Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients

Abstract

Key Points Ponatinib induces durable responses regardless of baseline BCR-ABL1 mutation status in CP-CML patients. No single or compound mutant consistently confers primary or secondary resistance to ponatinib in CP-CML.

BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib

“…Two patients who had received 42 and 45 mg daily (efCave ~26 and 28 nM) achieved durable major molecular response (MMR) in 168 and 87 days, respectively, whereas the other patient with this CM, who had received an average daily dose of 32 mg (corresponding to an efCave of ~24 nM), needed 583 days to reach MMR, and was withdrawn from the study 82 days after having achieved this. 5 The latter observation is in line with an inadequately low dose of ponatinib, but it is necessary to consider the possibility that the slow response may have been attributable to a mutation-independent mechanism.…”

Chronic myeloid leukemia: reminiscences and dreams

“…This feature is attributed to the compound's unique structure which allows it to bind and inhibit ABL1 with no steric hindrance due to the T315I mutation. 132,133 The drug was tested in the Ponatinib Phpositive acute lymphoblastic leukemia (ALL) and CML Evaluation (PACE) phase II study in which 449 patients with CML in the chronic and advanced phases and Phpositive ALL with resistant to or intolerance from dasatinib or nilotinib or with the T315I mutation were enrolled. The patients received once daily 45 mg ponatinib, and the results indicated that the drug had considerable activity in all patients, including those in advanced phase disease, regardless of base-line kinase domain mutations and the responses seemed to be durable.…”

Ultra-deep sequencing leads to earlier and more sensitive detection of the tyrosine kinase inhibitor resistance mutation T315I in chronic myeloid leukemia

“…To determine the extent of false compound mutations in our sequencing assay, we mixed cDNA from patients with only one mutation (Y253H+E255K; Y253H+T315I; E255K+T315I). The recombination rate (calculated as previously described by Deininger et al 29 ) was on average 17% per 100 bp (data not shown).…”

“…In future studies, the generation of chimeric reads could be reduced by modified sequencing strategies (single molecule consensus sequencing) 28 or could be mathematically corrected. 29 However, the aforementioned advances are not sufficient to resolve the clonal evolution of cases with cytogenetic aberrations in addition to the initial Philadelphia chromosome, e.g. duplication of the Philadelphia chromosome.…”

“…In vitro data suggested that many combinations of mutations (including those with T315I) render cells resistant to available TKIs including ponatinib, 19,34 However, recent data from the PACE trial encourages the use of ponatinib in heavily pre-treated patients with compound mutations. 29 Compound mutated CML cases can be distinguished from cases with multiple independent clones by their read distribution using the longer amplicons design of 454 XL+ sequencing. However, a study by Parker et al suggested that technical artifacts cause a false classification of multiclonal cases as compound mutated.…”