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Mutation type linked to TKI resistance in PH+ALL
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Resistance to tyrosine kinase inhibitors was linked to mutation type rather than the frequency of mutations in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, according to a database review.
Researchers evaluated 450 BCR-ABL kinase domain mutations from 272 patients with PH+ALL.
Among 189 patients resistant to imatinib (Gleevec, Novartis), 131 (69.3%) harbored BCR-ABL kinase domain mutations. T315I, E255K and Y253H were mutated in 75% of these cases.
Most patients (n=117; 89.3%) harbored a single mutation, whereas 13 patients harbored two mutations and one patient harbored three mutations.
The researchers then conducted analyses in 98 patients who developed resistance to second-line dasatinib (Sprycel, Bristol-Myers Squibb) or nilotinib (Tasigna, Novartis) after imatinib. Seventy-eight percent of these patients were positive for BCR-ABL kinase domain mutations. More patients harbored multiple mutations (58%) than a single mutation (42%).
Among the patients who were analyzed first after imatinib failure, 67.6% developed new mutations at the time of dasatinib failure. T315I mutations accounted for 65.2% of those newly observed in this population.
“Second-generation TKIs may ensure a more rapid debulking of the leukemic clone and have much fewer insensitive mutations, but long-term disease control remains a problem and the T315I mutation has become an even tougher enemy because its frequency has increased, reducing the number of (currently available) therapeutic options,” the researchers wrote. “Patients with PH+ALL are thus those who might benefit most from ponatinib (Iclusig, Ariad), a third-generation, pan-TKI active against T315I BCR-ABL mutant approved for the treatment of patients (with) resistant or intolerant chronic myeloid leukemia and PH+ALL by the FDA just a few months ago.”
Disclosure: The researchers report consultant roles with and honoraria from Ariad, Bristol-Myers Squibb, Novartis and Pfizer.
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