FROM BLOOD
Depending on the number and type of BCR-ABL1 mutations, certain patients with chronic myeloid leukemia may have a better response to ponatinib than to other tyrosine kinase inhibitors, according to a report published in Blood.
For patients with CML treated with first- or second-generation tyrosine kinase inhibitors such as imatinib, nilotinib, and dasatinib, the most common cause of treatment failure is the acquisition of mutations in the BCR-ABL1 gene, particularly the T315I mutation, which interfere with drug binding and eventually confer drug resistance. Some of these cancers have proved susceptible to ponatinib, but treatment response varies among patients, said Dr. Wendy T. Parker of the Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, the Center for Cancer Biology, and the University of Adelaide (Australia) and her associates.
They retrospectively assessed peripheral blood samples from 363 CML patients who had taken part in a phase II study of ponatinib therapy, using their newly developed mass spectrometry–based mutation detection assay to determine which mutations correlated with which treatment outcomes. These study participants contributed blood samples before, during, and after ponatinib treatment. The mass spectrometry–based assay can detect BCR-ABL1 KD mutations present at levels between 10- and 100-fold below those detectable using conventional Sanger sequencing, the researchers said ( Blood. 2016;127[15]:1870-80 ).
Patients who had the T315I mutation plus additional mutations at baseline (32% of the study population) had significantly worse treatment responses and significantly worse outcomes than those who had only the T315I mutation at baseline. “Consequently, these patients may benefit from close monitoring, experimental approaches, or stem-cell transplantation to reduce the risk of tyrosine kinase inhibitor failure,” Dr. Parker and her associates said.
In addition, patients who didn’t have the T315I mutation but had multiple other mutations at baseline responded well to ponatinib. Historically, such patients have not responded well to first- or second-generation tyrosine kinase inhibitors, but ponatinib may prove to be a particularly effective option for this patient population, the investigators said (Blood. 2016;127[15]:1870-80).
These findings demonstrate that mutation analysis, such as that provided by their mass spectrometry–based assay, can be used to guide therapy even after patients have failed on some tyrosine kinase inhibitors, they added.
The study was supported by the maker of ponatinib ( Iclusig ) Ariad Pharmaceuticals, the Leukemia Foundation of Australia, and the A.R. Clarkson Foundation. Dr. Parker reported having no relevant financial disclosures; some of her associates were employed by Ariad.
