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Haematologica 2019 Volume 104(12):2400-2409
Chronic Myeloid Leukemia
Somatic variants in epigenetic modifiers can predict failure of response to imatinib but not to second-generation tyrosine kinase inhibitors
Georgios Nteliopoulos,1 Alexandra Bazeos,1* Simone Claudiani,1,2* Gareth Gerrard,1,3* Edward Curry,4 Richard Szydlo,1 Mary Alikian,1,2 Hui En Foong,2 Zacharoula Nikolakopoulou,1,5 Sandra Loaiza,1,2 Jamshid S. Khorashad,1,2 Dragana Milojkovic,1,2 Danilo Perrotti,1,6 Robert Peter Gale,1 Letizia Foroni1 and Jane F. Apperley1,2
*AB, SC and GG contributed equally to this work.
ABSTRACT
There are no validated molecular biomarkers to identify newly-diag- nosed individuals with chronic-phase chronic myeloid leukemia like- ly to respond poorly to imatinib and who might benefit from first- line treatment with a more potent second-generation tyrosine kinase inhibitor. Our inability to predict these ‘high-risk’ individuals reflects the poorly understood heterogeneity of the disease. To investigate the potential of genetic variants in epigenetic modifiers as biomarkers at diagnosis, we used Ion Torrent next-generation sequencing of 71 candidate genes for pre- dicting response to tyrosine kinase inhibitors and probability of disease pro- gression. A total of 124 subjects with newly-diagnosed chronic-phase chronic myeloid leukemia began with imatinib (n=62) or second-generation tyrosine kinase inhibitors (n=62) and were classified as responders or non- responders based on the BCRABL1 transcript levels within the first year and the European LeukemiaNet criteria for failure. Somatic variants affecting 21 genes (e.g. ASXL1, IKZF1, DNMT3A, CREBBP) were detected in 30% of subjects, most of whom were non-responders (41% non-responders, 18% responders to imatinib, 38% non-responders, 25% responders to second- generation tyrosine kinase inhibitors). The presence of variants predicted the rate of achieving a major molecular response, event-free survival, pro- gression-free survival and chronic myeloid leukemia-related survival in the imatinib but not the second-generation tyrosine kinase inhibitors cohort. Rare germline variants had no prognostic significance irrespective of treat- ment while some pre-leukemia variants suggest a multi-step development of chronic myeloid leukemia. Our data suggest that identification of somat- ic variants at diagnosis facilitates stratification into imatinib responders/non-responders, thereby allowing earlier use of second-genera- tion tyrosine kinase inhibitors, which, in turn, may overcome the negative impact of such variants on disease progression.
Introduction
Although tyrosine kinase inhibitors (TKI) have profoundly changed the progno- sis of chronic-phase chronic myeloid leukemia (CML-CP), some 10-15% of affect- ed individuals do not respond and need other therapies.1 Four TKI are approved for use in newly-diagnosed CML, including imatinib and the second-generation TKI
1Centre for Haematology, Department of Medicine, Imperial College, London, UK;
2Imperial College Healthcare NHS Trust, London, UK; 3Sarah Cannon Molecular Diagnostics, HCA Healthcare UK, London, UK; 4Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College, London, UK; 5Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK and 6Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore MD, USA
Correspondence:
GEORGIOS NTELIOPOULOS
georgios.nteliopoulos04@imperial.ac.uk
Received: June 20, 2018. Accepted: May 6, 2019. Pre-published: May 9, 2019.
doi:10.3324/haematol.2018.200220
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