Gene expression signature that predicts early molecular response failure in chronic-phase CML patients on frontline imatinib

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Abstract

In chronic-phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR; EMR failure: BCR-ABL1 .10% on the international scale at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (eg, Myc, b-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared with low-risk (LR-GES) patients (78% vs 5%; P, .0001), with an overall accuracy of 93%. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10%). However, HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared with LR-GES patients. This novel multigene signature may be useful for selecting patients at high risk of EMR failure on standard therapy who may benefit from trials of more potent kinase inhibitors or other experimental approaches.

LanguageEnglish
Pages1610-1621
Number of pages12
JournalBlood Advances
Volume3
Issue number10
DOIs
Publication statusPublished - 28 May 2019

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{010076ecf3dd4ff9a498f06da11b893d,
title = "Gene expression signature that predicts early molecular response failure in chronic-phase CML patients on frontline imatinib",
abstract = "In chronic-phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR; EMR failure: BCR-ABL1 .10{\%} on the international scale at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (eg, Myc, b-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared with low-risk (LR-GES) patients (78{\%} vs 5{\%}; P, .0001), with an overall accuracy of 93{\%}. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10{\%}). However, HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared with LR-GES patients. This novel multigene signature may be useful for selecting patients at high risk of EMR failure on standard therapy who may benefit from trials of more potent kinase inhibitors or other experimental approaches.",
author = "Chung Kok and David Yeung and Liu Lu and Watkins, {Dale B.} and Tamara Gray and Yen Dang and Verity Saunders and John Reynolds and Deborah White and Timothy Hughes",
year = "2019",
month = "5",
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doi = "10.1182/bloodadvances.2019000195",
language = "English",
volume = "3",
pages = "1610--1621",
journal = "Blood advances",
issn = "2473-9529",
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AU - Kok, Chung

AU - Yeung, David

AU - Lu, Liu

AU - Watkins, Dale B.

AU - Gray, Tamara

AU - Dang, Yen

AU - Saunders, Verity

AU - Reynolds, John

AU - White, Deborah

AU - Hughes, Timothy

PY - 2019/5/28

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N2 - In chronic-phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR; EMR failure: BCR-ABL1 .10% on the international scale at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (eg, Myc, b-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared with low-risk (LR-GES) patients (78% vs 5%; P, .0001), with an overall accuracy of 93%. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10%). However, HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared with LR-GES patients. This novel multigene signature may be useful for selecting patients at high risk of EMR failure on standard therapy who may benefit from trials of more potent kinase inhibitors or other experimental approaches.

AB - In chronic-phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR; EMR failure: BCR-ABL1 .10% on the international scale at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (eg, Myc, b-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared with low-risk (LR-GES) patients (78% vs 5%; P, .0001), with an overall accuracy of 93%. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10%). However, HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared with LR-GES patients. This novel multigene signature may be useful for selecting patients at high risk of EMR failure on standard therapy who may benefit from trials of more potent kinase inhibitors or other experimental approaches.

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