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 greater than 0.1% (MMR). The primary endpoint was 12‐month MMR rate in patients who received de‐escalation or discontinuation of TKIs. This study was registered at ClinicalTrials.gov (NCT04143087). Results: Around 125 patients were enrolled between October 23, 2019 and October 31, 2020, 62 patients received dose de‐escalation of TKIs, while 63 patients in the discontinuation group. In the de‐escalation group, molecular recurrence‐free survival at 12 months was 88.32% (95% CI 79%–98%), whereas molecular recurrence‐free survival in the discontinuation group at 12 months was 59.98% (95% CI 47–73). No progressions occurred at the data cut‐off date. All 29 recurrence cases restart TKI treatment returned to MMR. Cytolytic NK cells as a proportion of lymphocyte cells were significantly increased from baseline after 6 months whether in the de‐escalation or TKIs cessation group (P = 0.048, 0.001, respectively); compared with the relapsing patients, Tregs proportion was decreased (P = 0.003), and higher proportion of NK cells were found in non‐relapsing patients whether in TKI de‐escalation or discontinuation group (P = 0.011, 0.007, respectively). We also found that the de‐escalation group showed better disease‐specific HRQOL in regards to its impact on emotional functioning, fatigue, pain, and financial difficulties. Conclusion: With 88.32% MMR in 12‐months follow‐up after de‐escalation TKIs’ treatment, dose‐halving could become a new treatment paradigm for CML patients who with DMR under continuing maintenance therapy with TKIs