Date Published: July 13, 2017
Publisher: Public Library of Science
Author(s): Juan M. Alonso-Dominguez, Luis Felipe Casado, Eduardo Anguita, Maria Teresa Gomez-Casares, Ismael Buño, Francisca Ferrer-Marín, Alicia Arenas, Rafael Del Orbe, Rosa Ayala, Pilar Llamas, Rocio N. Salgado, Santiago Osorio, Pedro Sanchez-Godoy, Carmen Burgaleta, Ignacio Mahíllo-Fernández, Valentin Garcia-Gutierrez, Juan Luis Steegmann, Joaquín Martinez-Lopez, Persio Dello Sbarba.
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.
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). However, roughly 25% of patients discontinue imatinib due to lack of efficacy . A few years ago, two second-generation tyrosine kinase inhibitors (TKIs), dasatinib and nilotinib, were approved for first-line treatment, increasing the armamentarium available for patients diagnosed with CML in chronic phase (CP-CML) [2,3].
The characteristics of the cohort are provided in Table 1. The median follow-up was 2.8 years (range 0.2–12.6 years). Fourteen patients discontinued imatinib due to lack of efficacy. Five presented with primary resistance (i.e., failed to achieve CCyR with imatinib), and nine presented with secondary resistance (i.e., positive response followed by a loss of response). Among patients with secondary resistance, five achieved CCyR and four achieved MMR on imatinib, but subsequently lost the response. Twelve patients discontinued imatinib due to side effects.
This study included 101 patients diagnosed with CP-CML to obtain external validation and compare the predictive power of PTCH1 expression and the PTCH1/SMO expression ratio. PTCH1 expression had the greatest AUC for predicting IF, and the PTCH1/SMO ratio had a slightly reduced AUC. 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].