Similar expression profiles in CD34+ cells from chronic phase chronic myeloid leukemia patients with and without deep molecular responses to nilotinib.

Ami B Patel,Christina A Harrington,Todd W Kelley,Kimberly R Reynolds,Thomas O’Hare,Anthony D Pomicter,Michael W Deininger,Christopher J Conley,Thoralf Lange

doi:10.18632/oncotarget.24954

Abstract

The life expectancy of patients with chronic phase chronic myeloid leukemia on tyrosine kinase inhibitor therapy now approaches that of the general population. Approximately 60% of patients treated with second generation tyrosine kinase inhibitors achieve a deep molecular response, the prerequisite for a trial of treatment-free remission. Those patients unlikely to achieve deep molecular response may benefit from more intensive therapy up front. To identify biomarkers predicting deep molecular response we performed transcriptional profiling on CD34+ progenitor cells from newly diagnosed chronic phase chronic myeloid leukemia patients treated with nilotinib on a prospective clinical trial. Using unsupervised and targeted analytical strategies, we show that gene expression profiles are similar in patients with and without subsequent deep molecular response. This result is in contrast to the distinct expression signature of CD34+ chronic phase chronic myeloid leukemia patients failing to achieve a cytogenetic response on imatinib and suggests that deep molecular response to second-generation tyrosine kinase inhibitors is governed by the biology of more primitive chronic myeloid leukemia cells or extrinsic factors.

Highlights

Most chronic phase chronic myeloid leukemia (CPCML) patients treated with tyrosine kinase inhibitors (TKIs) have excellent outcomes, with overall survival driven primarily by co-morbidities [1]
This result is in contrast to the distinct expression signature of CD34+ chronic phase chronic myeloid leukemia patients failing to achieve a cytogenetic response on imatinib and suggests that deep molecular response to second-generation tyrosine kinase inhibitors is governed by the biology of more primitive chronic myeloid leukemia cells or extrinsic factors
Since data from the unsupervised analysis failed to identify differences in global gene expression profiles of responders and non-responders, we investigated three prespecified sets of non-overlapping probes with a potential role in governing molecular response to nilotinib: (i) a 75-probe set signature previously shown to predict major cytogenetic response in CP-CML patients treated with imatinib (Supplementary Figure 3); (ii) 50 probes corresponding to genes implicated in CML stem cell persistence identified by literature review (Supplementary Figure 4A); and (iii) 365 probes associated with Wnt/β-catenin signaling (KEGG ID hsa04310) based on our finding that β-catenin activation is a feature of primary cytogenetic resistance (Supplementary Figure 4B) [8]

Summary

Introduction

Most chronic phase chronic myeloid leukemia (CPCML) patients treated with tyrosine kinase inhibitors (TKIs) have excellent outcomes, with overall survival driven primarily by co-morbidities [1]. TKIs are generally well tolerated, long-term use can lead to complications. Therapeutic goals in CML have shifted from overall survival to treatment free remission (TFR), defined as the ability to maintain major molecular response (MMR) after TKI discontinuation. Current guidelines recommend stable deep molecular response (DMR; reduction of BCR-ABL1 transcripts by ≥4-log) as the minimum prerequisite for a trial of TFR [4, 5]. In the DASISION and ENESTnd trials, DMR rates by 5 years were approximately 40% on imatinib and 60% on 2G TKIs [6, 7]

Methods

Results

Conclusion