慢性髓性白血病患者中酪氨酸激酶抑制剂的降阶梯或停药：中国多中心、开放标签、前瞻性试验

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.