Ponatinib may be invulnerable to BCR–ABL1 mutations
medwireNews: Ponatinib is effective in patients with chronic myeloid leukaemia (CML) regardless of pre-existing mutations to BCR–ABL1, suggest study finding published in Blood.
Moreover, next-generation sequencing (NGS) did not detect any novel mutations in the tyrosine kinase inhibitor (TKI) target in CML patients who had been treated with ponatinib, report Michael Deininger, from the University of Utah in Salt Lake City, USA, and co-authors.
“No single or compound mutation was identified that consistently conferred primary and/or secondary resistance to ponatinib in [chronic phase CML] patients”, they emphasize.
The team determined the baseline mutation status of 267 PACE trial participants with chronic phase CML who had been heavily pretreated with TKIs and were resistant to dasatinib or nilotinib, or harbouring the gatekeeper T315I resistance mutation. Mutations were analysed using both Sanger sequencing and NGS, designed to detect low level (LL) mutations occurring at a frequency of 1–11%.
In all, 61% of the patients at baseline carried 266 mutations including 105 LL mutations found only using NGS. Twenty-three percent of patients had more than one mutation. Compound mutations were detected in 9% of the patients, rising to 42% in those with multiple mutations.
The patients were treated with ponatinib for a median of 30.1 months and had “robust and durable responses” to treatment regardless of baseline mutation status, with 1-year rates of major cytogenetic response of 50–61% in patients with 0, 1, or at least 2 BCR–ABL1 mutations as detected with NGS, and 29–45% achieved a major molecular response at any time point.
Response rates were also comparable in patients with LL mutations and those with no mutations, the researchers add.
Ten baseline single mutations occurred in at least two patients, one of which – F359C – was associated with low rates of response to ponatinib. This was the only single or compound recurring mutation that may confer primary ponatinib resistance, the team observes.
Moreover, re-evaluation of 129 of the patients, 24 of whom had discontinued ponatinib for at least 1 month, showed further mutations were “rare events” with just eight patients developing novel single mutations, while three compound mutations were detected in one or two patients. None of these were F359C.
“The role of NGS in this setting may be to identify patients with LL T315I who are unlikely to derive lasting benefit from second-generation TKIs, but have a high likelihood of achieving durable cytogenetic and molecular responses to ponatinib”, Deininger et al write.
Acknowledging that ponatinib is associated with cardiovascular side effects, possibly on a dose–dependent basis, the researchers conclude that this molecular marker may be “an important factor for balancing risks and benefits of salvage therapy selection.”
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