BCR–ABL transcript type linked to TKI response, outcomes

By Shreeya Nanda, Senior medwireNews Reporter

The type of BCR–ABL transcript could have an impact on tyrosine kinase inhibitor (TKI) choice in patients with chronic myeloid leukaemia (CML), according to research published in Blood.

Researcher Jorge Cortes (The University of Texas MD Anderson Cancer Center, Houston, USA) and colleagues explain that patients can harbour different BCR–ABL transcripts depending on the breakpoints on the BCR gene, where the most common transcript types are e13a2 and e14a2.

In this study, patients with the e14a2 transcript had favourable outcomes irrespective of the TKI used, while those with the e13a2 had inferior outcomes when treated with imatinib 400 mg/day compared with other TKI modalities, they report.

The study authors write: “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, 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.”

Of 481 chronic phase CML patients included in this medical review, 42% expressed the e13a2 transcript, 41% the e14a2 transcript and 18% expressed both transcripts. Participants had received first-line treatment with either imatinib 400 mg/day, imatinib 800 mg/day, dasatinib 50 mg twice a day or 100 mg/day, or nilotinib 400 mg twice a day.

Patients expressing the e13a2 transcript had a significantly lower cumulative rate for major molecular response (MMR) than those expressing the e14a2 transcript or co-expressing both (79 vs 91 and 95%).

This was also true for cumulative rates of deep molecular response (MR4.5; 57 vs 79 and 80%), and the cumulative complete cytogenetic response (CCyR) was also lower for the e13a2 group, but the difference was not significant.

Among patients with the e13a2 transcript, those who received imatinib 400 mg/day tended to have worse MMR, MR4.5 and CCyR rates compared with other treatment modalities (for instance, CCyR rates of 77% vs 90–95%).

These trends were not observed in participants with e14a2 or both transcripts, where the response rates were comparable across modalities, say the researchers.

Furthermore, 5-year probabilities of event-free survival (79 vs 89 and 87%) and transformation-free survival (91 vs 97 and 99%) also tended to be lower for the e13a2 group than for the e14a2 and co-expression groups.

And multivariable analysis showed that presence of the e14a2 transcript (either alone or together with e13a2) was a significant predictor of longer event-free and transformation-free survival as well of optimal response as defined by European LeukemiaNet.

However, the estimated 5-year overall survival rates did not differ significantly between transcript types and expression of the e14a2 transcript was not a significant predictor of overall survival.

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