Dasatinib, Imatinib, Associated With Differing Mutation Patterns in CML

Patients with chronic myeloid leukemia (CML) undergoing treatment with dasatinib had a narrower spectrum of mutations in BCR-ABL1 compared to those treated with imatinib, according to a new study, a finding which could aid in selection of second-line treatments.

“Patients treated with imatinib are susceptible to numerous mutations that reduce the binding of imatinib, and BCR-ABL1 mutations may be responsible for 9% to 48% of primary resistance and 10% to 68% of secondary or acquired resistance to imatinib,” wrote study authors led by Timothy P. Hughes, MD, of the University of Adelaide in Australia. Less is known regarding mutations that develop during treatment with dasatinib and other agents than with imatinib.

In the current study, researchers retrospectively analyzed mutation development in dasatinib (259 patients) and imatinib patients (260 patients) in the DASISION trial. Results were published online ahead of print in the journal Leukemia.

The study included only patients with a minimum of 3 years of follow-up who had discontinued treatment for any reason, and for those still on treatment with clinically relevant events; the final analysis included 169 dasatinib patients (65% of full dasatinib group) and 194 imatinib patients (75%). A small number of BCR-ABL1 mutations were found in both groups, with 17 (10%) in the dasatinib group and 18 (9.3%) in the imatinib group.

Those in the dasatinib group had a “more narrow spectrum of mutations” than those in the imatinib group-the mutations affected 4 sites vs 12 sites. There were also fewer phosphate-binding loop mutations in the dasatinib group. T315I mutations were found only in the dasatinib group (11 patients), and not at all in the imatinib group.

A 4-year minimum follow-up was completed in patients with identified mutations. The researchers found “poor outcomes” in both treatment groups, with high rates of treatment discontinuation in 14 of 17 in the dasatinib group and 14 of 18 in the imatinib group. Among all the patients in the full trial who discontinued treatment due to disease progression, 61% of dasatinib patients and 42% of imatinib patients had BCR-ABL1 mutations.

The authors wrote that these results suggest CML patients who fail to achieve and maintain a treatment response are candidates for mutation screening. “Mutational testing provides arguably the most important measure for treatment selection in patients with CML, especially when selecting an alternative therapy because of current treatment failure,” they concluded. “In patients with less-resistant mutations, other factors, such as patient comorbidities, the potential for cross-intolerance, and adherence, should also be considered to ensure patients achieve good long-term outcomes.”