Gene expression analysis of patients with chronic myeloid leukemia who discontinued tyrosine kinase inhibitor

Abstract

The immunological mechanism of treatment-free remission is not clearly understood. We aimed to identify immune-related genetic differences that predict molecular relapse after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic phase chronic myeloid leukemia (CML). In this prospective multicenter study, patients who were treated with TKI for at least 3 years discontinued TKI and were monitored for loss of major molecular response. We used NanoString profiling to find gene expression differences associated with relapse. From August 2019 to April 2020, 42 patients were enrolled from five centers in South Korea. During the median follow-up of 16.9 months, 47.6% (20/42) of patients experienced molecular relapse. The 6- and 12-month molecular relapse-free survival (RFS) rates were 52.5% and 50%, respectively. The e14a2 transcript type and longer duration (≥ 50 months) of deep molecular response before TKI discontinuation were associated with longer molecular RFS. NanoString analysis revealed significant differences in immune-related gene expression between relapsed and non-relapsed patients at the time of TKI discontinuation, including T cell-related genes such as SIGLEC1, ARG2, CD160, and IFNG. In conclusion, differences in expression of immune-related genes may provide a prognostic marker for relapse after TKI discontinuation in patients with CML.

Keywords: Chronic myeloid leukemia; Generic difference; NanoString method; Treatment-free remission; Tyrosine kinase inhibitor.

Fig. 1

CONSORT flow diagram

Fig. 2

(a, b) The probability of molecular relapse-free survival (a) and sustained DMR after TKI discontinuation (b). (c, d, e) The probability of molecular relapse-free survival according to BCR::ABL1 transcript type (c), duration of DMR (d), and RT-qPCR values at the time of TKI discontinuation (e). Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. DMR, deep molecular response; TKI, tyrosine kinase inhibitor; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; IS, International Scale

Fig. 3

Comparison between molecular relapse and non-relapse groups according to (a) WBC count at TKI stop, (b) BCR::ABL1 transcript type, and (c) RT-qPCR values at TKI stop. Statistical comparisons between groups were performed using Pearson’s chi-squared test or Fisher’s exact test, as appropriate. WBC, white blood cell; TKI, tyrosine kinase inhibitor; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; IS, International Scale