De-escalation Strategy of Tyrosine Kinase Inhibitors Before Treatment Discontinuation in Patients With Chronic Myeloid Leukemia

Phase 4Not Yet RecruitingNCT07839988

Nanfang Hospital, Southern Medical University280 enrolled

Overview

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;

Chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) have significantly prolonged survival, but long-term medication leads to adverse events, financial burden, and reduced quality of life, creating a strong desire for treatment discontinuation. Chinese CML patients are diagnosed at a younger median age (45-50 years) than Western populations, exposing them to TKIs earlier and making treatment-free remission (TFR) a particularly urgent goal. Current studies show that direct discontinuation after achieving deep molecular response yields a 2-year molecular relapse-free survival rate of approximately 50%, with some patients experiencing "withdrawal syndrome." Recent evidence suggests that TKI dose reduction may lower relapse risk and reduce adverse effects without compromising efficacy. Therefore, investigating whether a tapering strategy before discontinuation is superior to immediate cessation is of great significance for optimising CML management and improving patients' quality of life. This study aims to investigate the difference in 2-year molecular relapse-free survival between Chinese CML patients who undergo gradual TKI dose reduction and those who discontinue TKI immediately after meeting the criteria for treatment-free remission, and to evaluate whether the dose-reduction strategy is superior to immediate discontinuation in improving molecular relapse-free survival.

Interventions

Halve TKIsDRUG

Participants 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 TKIsDRUG

Participants 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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥ 18 years. 2. Patients in chronic phase, with no history of accelerated phase (AP-CML) or blast phase (BP-CML). 3. 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. 4. 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. 5. Availability of reliable qPCR testing with a sensitivity of at least MR⁴·⁵ (BCR::ABL1¹⁵ ≤0.0032%), and test results available within 2 weeks. Exclusion Criteria: 1. Received stem cell transplantation before study entry. 2. Presence of diseases associated with immunodeficiency, such as syphilis, hepatitis C, or HIV. 3. Concurrent participation in other clinical studies. 4. Having another malignant disease, unless the other primary malignancy is currently of no clinical significance or does not require active intervention. 5. Major surgery within 4 weeks, or not recovered from a previous surgery. 6. Pregnancy, lactation, or women planning to become pregnant. 7. Eastern Cooperative Oncology Group performance status (ECOG PS) ≥3. 8. Inability to comply with protocol procedures or to attend follow-up visits on time. 9. Known allergy or contraindication to the study drug (active pharmaceutical ingredient and/or excipients). 10. Any other condition that the investigator considers makes the patient unsuitable for enrolment.

Outcomes

Primary Outcomes

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.

Time frame: From enrollment until molecular relapse (loss of MMR) or death from any cause, whichever came first, assessed up to 2 years.

Secondary Outcomes

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.

Time frame: From date of enrollment until the date of first documented confirmed loss of MMR (BCR-ABL1 > 0.1%), progression to advanced phase, or death from any cause, whichever came first, assessed up to 24 months.

Changes in T cell subsets

Changes in T cell subsets at 3 months, 6 months, 12 months and 24 months after enrollment.

Time frame: Changes in T cell subsets at 3 months, 6 months, 12 months and 24 months after enrollment.