The goal of this clinical trial is to learn if a 1-year dose-reduction strategy with tyrosine kinase inhibitors (TKIs) - before complete discontinuation - works to improve treatment-free remission in adults with chronic-phase chronic myeloid leukaemia (CML) who have already achieved stable deep molecular response and are eligible to stop therapy. It will also learn about the safety of this gradual reduction approach.
The main questions it aims to answer are:
Does the dose-reduction strategy lead to a higher 2-year molecular relapse-free survival rate (maintaining major molecular response, BCR-ABL1 ≤0.1%) compared with immediate TKI discontinuation? What medical problems (adverse events) do participants experience during and after dose reduction, and how do they differ from those in the direct-stop group? Researchers will compare the dose-reduction group (reduced daily TKI for 12 months, then 1-year follow-up) with the direct-discontinuation group (immediate stop, 2-year follow-up) to see whether gradual reduction is superior in preserving molecular remission. In addition, they will compare the changes in T-cell subsets between the two groups to explore immune mechanisms that may influence treatment-free remission.
Participants will:
Be randomly assigned to either dose reduction or immediate discontinuation; Take reduced TKI (or no drug) daily for 1 year, followed by 1-year observation (total 24 months); Visit the clinic every 2 months for the first 6 months, then every 3 months thereafter, for physical exams, blood tests, molecular monitoring (BCR-ABL1 PCR), and ECG; Have T-cell subsets measured by flow cytometry at months 3, 6, 12, and 24; Complete quality-of-life questionnaires (EORTC QLQ-CML24) at baseline and at months 3, 6, 12, and 24; Report all adverse events; if MMR is lost, they must restart full-dose TKI and be monitored monthly until remission is regained;
Age ≥ 18 years.
Patients in chronic phase, with no history of accelerated phase (AP-CML) or blast phase (BP-CML).
Treatment with a first-generation TKI for ≥5 years; treatment with a second-generation TKI for ≥3 years; for resistant patients, treatment with an effective TKI for ≥5 years.
Prior evidence of detectable BCR::ABL1 transcripts. Stable deep molecular response (DMR) for >2 years (MR⁴, BCR::ABL1¹⁵ ≤0.01%), with at least 4 test results meeting the criterion and each test at least 3 months apart.
Received stem cell transplantation before study entry.
Presence of diseases associated with immunodeficiency, such as syphilis, hepatitis C, or HIV.
Concurrent participation in other clinical studies.
Having another malignant disease, unless the other primary malignancy is currently of no clinical significance or does not require active intervention.
Parallel
Halve TKIs
DrugParticipants receive a reduced dose of their current tyrosine kinase inhibitor (TKI) for 12 months. Doses are halved/reduced per protocol: Flumatinib 400/200 mg QD, Imatinib 200 mg QD, Nilotinib 300 mg QD, Dasatinib 50 mg QD, or Olverembatinib 20 mg QD, based on pre-entry therapy. Followed by 12 months of observation without TKI
Withdrawal TKIs
DrugParticipants discontinue all tyrosine kinase inhibitor (TKI) therapy immediately after enrollment. No study drug is administered during the 24-month follow-up period. Regular molecular monitoring (BCR-ABL1 qPCR) is performed according to protocol: every 2 months for the first 6 months, and every 3 months thereafter until month 24. Upon confirmed loss of major molecular response (MMR, BCR-ABL1 \> 0.1%), TKI must be re-initiated at the original pre-enrollment dose.
2-year molecular relapse-free survival
Molecular relapse is defined as loss of major molecular response (MMR; BCR-ABL1 \> 0.1%) at a single time point.
Event-Free Survival (EFS)
EFS is defined as the time from enrollment to the first occurrence of confirmed loss of major molecular response (MMR; BCR-ABL1 \> 0.1%), progression to advanced phase disease, or death from any cause, whichever occurs first. Participants without an event are censored at the end of follow-up.
Changes in T cell subsets
Changes in T cell subsets at 3 months, 6 months, 12 months and 24 months after enrollment.
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