Evaluation of Tyrosine Kinase Inhibitor Discontinuation Post-Dose Reduction in Chronic Myeloid Leukemia Patients in Deep Molecular Remission

The primary objective of this study is to evaluate the **efficacy** of discontinuing tyrosine kinase inhibitors (TKIs) during and after a two-step dose reduction in patients with **chronic myeloid leukemia** (CML) who are in deep molecular remission. This is clinically relevant as it aims to determine whether patients can safely cease TKI therapy, potentially reducing long-term medication exposure and associated side effects while maintaining remission.

The secondary objective is to assess the **safety** of TKI discontinuation during and after the two-step dose reduction in the same patient population. This evaluation is crucial to ensure that the withdrawal of TKIs does not compromise patient safety or lead to adverse outcomes.

The clinical trial involves participants diagnosed with **chronic myeloid leukemia** (CML) who are in a documented first chronic phase. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a documented Ph1-positive and/or BCR-ABL1-positive CML, with specific hematological criteria met, such as less than 15% blasts in peripheral blood or bone marrow. The trial does not include a vulnerable population. Participants must have been treated with a tyrosine kinase inhibitor (TKI) for more than four years and have achieved a deep molecular response of MR4.0 or greater, lasting over two years. The trial population was selected based on these criteria, and participants must agree to use prescribed contraceptive methods during and after the study. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase II** study designed to evaluate the efficacy and safety of **tyrosine kinase inhibitors** (TKIs) withdrawal following a two-step dose reduction in patients with **chronic myeloid leukemia** (CML) in deep molecular remission. The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The overall duration of the trial is estimated to extend until June 2026, with recruitment having commenced in June 2020. Participants will be involved in the study for a maximum treatment period of 12 months, with the possibility of early termination if specific conditions arise, such as loss of major molecular response (MMR) or adverse events necessitating discontinuation of the study medication.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including documented Ph1-positive and/or BCR-ABL1-positive CML in the first chronic phase, age of 18 years or older, and a deep molecular response lasting more than two years. Following the screening, participants will undergo regular follow-up visits to monitor their molecular response and assess any adverse effects. The primary endpoints include the proportion of patients maintaining MMR and molecular recurrence-free survival (MRFS) at six and twelve months post-study entry. Secondary endpoints focus on the recovery of MMR and MR4.0 after TKI re-introduction, the dynamics of adverse effects during dose reduction, and the assessment of TKI withdrawal syndrome.

The end-of-study visit will evaluate the long-term outcomes of TKI discontinuation, including treatment-free survival (TFS) and the correlation of BCR-ABL1 kinetics with potential molecular relapse. Participants are expected to adhere to prescribed contraceptive methods throughout the study and for one year after the last dose of study medication. Conditions that may lead to early termination from the study include the loss of MMR, progression of the disease, or any cause of death. The trial aims to provide valuable insights into the feasibility of TKI withdrawal in patients with CML in deep molecular remission, potentially impacting future treatment strategies for this condition.

The clinical trial involves the administration of **Tasigna 150 mg hard capsules**, which contain the active substance **nilotinib**. This medication is provided in the form of hard capsules and is intended for **oral use**. The maximum daily dose is 800 mg, with a total treatment period of up to 12 months. The capsules are manufactured by Novartis Europharm Limited and are classified under the ATC code L01EA03. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the study.

Another experimental treatment in the trial is **Tasigna 200 mg hard capsules**, also containing **nilotinib**. Similar to the 150 mg formulation, these capsules are administered orally with a maximum daily dose of 800 mg. The treatment duration is capped at 12 months. The pharmaceutical form and manufacturer remain consistent with the 150 mg capsules, ensuring uniformity in administration and monitoring.

The study also includes **Glivec 100 mg hard capsules**, which contain the active substance **imatinib**. These capsules are designed for oral administration, with a maximum daily dose of 800 mg. The treatment period is limited to 12 months. Glivec is produced by Novartis Europharm Limited and is categorized under the ATC code L01EA01. Participant adherence to the dosing regimen will be closely monitored to ensure compliance.

Additionally, the trial incorporates **SPRYCEL 20 mg film-coated tablets**, containing the active substance **dasatinib**. These tablets are administered orally, with a maximum daily dose of 140 mg. The treatment duration is set at 12 months. Manufactured by Bristol-Myers Squibb Pharma EEIG, SPRYCEL is classified under the ATC code L01EA02. Compliance with the dosing schedule is essential and will be monitored throughout the study.

All medications in this trial are chemically derived and are not pediatric formulations. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Participants' adherence to the prescribed dosing schedules will be monitored to ensure the integrity of the study results.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the proportion of patients maintaining a **major molecular response (MMR)**, defined as BCR-ABL1 transcript levels ≤ 0.1%, and **Molecular Recurrence-Free Survival (MRFS)**, which is the time from study entry to loss of MMR or death from any cause. These will be evaluated at month 6 and month 12 after study entry. Additionally, the proportion of patients in MMR without treatment and **treatment-free survival (TFS)**, defined as the time from withdrawal of tyrosine kinase inhibitors (TKIs) to loss of MMR, reinitiation of TKI therapy, progression, or death, will be assessed at months 18, 24, and 36 after study entry.

Secondary endpoints will focus on the proportion of patients who lose MMR during de-escalation and after TKI discontinuation, and their recovery of MMR and **MR4.0** after TKI re-introduction. The time to re-establish MMR and MR4.0 after TKI restart will also be measured. Additional assessments include the dynamics of TKI's adverse effects during dose reduction, the incidence and severity of TKI withdrawal syndrome, and the correlation between adverse effects during previous TKI treatment and potential withdrawal syndrome. The study will also evaluate the correlation of BCR-ABL1 kinetics during TKI therapy with potential molecular relapse after TKI discontinuation, as well as the effect of TKI dose reduction and subsequent discontinuation on lipid metabolism and glycemia.