In heavily pretreated patients with chronic phase chronic myeloid leukemia (CP-CML), response to the tyrosine kinase inhibitor ponatinib did not depend on baseline mutation status, and no single or compound mutation was a major driver of primary or secondary resistance to ponatinib, according to researchers.
Irrespective of baseline mutation status, responses to ponatinib were durable. As determined by next-generation sequencing (NGS), patients with zero, one, or two or more BCR-ABL1 mutations had rates of 50%-61% for major cytogenetic response (MCyR) by 1 year and 29%-45% for major molecular response (MMR) at any time. The rates were similar to those observed with mutation status determined by Sanger sequencing. Rates of sustained response at 2 years for MCyR and MMR were 87% and 65%, respectively (Blood. 2016 Feb 11. doi: 10.1182/blood-2015-08-660977).
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Sanger sequencing typically is used to identify BCR-ABL1 mutations associated with tyrosine kinase inhibitor (TKI) resistance, but the method fails to detect low-level mutations that occur in less than 10%-20% of cells. Researchers used NGS to determine the impact of low-level mutations, as well as compound mutations, on the efficacy of the third generation TKI ponatinib.
Ponatinib is the most potent BCR-ABL1 TKI but is associated with considerable cardiovascular toxicity.
“The role of NGS in this setting may be to identify patients with (low level) 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, an important factor for balancing risks and benefits of salvage therapy selection,” wrote Dr. Michael W. Deininger, Chief of Hematology at the Huntsman Cancer Institute at the University of Utah, Salt Lake City, and his colleagues.
Patients with low-level mutations had similar response rates to those with no mutations: MCyR by one year and MMR at any time were 43% and 31%, respectively, compared with 50% and 29%. Response rates were higher in patients with compound mutations (64% and 52%) or one or more mutation (57% and 64%). The researchers speculated that the lower response rates in patients with low level or no mutations may reflect resistance mechanisms independent of BCR-ABL1.
Analysis of postbaseline samples from 127 patients (24 of whom had discontinued ponatinib for at least 1 month) determined the impact of acquired resistance. At a median follow-up of 30.1 months, emergence of previously undetected single and compound mutants during ponatinib therapy was observed in 8 patients.
The study analyzed patients from the PACE trial who had CP-CML with resistance or intolerance to dasatinib or nilotinib, or with a T315I mutation, and who were treated with ponatinib. All 267 patients had baseline mutation status determined by Sanger sequencing, with 161 mutations detected in 131 patients. NGS identified these and 105 additional mutations. Consistent with greater sensitivity of NGS, the proportion of patients with no baseline mutations by 39% by NGS vs. 51% by Sanger sequencing, and the proportion with multiple mutations was 23% vs. 10%.
The study was funded by ARIAD Pharmaceuticals. Dr. Deininger reported financial ties to ARIAD, Bristol Myers-Squibb, Novartis, Celgene, Genzyme, Gilead, Incyte, and Pfizer. Several of his coauthors reported ties to industry.