Mutation testing aids CML treatment decisions




Patients with Ph+ CML-CP (Philadelphia chromosome–positive chronic myeloid leukemia, chronic phase) who fail to achieve and maintain treatment response at key milestones should be considered for mutation screening, based on data from the DASISION trial.

Patients with mutations had poor outcomes and high rates of treatment discontinuation in an extended 4-year minimum follow-up of patients in the trial; 14 of 17 dasatinib-treated patients and 14 of 18 imatinib-treated patients with mutations discontinued treatment. The primary reason for treatment discontinuation was protocol-defined disease progression (dasatinib, n = 11; imatinib, n = 8); patients with mutations accounted for 61% of discontinuations on dasatinib (n = 11/18) and 42% on imatinib (n = 8/19).

The crystal structure of the Abl kinase domain (blue) is shown in a complex with dasatinib (red). Courtesy Wikimedia Commons

The crystal structure of the Abl kinase domain (blue) is shown in a complex with dasatinib (red).

“With the introduction of generic imatinib into the market in 2016, choosing the most appropriate second-line tyrosine-kinase inhibitor for patients, based on factors such as mutation status, will become increasingly important,” Dr. Tim Hughes of the South Australian Health and Medical Research Institute in Adelaide and his colleagues wrote. Having the option to choose the most suitable second-line therapy may ensure improved outcomes and decreased health care costs.

In the DASISION (Dasatinib vs. Imatinib Study in Treatment-Naive CML-CP) trial, all participants had newly diagnosed Ph+ CML-CP; they were treated with dasatinib (n = 259) or imatinib (n = 260) and followed for a minimum of 3 years (Leukemia. 2015 Sep;29[9]:1832-8). Dr. Hughes and his colleagues conducted a retrospective study of the patients who were potentially at a higher risk for developing mutations. This included patients on treatment who had at least one clinically relevant event – no confirmed complete cytogenetic response (cCCyR) within 12 months, no major molecular response (MMR) within 12 months; a fivefold increase in BCR-ABL1 transcript levels with loss of MMR; loss of CCyR – and/or who discontinued treatment for any reason.

Screening identified only a small number of patients with mutations (dasatinib, n = 17; imatinib, n = 18). Those on dasatinib had a narrower spectrum of mutations (4 sites for dasatinib vs. 12 sites for imatinib), fewer phosphate-binding loop mutations (1 mutation for dasatinib vs, 9 mutations for imatinib), and fewer multiple mutations (1 patient on dasatinib vs. 6 patients on imatinib).

However, patients on dasatinib had a greater occurrence of T315I mutations (11 patients on dasatinib vs. 0 patients on imatinib). The researchers hypothesized that this finding resulted from differences in competitive advantage between mutant clones. For example, P-loop mutations Y253F, E255K were found to have higher transformation potency and proliferation rates, compared with T315I, even in the absence of BCR-ABL1 inhibitors. If one assumes that imatinib has lower activity than dasatinib against these mutations, then mutant clones with select P-loop mutations might expand more rapidly than clones with the T315I mutation when exposed to imatinib.

Consistent with this idea, T315I is less common than all P-loop mutations in CML-CP patients with imatinib resistance. In addition, dasatinib suppresses P-loop mutations to a greater extent than does T315I; therefore, T315I may be able to develop during dasatinib treatment with relatively little competition from rapidly proliferating clones.

“Dasatinib, nilotinib, bosutinib, and ponatinib have enabled many patients, including those with mutations, to overcome imatinib resistance; however, each lack[s] efficacy against a small number of different leukemic clones, and all except ponatinib lack efficacy against T315I,” the researchers wrote.

The study was sponsored by Bristol-Myers Squibb. Dr. Hughes reported receiving honoraria and research funding from ARIAD, the maker of ponatinib; Bristol-Myers Squibb, the maker of dasatinib; and Novartis, the maker of imatinib.

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