De‐escalation or discontinuation of tyrosine kinase inhibitor in patients with chronic myeloid leukemia: A multicentral, open‐label, prospective trial in China

Abstract

Background: Long-term treatment-free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). Optimizing dose of tyrosine kinase inhibitors (TKIs) in the CML treatment maybe a new challenge to maintain effective and improving patients' quality of life. We hypothesized that administration of low-dose TKIs does not compromise major molecular response (MMR) in patients with CML who have a deep molecular response (DMR). Methods:We did an open-label, randomized trial at eight hospitals in China. Eligible CML-CP patients (aged 18-70 years) had shown continuous response to TKI more than 5 years and maintained MR4.5 (BCR-ABLIS ≤ 0.0032%) in recent 18 months. Patients were randomly assigned (1:1) to the TKI de-escalation group or the discontinuation group. Randomization was done with permuted blocks (block size four) and implemented through an interactive web-based randomization system. Recurrence was defined as the single sample with real time Quantitative PCR (RT-qPCR) measurement Jie Luo and Xin Du contributed equally to this study.

Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study

“…The molecular recurrence-free survival was lower in the discontinued group compared to the dose de-escalation group (59.9 versus 88.3) p= 0.0002. In the 12 months of dose de-escalation, 8% of patients lost MMR ( 22 ).…”

“…The duration of previous treatment, the depth of molecular response, previous resistance, type of BCR::ABL1 transcripts, halving time, and lymphocyte subtypes are known predictive factors of molecular recurrence after tyrosine kinase inhibitors (TKI) discontinuation (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Few studies investigated the kinetics of BCR::ABL1 transcripts during a dose de-escalation phase before discontinuation in predicting molecular relapse (21,22).…”

Peripheral lymphocyte subsets as predicting factors for molecular recurrence after imatinib discontinuation in a phase 2 imatinib discontinuation trial in patients with chronic myeloid leukemia

“…Other discontinuation trials analyzed the immunological profile of CML patients by flow cytometry. Recently, Luo et al 15 showed that NK cells were increased at baseline in CML patients who did not relapse after stopping TKI compared to relapsing patients, but they did not analyze DP T cells. Irani et al also reported that patients who had a successful TFR had a higher proportion of NK cells at TKI discontinuation, but they did not evaluate the role of DP T cells.…”

Successful treatment discontinuation in CML patients with full-dose and low-dose TKI: Results from real-world practice

“…In addition, several studies have shown that low-dose TKI treatment is effective in maintaining major molecular response (MMR) ( Rea et al, 2017a ; Clark et al, 2017 ; Claudiani et al, 2021 ). Moreover, dose-halving therapy yields higher molecular recurrence-free survival rate compared to direct TKI discontinuation ( Luo et al, 2022 ). Our recent study also confirmed the feasibility of TKI dose reduction therapy for Chinese CML patients ( Chen et al, 2022 ).…”