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

on behalf of the International CML Foundation Genomics Alliance, Susan Branford, Dennis Dong Hwan Kim, Jane F. Apperley, Christopher A. Eide, Satu Mustjoki, S. Tiong Ong, Georgios Nteliopoulos, Thomas Ernst, Charles Chuah, Carlo Gambacorti-Passerini, Michael J. Mauro, Brian J. Druker, Dong Wook Kim, Francois Xavier Mahon, Jorge Cortes, Jerry P. Radich, Andreas Hochhaus, Timothy Hughes

Research output: Contribution to journalReview article

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.

LanguageEnglish
Pages1835-1850
Number of pages16
JournalLeukemia
Volume33
Issue number8
DOIs
Publication statusPublished - 1 Aug 2019

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

on behalf of the International CML Foundation Genomics Alliance (2019). Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia, 33(8), 1835-1850. https://doi.org/10.1038/s41375-019-0512-y
on behalf of the International CML Foundation Genomics Alliance. / Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. In: Leukemia. 2019 ; Vol. 33, No. 8. pp. 1835-1850.
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on behalf of the International CML Foundation Genomics Alliance 2019, 'Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia', Leukemia, vol. 33, no. 8, pp. 1835-1850. https://doi.org/10.1038/s41375-019-0512-y

Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. / on behalf of the International CML Foundation Genomics Alliance.

In: Leukemia, Vol. 33, No. 8, 01.08.2019, p. 1835-1850.

Research output: Contribution to journalReview article

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T1 - Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia

AU - on behalf of the International CML Foundation Genomics Alliance

AU - Branford, Susan

AU - Kim, Dennis Dong Hwan

AU - Apperley, Jane F.

AU - Eide, Christopher A.

AU - Mustjoki, Satu

AU - Ong, S. Tiong

AU - Nteliopoulos, Georgios

AU - Ernst, Thomas

AU - Chuah, Charles

AU - Gambacorti-Passerini, Carlo

AU - Mauro, Michael J.

AU - Druker, Brian J.

AU - Kim, Dong Wook

AU - Mahon, Francois Xavier

AU - Cortes, Jorge

AU - Radich, Jerry P.

AU - Hochhaus, Andreas

AU - Hughes, Timothy

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41375-019-0512-y

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on behalf of the International CML Foundation Genomics Alliance. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019 Aug 1;33(8):1835-1850. https://doi.org/10.1038/s41375-019-0512-y