Regulatory T Cell as a Biomarker of Treatment-Free Remission in Patients with Chronic Myeloid Leukemia.

Yuki Fujioka,Masatomo Miura,Hiroyoshi Nishikawa,Yosuke Minami,Daisuke Sugiyama,Yoshiko Atsuta,Yasushi Miyazaki,Naoto Takahashi,Itaru Matsumura,Hitoshi Kiyoi,Shigeki Ohtake

doi:10.3390/cancers13235904

Abstract

Simple SummaryTyrosine kinase inhibitors (TKIs) have dramatically improved the treatment of chronic myeloid leukemia (CML). Recently, TKIs were discontinued in patients with CML with deep molecular remission, and some patients have been reported to be able to maintain long-term treatment-free remission (TFR). However, there is no certainty regarding which patients can maintain TFR. We focused on immunity in the TFR phase and investigated the immunological mechanism of continuous TFR or recurrence. Our results suggest that the group that maintains the TFR is immunologically activated. In addition, regulatory T cells can be used as a biomarker. These results may have important implications for future strategies for maintaining TFR in CML treatment. Treatment-free remission (TFR) has become a therapeutic goal in chronic myeloid leukemia (CML), and approximately half of the patients with chronic phase-CML (CML-CP) with deep molecular remission (DMR) by tyrosine-kinase inhibitors (TKIs) have achieved TFR. However, the mechanism of continuous TFR is still unclear, as there are “fluctuate” patients who have BCR–ABL-positive leukemia cells but do not observe obvious relapse. We focused on the immune response and conducted an immune analysis using clinical samples from the imatinib discontinuation study, JALSG-STIM213. The results showed that, in the group that maintained TFR for 3 years, changes in regulatory T (Treg) cells were observed early after stopping imatinib treatment. The effector Treg (eTreg) cells increased transiently at 1 month after stopping imatinib and then returned to baseline at 3 months after stopping imatinib treatment. There was no difference in the Treg phenotype, and CD8+ T cells in the TFR group were relatively activated. High concentrations of imatinib before stopping were negatively correlated with eTreg cells after stopping imatinib. These data suggest immunological involvement in the maintenance of the TFR, and that Treg cells after stopping imatinib might be a biomarker for TFR. Furthermore, high imatinib exposure may have a negative immunological impact on the continuous TFR.

Highlights

Chronic myeloid leukemia (CML) occurs in hematopoietic stem cells and is characterized by the presence of the BCR–ABL1 fusion gene on the Philadelphia chromosome
We conducted an imatinib discontinuation trial in patients with chronic myeloid leukemia (CML) chronic phase (CP) who were treated with imatinib for at least 3 years and had a deep molecular remission (DMR) of at least 2 years (JALSG-STIM213) [11]
Similar to the results obtained by mass cytometry, effector the kinetics of regulatory (Treg) (eTreg) cells tended to increase after imatinib discontinuation in the treatment-free remission (TFR) group (Figure 2A), but there was no significant difference in the eTreg, naïve Treg (nTreg), and non-Treg cells between the TFR and retreatment groups (Figure 2B and Figure S3A–D)

Summary

Introduction

Chronic myeloid leukemia (CML) occurs in hematopoietic stem cells and is characterized by the presence of the BCR–ABL1 fusion gene on the Philadelphia chromosome. The advent of imatinib, the first BCR–ABL1 tyrosine kinase inhibitor (TKI), has dramatically improved the prognosis of CML [1,2,3] and has become standard therapy for CML since. Treatment-free remission (TFR) has become the new goal of CML therapy according to various TKI discontinuation trials [6,7,8,9,10,11]. TFR cannot be determined by estimating the absence or presence of BCR–ABL1-positive leukemia cells in the peripheral blood, because international-scale polymerase chain reaction (IS-PCR) has shown that patients with fluctuating values of the BCR–ABL1 fusion gene can maintain TFR [10,11].

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