PTCH1 is a reliable marker for predicting imatinib response in chronic myeloid leukemia patients in chronic phase.

Juan M Alonso-Dominguez,Joaquín Martinez-Lopez,Luis Felipe Casado,Ismael Buño,Pilar Llamas,Ignacio Mahíllo-Fernández,Carmen Burgaleta,Alicia Arenas,Valentin Garcia-Gutierrez,Rosa Ayala,Eduardo Anguita,Santiago Osorio,Maria Teresa Gomez-Casares,Rafael Del Orbe,Francisca Ferrer-Marín,Pedro Sanchez-Godoy,Juan Luis Steegmann,Rocio N Salgado,Persio Dello Sbarba

doi:10.1371/journal.pone.0181366

Abstract

Patched homolog 1 gene (PTCH1) expression and the ratio of PTCH1 to Smoothened (SMO) expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML) patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP) using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72). In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF), which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013), probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02), and proportions of early molecular failure (14% vs. 43%, P = 0.015). Every progression to an advanced phase (n = 3) and CML-related death (n = 2) occurred in the low PTCH1 group (P<0.001 for both comparisons). PTCH1 was an independent prognostic factor for the prediction of IF. We also validated previously published thresholds for PTCH1 expression. Therefore, we confirmed that PTCH1 expression can predict the imatinib response in CML patients in CP by applying a more rigorous statistical analysis. Thus, PTCH1 expression is a promising molecular marker for predicting the imatinib response in CML patients in CP.

Highlights

At the beginning of this century, aberrant tyrosine kinase activity of the BCR-ABL1 oncogene protein was identified as a putative therapeutic target
This study included 101 patients diagnosed with chronic phase (CP)-chronic myeloid leukaemia (CML) to obtain external validation and compare the predictive power of Patched homolog 1 gene (PTCH1) expression and the PTCH1/SMO expression ratio
Given that we sought to reduce the number of genes to be quantified and the lack of improvement in the predictive power of the PTCH1/SMO expression ratio, we determined that measuring PTCH1 was optimal for the present study [16,27]

Summary

Introduction

At the beginning of this century, aberrant tyrosine kinase activity of the BCR-ABL1 oncogene protein was identified as a putative therapeutic target. This finding led to the development of imatinib, which revolutionized the treatment of chronic myeloid leukaemia (CML). Three different clinical scores (Sokal, EUTOS, and Hasford) are currently used to predict the outcome of patients diagnosed with CP-CML [6,7,8]. Developed in the pre-TKI era, the Sokal and Hasford scores have retained their predictive power in patients treated with TKIs. The European Leukemia Net (ELN) states that a high risk classification in any of the scores should be considered a warning, but no clear recommendation has been made regarding treatment [5]

Methods

Results

Conclusion