Major molecular response achievement in CML Patients can be predicted by BCR-ABL1/ABL1 or BCR-ABL1/GUS ratio at an earlier time point of follow-up than currently recommended.

Sarah Huet,Amine Belhabri,Denis Souche,Jean-Pierre Magaud,Sandrine Hayette,Isabelle Tigaud,Pascale Cony-Makhoul,Sophie Gazzo,Franck Nicolini,Mauricette Michallet,Maël Heiblig,Zhuang Zuo

doi:10.1371/journal.pone.0106250

Abstract

Recent studies demonstrate that early molecular response to tyrosine-kinase inhibitors is strongly predictive of outcome in chronic myeloid leukemia patients and that early response landmarks may identify patients at higher risk for transformation who would benefit from an early switch to second-line therapy. In this study, we evaluated the ability of the control gene GUS to identify relevant thresholds for known therapeutic decision levels (BCR-ABL1/ABL1IS = 10% and 0.1%). We then defined the most relevant cut-offs for early molecular response markers (transcript level at 3 months, halving time and log reduction between diagnosis and 3 months of treatment) using GUS or ABL1. We demonstrated that, although both control genes could be used (in an equivalent way) to accurately assess early molecular response, the BCR-ABL1/GUS level at diagnosis is impacted by the higher GUS copy number over-expressed in CML cells, thus negatively impacting its ability to completely replace ABL1 at diagnosis. Furthermore, we pointed out, for the first time, that it would be helpful to monitor BCR-ABL1 levels at an earlier time point than that currently performed, in order to assess response to first-line tyrosine-kinase inhibitors and consider a potential switch of therapy as early as possible. We evaluated this optimal time point as being 19 days after the start of treatment in our cohort.

Highlights

The European Leukemia Network (ELN) recommendations for the management of chronic myeloid leukemia (CML) patients define optimal response, warning or failure according to cytogenetic and/or molecular criteria obtained at 3, 6 and 12 months on tyrosine-kinase inhibitors (TKI) therapy [1] and optimal response is associated with best long-term outcome
Several studies have highlighted that the achievement of early molecular and cytogenetic responses on TKI was predictive of long term eventfree survival (EFS), treatment-free survival (TFS) and overall survival (OS) and that this ability to predict outcome is observed for all TKI with different kinetics [2,3,4,5,6,7,8,9,10,11]
GUS may be used as control gene (CG) to quantify the BCR-ABL1 transcript, our study highlights that the use of BCR-ABL1/GUS instead of BCR-ABL1/ABL1 would have several consequences

Summary

Introduction

The European Leukemia Network (ELN) recommendations for the management of chronic myeloid leukemia (CML) patients define optimal response, warning or failure according to cytogenetic and/or molecular criteria obtained at 3, 6 and 12 months on tyrosine-kinase inhibitors (TKI) therapy [1] and optimal response is associated with best long-term outcome. Early molecular response (EMR) to TKI is currently identified as being one of the most important prognostic factors, and early response landmarks may identify patients at higher risk for transformation and poor outcome, who may benefit from alternative treatments in order to improve response and thereby minimize exposure to risk over time. The prognostic significance of achieving MMR at 12 or 18 months has been controversial in the past [14,15], Hughes et al showed that patients who achieved MMR by 12 and 18 months while on Imatinib therapy had significantly improved 7-year EFS and PFS rates [4], demonstrating a strong association between MMR achievement and long-term clinical outcome. Reaching the 12-month MMR still represents an ELN criterion of optimal response and should be a main goal in the management of the patient

Methods

Results

Conclusion