PTCH1 expression at diagnosis predicts imatinib failure in chronic myeloid leukaemia patients in chronic phase

Juan M. Alonso-Dominguez, Jacob Grinfeld, Mary Alikian, David Marin, Alistair Reid, Mustafa Daghistani, Corinne Hedgley, Stephen O'Brien, Richard E. Clark, Jane Apperley, Letizia Foroni, Gareth Gerrard

Research output: Contribution to journalArticle

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Abstract

The tyrosine kinase inhibitor (TKI) imatinib has revolutionized the management of chronic myeloid leukaemia (CML). However, around 25% of patients fail to sustain an adequate response. We sought to identify gene-expression biomarkers that could be used to predict imatinib response. The expression of 29 genes, previously implicated in CML pathogenesis, were measured by TaqMan Low Density Array in 73 CML patient samples. Patients were divided into low and high expression for each gene and imatinib failure (IF), probability of achieving CCyR, progression free survival and CML related OS were compared by Kaplan-Meier and log-rank. Results were validated in a second cohort of 56 patients, with a further technical validation using custom gene-expression assays in a conventional RT-qPCR in a sub-cohort of 37 patients. Patients with low PTCH1 expression showed a worse clinical response for all variables in all cohorts. PTCH1 was the most significant predictor in the multivariate analysis compared with Sokal, age and EUTOS. PTCH1 expression assay showed the adequate sensitivity, specificity and predictive values to predict for IF. Given the different treatments available for CML, measuring PTCH1 expression at diagnosis may help establish who will benefit best from imatinib and who is better selected for second generation TKI.

Original languageEnglish (US)
Pages (from-to)20-26
Number of pages7
JournalAmerican journal of hematology
Volume90
Issue number1
DOIs
StatePublished - Jan 1 2015

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Gene Expression
Protein-Tyrosine Kinases
Disease-Free Survival
Imatinib Mesylate
Multivariate Analysis
Biomarkers
Sensitivity and Specificity

ASJC Scopus subject areas

  • Hematology

Cite this

PTCH1 expression at diagnosis predicts imatinib failure in chronic myeloid leukaemia patients in chronic phase. / Alonso-Dominguez, Juan M.; Grinfeld, Jacob; Alikian, Mary; Marin, David; Reid, Alistair; Daghistani, Mustafa; Hedgley, Corinne; O'Brien, Stephen; Clark, Richard E.; Apperley, Jane; Foroni, Letizia; Gerrard, Gareth.

In: American journal of hematology, Vol. 90, No. 1, 01.01.2015, p. 20-26.

Research output: Contribution to journalArticle

Alonso-Dominguez, JM, Grinfeld, J, Alikian, M, Marin, D, Reid, A, Daghistani, M, Hedgley, C, O'Brien, S, Clark, RE, Apperley, J, Foroni, L & Gerrard, G 2015, 'PTCH1 expression at diagnosis predicts imatinib failure in chronic myeloid leukaemia patients in chronic phase', American journal of hematology, vol. 90, no. 1, pp. 20-26. https://doi.org/10.1002/ajh.23857
Alonso-Dominguez, Juan M. ; Grinfeld, Jacob ; Alikian, Mary ; Marin, David ; Reid, Alistair ; Daghistani, Mustafa ; Hedgley, Corinne ; O'Brien, Stephen ; Clark, Richard E. ; Apperley, Jane ; Foroni, Letizia ; Gerrard, Gareth. / PTCH1 expression at diagnosis predicts imatinib failure in chronic myeloid leukaemia patients in chronic phase. In: American journal of hematology. 2015 ; Vol. 90, No. 1. pp. 20-26.
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