67% 70%

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