Cessation of Tyrosine Kinase Inhibitors in Patients With Chronic-phase Chronic Myelogenous Leukaemia

June 8, 2018 updated by: Professor Yok-lam Kwong, The University of Hong Kong

Cessation of Tyrosine Kinase Inhibitors in Patients With Chronic-phase Chronic Myelogenous Leukaemia Who Achieve Stable Deep Molecular Response

Since the debut of imatinib, the first tyrosine kinase inhibitor(TKI), more than two decades ago, the prognosis of patients with chronic myelogenous leukaemia (CML) has continued to improve. It has been shown that life expectancy of CML patients is approaching that of the general population nowadays. Currently, indefinite use of TKIs in patients with chronic-phase CML who achieve optimal response remains the standard practice. Nevertheless, the concepts of "treatment-free remission" and "functional" cure have been hotly discussed in recent years. A number of major international clinical trials have demonstrated that about 40-60% of CML patients who previously enjoyed deep molecular response on TKI manage to stay free from molecular relapse after cessation of TKI therapy.

Local experience of TKI cessation is lacking. This study aims to recruit patients diagnosed with CML, chronic phase who are treated with TKIs and remain in stable deep molecular response for at least two years. It is planned to stop TKI in these patients with regular monitoring, and determine their outcomes.

Study Overview

Status

Unknown

Conditions

Detailed Description

Major clinical trials including multicentre Stop Imatinib (STIM) trial, According to Stop Imatinib (A-STIM), TWISTER, Korean Imatinib Discontinuation Study (KIDS), European Stop Tyrosine Kinase Inhibitor Trial (EURO-SKI), and stop second generation (2G-TKI) showed that it is safe to stop TKI in patients who achieve stable deep molecular response (DMR) as defined by respective study groups. Around 40-60% of study participants managed to remain in treatment-free remission (TFR). For patients who experience molecular relapse after TKI withdrawal, most do so within the first 6 months. In addition, they all remained sensitive to TKI and majority of them were able to achieve the original molecular response. No loss of complete haematological response or progression to advanced phase CML was observed when the TKI was stopped.

Cessation of TKI in selected CML patients leads to freedom from treatment-related toxic effects. It is expected that at least 40% of enrolled patients will be in a sustained molecular remission after stopping TKI. Successful cessation would also reduce long-term treatment costs.

After cessation of TKI, fluctuation in molecular response, or even molecular relapse of the disease might bring about anxiety and distress in the patients. Some patients, estimated at around 40-60%, would experience molecular relapse and require resumption of TKI. Close molecular monitoring real-time polymerase chain reaction (RT-QPCR) after stopping TKI (every month in the first year and every 2 months in the second year) will allow early detection of possible molecular relapse and thus prompt resumption of TKI. Long-term risks of disease progression and drug resistance are uncertain, though the safety data from the TFR studies reported to date are sufficiently reassuring. Some patients might have musculoskeletal pain and pruritus after cessation of TKI, especially imatinib, which is also commonly known as "imatinib withdrawal syndrome".

Patients with chronic-phase CML who have been treated with a tyrosine kinase inhibitor for more than 3 years and had deep molecular response (breakpoint cluster region/Abelson murine leukemia (BCR-ABL1) transcript ≤0.0032% IS ratio, i.e. molecular response (MR4.5) for at least 2 years

Study Type

Observational

Enrollment (Anticipated)

30

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Hong Kong
      • Hong Kong, Hong Kong
        • Recruiting
        • The University of Hong Kong
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

All patients on TKI treatment for at least 3 years and DMR for at least 24 months and potentially eligible for the study will be recruited.

Description

Inclusion Criteria:

  • Adult (aged 18 years or above) patients diagnosed with chronic-phase CML
  • In deep molecular response (i.e. MR4.5 or below, or those whose breakpoint cluster region -Abelson murine leukemia (BCR-ABL) transcripts were undetectable with at least 20,000 amplified copies of the control gene) for at least 2 years, confirmed by at least 3 data points with no more than one assessment between MR4 and MR4.5
  • Under treatment with a TKI in first line, or in second line due to intolerance of another first-line TKI
  • At least three years of treatment with the same TKI before enrolment

Exclusion Criteria:

  • Under 18 years old
  • Adults under law protection or without ability to consent
  • Previous or planned autologous/allogeneic haematopoietic stem cell transplantation
  • Documented kinase domain mutation
  • History of disease progression (accelerated or blast phase)
  • A change to the current TKI because of unsatisfactory response to a previous TKI in those who are on second line TKI (Note: patients are still considered eligible if the switch of TKI was due to intolerance or side effects)
  • Patients who can speak neither Chinese nor English

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
disease free survival
Time Frame: 12 months
molecular relapse-free survival without treatment
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
disease free survival
Time Frame: 24 months
molecular relapse-free survival without treatment
24 months
Overall survival
Time Frame: 24 months
Overall survival without treatment
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The University of Hong Kong

Investigators

  • Principal Investigator: Yuk Man Cheung, MBBS(HK), Queen Mary Hospital, Hong Kong

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 18, 2017

Primary Completion (Anticipated)

March 30, 2019

Study Completion (Anticipated)

March 30, 2019

Study Registration Dates

First Submitted

April 24, 2017

First Submitted That Met QC Criteria

April 24, 2017

First Posted (Actual)

April 27, 2017

Study Record Updates

Last Update Posted (Actual)

June 11, 2018

Last Update Submitted That Met QC Criteria

June 8, 2018

Last Verified

June 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • QMH-CML-001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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