Multiple Low-level BCR-ABL1 Mutations Not Associated With Poor Response to Ponatinib in CML

No association was found between multiple low-level BCR-ABL1 mutations and inferior response to ponatinib therapy like there is for nilotinib or dasatinib response in patients with chronic myeloid leukemia (CML), a study published in Blood has shown.¹

Although ponatinib, a third-generation tyrosine kinase inhibitor (TKI), demonstrates activity against all common BCR-ABL1 single mutations, including a T315I mutation, thereby improving outcomes for patients with refractory CML, responses are variable and baseline factors that influence response have not been well studied.

Because the type and number of low-level BCR-ABL1 mutations present after imatinib resistance has prognostic significant for subsequent treatment with dasatinib or nilotinib as second-line therapy, researchers sought to evaluate the impact of low-level mutations before ponatinib initiation on treatment response in patients with CML.

For the study, researchers analyzed data from 363 patients enrolled in the PACE trial who were resistant to TKIs, including 231 patients with CML in chronic phase (CML-CP).

Results showed that low-level mutations were present in 53 patients, of which 14 patients had a low-level T315I mutation. Researchers found that most patients did not undergo clonal expansion during ponatinib therapy and did not identify any particular mutations that were associated with inferior outcome; however, researchers observed an association between the number of mutations after TKI resistance and ponatinib therapy response.

The study also demonstrated that despite superior responses among T315I mutation-positive patients with CML-CP, those with multiple mutations had substantially inferior responses compared with those who only had a T315I mutation.

In contrast, T315I mutation-negative patients with CML-CP and multiple mutations that had inferior responses with nilotinib and dasatinib therapy after imatinib resistance did not have an inferior response to ponatinib treatment.

The findings suggested “that ponatinib may prove to be particularly advantageous for patients with multiple mutations detectable by mass-spectrometry after TKI resistance.”

Reference

1. Parker WT, Yeung DTO, Yeoman AL, et al. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib [published online ahead of print January 14, 2016]. Blood. doi: 10.1182/blood-2015-09-666214.