RESEARCH HIGHLIGHTS Nature Reviews Clinical Oncology | Published online 2 February 2016; doi:10.1038/nrclinonc.2016.13
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Ponatinib in CML — keeping PACE with multiple mutations The introduction of the thirdgeneration, multitargeted tyrosinekinase inhibitor (TKI) ponatinib has improved the outcomes of patients with treatment-refractory chronic myeloid leukaemia (CML). Now, in a high-sensitivity analysis of samples from patients enrolled in the PACE trial, ponatinib has been shown to be more effective than nilotinib or dasatinib in patients with >1 baseline BCR–ABL1 mutation; although, this effectiveness of ponatinib largely depends upon the absence of the T315I alteration. Highlighting the reasons for this approach, lead author Wendy Parker explains: “we previously used our S. Bradbrook/NPG
highly-sensitive, BCR–ABL1 mutation mass-spectrometry analysis method to demonstrate a clinical association between low-level mutations and outcomes in patients with CML treated with second-generation TKIs”. Parker continues, “we decided to use our mass-spectrometry assay to examine the mutation profile of patients treated with ponatinib, anticipating that there may also be an association between low-level mutations and a response to ponatinib treatment”. Researchers used this highlysensitive mass-spectrometry approach to detect low-level BCR–ABL1 mutations in blood samples from patients with either CML, mostly of the chronic phase (CP‑CML) type, or Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): 66 patients were found to have >1 different BCR–ABL1 mutation at baseline when samples were analysed using mass spectrometry, compared with only 43 patients whose samples were analysed using Sanger sequencing. Furthermore, use of mass-spectrometry analysis enabled the detection of up to eight different low-level mutations, compared with a maximum of three with Sanger sequencing. Similar to the outcomes of the PACE trial, patients with CP‑CML harbouring BCR–ABL1 mutations did not have significant differences in responses to treatment, or outcomes than those with other mutations;
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however, among patients with CP‑CML, those with T315I as the sole baseline mutation had significantly improved outcomes compared with patients with several low-level mutations, including T315I. These data suggest that the presence of several mutations, even those that are not detectable using Sanger sequencing, prior to commencing treatment with ponatinib is predictive of an inferior response to ponatinib treatment — presumably owing to these low-level mutations serving as a reservoir for the development of potentially TKI-resistant clones. Thus, a clinical need exists for high- sensitivity genetic analyses to confirm the presence of low-level mutations before treatment. Parker concludes, “for patients with low-level T315I or multiple BCR–ABL1 mutations, treatment with a potent TKI such as ponatinib may be preferable over t reatment with second-generation TKIs.” Commenting on the clinical relevance of these findings, Parker adds “This result suggests that patients with CP‑CML with the T315I, plus other additional mutations, might benefit from close monitoring during ponatinib therapy, or alternatively, treatment with experimental approaches or stem-cell transplantation to reduce the risk of TKI failure”. Peter Sidaway ORIGINAL ARTICLE Parker, W. T. et al. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib. Blood http://dx.doi. org/10.1182/blood-2015-09-666214 (2016)
www.nature.com/nrclinonc © 2016 Macmillan Publishers Limited. All rights reserved
H A E M AT O L O G I C A L C A N C E R
Ponatinib in CML — keeping PACE with multiple mutations The introduction of the thirdgeneration, multitargeted tyrosinekinase inhibitor (TKI) ponatinib has improved the outcomes of patients with treatment-refractory chronic myeloid leukaemia (CML). Now, in a high-sensitivity analysis of samples from patients enrolled in the PACE trial, ponatinib has been shown to be more effective than nilotinib or dasatinib in patients with >1 baseline BCR–ABL1 mutation; although, this effectiveness of ponatinib largely depends upon the absence of the T315I alteration. Highlighting the reasons for this approach, lead author Wendy Parker explains: “we previously used our S. Bradbrook/NPG
highly-sensitive, BCR–ABL1 mutation mass-spectrometry analysis method to demonstrate a clinical association between low-level mutations and outcomes in patients with CML treated with second-generation TKIs”. Parker continues, “we decided to use our mass-spectrometry assay to examine the mutation profile of patients treated with ponatinib, anticipating that there may also be an association between low-level mutations and a response to ponatinib treatment”. Researchers used this highlysensitive mass-spectrometry approach to detect low-level BCR–ABL1 mutations in blood samples from patients with either CML, mostly of the chronic phase (CP‑CML) type, or Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): 66 patients were found to have >1 different BCR–ABL1 mutation at baseline when samples were analysed using mass spectrometry, compared with only 43 patients whose samples were analysed using Sanger sequencing. Furthermore, use of mass-spectrometry analysis enabled the detection of up to eight different low-level mutations, compared with a maximum of three with Sanger sequencing. Similar to the outcomes of the PACE trial, patients with CP‑CML harbouring BCR–ABL1 mutations did not have significant differences in responses to treatment, or outcomes than those with other mutations;
NATURE REVIEWS | CLINICAL ONCOLOGY
however, among patients with CP‑CML, those with T315I as the sole baseline mutation had significantly improved outcomes compared with patients with several low-level mutations, including T315I. These data suggest that the presence of several mutations, even those that are not detectable using Sanger sequencing, prior to commencing treatment with ponatinib is predictive of an inferior response to ponatinib treatment — presumably owing to these low-level mutations serving as a reservoir for the development of potentially TKI-resistant clones. Thus, a clinical need exists for high- sensitivity genetic analyses to confirm the presence of low-level mutations before treatment. Parker concludes, “for patients with low-level T315I or multiple BCR–ABL1 mutations, treatment with a potent TKI such as ponatinib may be preferable over t reatment with second-generation TKIs.” Commenting on the clinical relevance of these findings, Parker adds “This result suggests that patients with CP‑CML with the T315I, plus other additional mutations, might benefit from close monitoring during ponatinib therapy, or alternatively, treatment with experimental approaches or stem-cell transplantation to reduce the risk of TKI failure”. Peter Sidaway ORIGINAL ARTICLE Parker, W. T. et al. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib. Blood http://dx.doi. org/10.1182/blood-2015-09-666214 (2016)
www.nature.com/nrclinonc © 2016 Macmillan Publishers Limited. All rights reserved
