Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/32556
Title: Impact of additional genetic abnormalities at diagnosis of chronic myeloid leukemia for first-line imatinib-treated patients receiving proactive treatment intervention.
Austin Authors: Shanmuganathan, Naranie;Wadham, Carol;Shahrin, NurHezrin;Feng, Jinghua;Thomson, Daniel;Wang, Paul;Saunders, Verity;Kok, Chung Hoow;King, Rob M;Kenyon, Rosalie R;Lin, Ming;Pagani, Ilaria S;Ross, David M;Yong, Agnes S M;Grigg, Andrew P ;Mills, Anthony K;Schwarer, Anthony P ;Braley, Jodi;Altamura, Haley;Yeung, David T;Scott, Hamish S;Schreiber, Andreas W;Hughes, Timothy P;Branford, Susan
Affiliation: Department of Hematology, Royal Adelaide Hospital and SA Pathology, Adelaide, Australia
Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide
Clinical and Health Sciences, University of South Australia, Adelaide, Australia
Australian Cancer Research Foundation Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide.
Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide.
Australasian Leukemia and Lymphoma Group (ALLG)
Adelaide Medical School, University of Adelaide, Adelaide, Australia
Department of Hematology, Flinders University and Medical Centre, Adelaide
The University of Western Australia Medical School, Western Australia
Department of Clinical Hematology, Austin Hospital and University of Melbourne, Melbourne
Department of Hematology, Princess Alexandra Hospital, Brisbane.
Department of Hematology, Box Hill Hospital, Melbourne.
Austin Health
School of Biological Sciences, University of Adelaide, Adelaide
Issue Date: 1-Sep-2023
Date: 2023-03
Publication information: Haematologica 2023-09-01; 108(9)
Abstract: The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML), however evidence has accumulated from studies of highly selected cohorts that variants in other cancer-related genes are associated with treatment failure. Nevertheless, the true incidence and impact of additional genetic abnormalities (AGAs) at diagnosis of chronic phase (CP)-CML is unknown. We sought to determine whether AGAs at diagnosis in a consecutive imatinib-treated cohort of 210 patients enrolled in the TIDEL-II trial influenced outcome despite a highly proactive treatment intervention strategy. Survival outcomes including overall survival, progression-free survival, failure-free survival and BCR::ABL1 kinase domain mutation acquisition were evaluated. Molecular outcomes were measured at a central laboratory and included major molecular response (MMR, BCR::ABL1 ≤0.1%IS), MR4 (BCR::ABL1 ≤0.01%IS) and MR4.5 (BCR::ABL1 ≤0.0032%IS). AGAs included variants in known cancer genes and novel rearrangements involving the formation of the Philadelphia chromosome. Clinical outcomes and molecular response were assessed based on the genetic profile and other baseline factors. AGAs were identified in 31% of patients. Potentially pathogenic variants in cancer-related genes were detected in 16% of patients at diagnosis (including gene fusions and deletions) and structural rearrangements involving the Philadelphia chromosome (Ph-associated rearrangements), detected in 18%. Multivariable analysis demonstrated that the combined genetic abnormalities plus the ELTS clinical risk score were independent predictors of lower molecular response rates and higher treatment failure. Despite a highly proactive treatment intervention strategy, first-line imatinib-treated patients with AGAs had poorer response rates. This data provides evidence for the incorporation of genomically-based risk assessment for CML.
URI: https://ahro.austin.org.au/austinjspui/handle/1/32556
DOI: 10.3324/haematol.2022.282184
ORCID: 
Journal: Haematologica
PubMed URL: 36951160
ISSN: 1592-8721
Type: Journal Article
Appears in Collections:Journal articles

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