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Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia.

ABSTRACT: Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.

SUBMITTER: Branford S

PROVIDER: S-EPMC6893870 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia.

Branford Susan S Kim Dennis Dong Hwan DDH Apperley Jane F JF Eide Christopher A CA Mustjoki Satu S Ong S Tiong ST Nteliopoulos Georgios G Ernst Thomas T Chuah Charles C Gambacorti-Passerini Carlo C Mauro Michael J MJ Druker Brian J BJ Kim Dong-Wook DW Mahon Francois-Xavier FX Cortes Jorge J Radich Jerry P JP Hochhaus Andreas A Hughes Timothy P TP

Leukemia 20190617 8

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established pro ...[more]

PMID: 31209280

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Project description:The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.

Project description:BackgroundDespite increasing availability of environmental health science (EHS) data, development, and implementation of relevant semantic standards, such as ontologies or hierarchical vocabularies, has lagged. Consequently, integration and analysis of information needed to better model environmental influences on human health remains a significant challenge.ObjectivesWe aimed to identify a committed community and mechanisms needed to develop EHS semantic standards that will advance understanding about the impacts of environmental exposures on human disease.MethodsThe National Institute of Environmental Health Sciences sponsored the "Workshop for the Development of a Framework for Environmental Health Science Language" hosted at North Carolina State University on 15-16 September 2014. Through the assembly of data generators, users, publishers, and funders, we aimed to develop a foundation for enabling the development of community-based and data-driven standards that will ultimately improve standardization, sharing, and interoperability of EHS information.DiscussionCreating and maintaining an EHS common language is a continuous and iterative process, requiring community building around research interests and needs, enabling integration and reuse of existing data, and providing a low barrier of access for researchers needing to use or extend such a resource.ConclusionsRecommendations included developing a community-supported web-based toolkit that would enable a) collaborative development of EHS research questions and use cases, b) construction of user-friendly tools for searching and extending existing semantic resources, c) education and guidance about standards and their implementation, and d) creation of a plan for governance and sustainability.CitationMattingly CJ, Boyles R, Lawler CP, Haugen AC, Dearry A, Haendel M. 2016. Laying a community-based foundation for data-driven semantic standards in environmental health sciences. Environ Health Perspect 124:1136-1140;?http://dx.doi.org/10.1289/ehp.1510438.

Dataset Information

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia.

Publications

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia.

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