Somatic variants in epigenetic modifiers can predict failure of response to imatinib but not to second-generation tyrosine kinase inhibitors

Nteliopoulos, Georgios; Bazeos, Alexandra; Claudiani, Simone; Gerrard, Gareth; Curry, Edward; Szydlo, Richard; Alikian, Mary; Foong, Hui En; Nikolakopoulou, Zacharoula; Loaiza, Sandra; Khorashad, Jamshid S.; Milojković, Dragana; Perrotti, Danilo; Gale, Robert Peter; Foroni, Letizia; Apperley, Jane F.

doi:10.3324/haematol.2018.200220

Cited by 43 publications

(47 citation statements)

References 48 publications

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“…The data from 15 studies of patients at diagnosis and 20 studies at AP/BC are reported where cancer genes were mutated in more than one patient at diagnosis and/or BC. [14,[20][21][22][23][24][25][26][27][28][29][30][31][32][42][43][44][45][46][47][48][49][50][51]] Some variants were not included, such as the ASXL1 E1102D variant, which is reported in the population databases at a frequency suggesting it represents the germline and is not pathogenic. Other variants reported in PAX5, TP53 and TET2 were also not included for the same reason.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple studies reported patients at diagnosis with mutated cancer-associated genes. [14,[20][21][22][23][24][25][26][27][28][29][30][31][32] The genes are as defined by the Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census. [33] Many of the studies did not detail whether the patients were in CP at diagnosis or how the patients were selected for testing.…”

Section: Mutational Landscape At CML Diagnosismentioning

confidence: 99%

“…This has been suggested in one study, but patients were selected based on their outcome. [32] NGS provides the opportunity for high throughput sequencing of multiple potentially relevant genes and comprehensive studies over the next few years should establish the specific mutations or combination of mutations at diagnosis that confer a worse prognosis. Of course, this is highly dependent on the uniform interpretation of variants and the appropriate assignment of their clinical relevance.…”

Section: Can Cancer Gene Mutation Status Aid Therapeutic Decisions Fomentioning

confidence: 99%

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

et al. 2019

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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 approximately 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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Section: Resultsmentioning

confidence: 99%

Section: Mutational Landscape At CML Diagnosismentioning

confidence: 99%

Section: Can Cancer Gene Mutation Status Aid Therapeutic Decisions Fomentioning

confidence: 99%

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

et al. 2019

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“…17,18,[44][45][46] Mutations in other epigenetic modifiers were also found and associated with unfavorable outcome, as recently reported. 19,47,48 AP/BP and CP cases with unfavorable response also harbored mutations in PTPR genes, which are tumor suppressors 49 and negative regulators of JAK/STAT signaling. 50 They have been reported to be downregulated in CML patients.…”

Section: Discussionmentioning

confidence: 99%

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

Awad

Kankainen

Ojala³

et al. 2020

Blood Advances

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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm accounting for ∼15% of all leukemia. Progress of the disease from an indolent chronic phase to the more aggressive accelerated phase or blast phase (BP) occurs in a minority of cases and is associated with an accumulation of somatic mutations. We performed genetic profiling of 85 samples and transcriptome profiling of 12 samples from 59 CML patients. We identified recurrent somatic mutations in ABL1 (37%), ASXL1 (26%), RUNX1 (16%), and BCOR (16%) in the BP and observed that mutation signatures in the BP resembled those of acute myeloid leukemia (AML). We found that mutation load differed between the indolent and aggressive phases and that nonoptimal responders had more nonsilent mutations than did optimal responders at the time of diagnosis, as well as in follow-up. Using RNA sequencing, we identified other than BCR-ABL1 cancer-associated hybrid genes in 6 of the 7 BP samples. Uncovered expression alterations were in turn associated with mechanisms and pathways that could be targeted in CML management and by which somatic alterations may emerge in CML. Last, we showed the value of genetic data in CML management in a personalized medicine setting.

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“…These differences may be accountable for higher rates of IMA failures and lower rates of DMR observed in the young adult populations than the older population [32,42]. This negative impact of young age on the disease course seems to be reduced with first-line 2nd generation TKIs [42][43][44]. Finally, we believe that the absence of a significant difference in terms of cumulative incidence of DMR between IMA and 2-3G TKI first-line observed in this study is related to the fact that younger patients were preferentially treated with 2-3G TKIs and older patients with first-line IMA.…”

Section: Discussionmentioning

confidence: 99%

Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Étienne

Dulucq

Bauduer

et al. 2020

Cancers

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Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

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Somatic variants in epigenetic modifiers can predict failure of response to imatinib but not to second-generation tyrosine kinase inhibitors

Cited by 43 publications

References 48 publications

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

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

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

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