Impact of <i>ASXL1</i> at diagnosis in patients with CML receiving frontline potent TKIs: high risk of kinase domain mutations
Abstract
Abstract Genomic profiling in patients with chronic-phase chronic myeloid leukemia (CP-CML) demonstrated somatic variants in blood cancer-related gene variants (CGVs) and rearrangements associated with the formation of the Philadelphia chromosome (Ph-associated rearrangements) at diagnosis, collectively termed additional genetic abnormalities (AGAs). AGAs had a negative impact on failure-free survival (FFS) and molecular response in imatinib-treated patients. We investigated whether treatment with more potent therapies could overcome the negative impact of AGAs at diagnosis. Targeted RNA-based next-generation sequencing was performed on diagnostic samples of 315 patients consecutively enrolled in 4 clinical trials of frontline potent tyrosine kinase inhibitors (TKIs) in CP-CML. AGAs were present in 34% of patients at diagnosis, including 20% harboring CGVs and 18% with Ph-associated rearrangements (4% had both). Although the negative impact of Ph-associated rearrangements was overcome by more potent inhibitors, patients with CGVs continued to experience inferior outcomes. This result was largely attributable to patients with ASXL1 variants, observed in 7% overall. Patients harboring ASXL1 variants also had inferior outcomes compared with those with wild-type ASXL1 in terms of 12-month major molecular response (55% vs 83%; P = .001), 2-year FFS (61% vs 91%; P &lt; .001), and notably, the development of treatment-emergent BCR::ABL1 kinase domain mutations at 2 years (35% vs 1%; P &lt; .001). In multivariable models, both CGVs and ASXL1 variants were predictors of each outcome. Treatment with frontline potent TKIs overcame the negative impact of Ph-associated rearrangements observed with frontline imatinib. However, inferior outcomes were still associated with the presence of CGVs. The acquisition of TKI-resistant BCR::ABL1 mutations was almost exclusively associated with mutated ASXL1 at diagnosis.
Article Details
Authors (21)
Naranie Shanmuganathan
1Department of Haematology, Royal Adelaide Hospital and SA Pathology, Adelaide, Australia
David T. Yeung
Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia
Carol Wadham
2Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
Adelina Fernandes
2Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
Muneeza Maqsood
2Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
NurHezrin Shahrin
2Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
Verity Saunders
4Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
Rosalie R. Kenyon
2Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
Ming Lin
Institute of Materials Research and Engineering (IMRE), Agency for Science, Technology and Research (A*STAR), 2 Fusionopolis Way, Innovis #08-03, Singapore 138634, Singapore
John Toubia
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Joe McConnell
2Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
Dominic Kaczorowski
2Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
David M. Ross
21Haematology Directorate, SA Pathology, Royal Adelaide Hospital and Flinders Medical Centre, Adelaide, Australia
Agnes S. M. Yong
4Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
Lynette Chee
6Australasian Leukemia and Lymphoma Group, Melbourne, Australia
Jake Shortt
6Australasian Leukemia and Lymphoma Group, Melbourne, Australia
Nicholas Viiala
6Australasian Leukemia and Lymphoma Group, Melbourne, Australia
Jodi Braley
2Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
Chung Hoow Kok
Centre for Cancer Biology, College of Health, Adelaide University and SA Pathology
Timothy P. Hughes
2Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, Australia
Susan Branford
2Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia