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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03131986
Recruitment Status : Unknown
Verified June 2018 by Professor Yok-lam Kwong, The University of Hong Kong.
Recruitment status was:  Recruiting
First Posted : April 27, 2017
Last Update Posted : June 11, 2018
Information provided by (Responsible Party):
Professor Yok-lam Kwong, The University of Hong Kong

Brief Summary:

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.

Condition or disease
Leukemia, Myelogenous, Chronic Phase

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

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Study Type : Observational
Estimated Enrollment : 30 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Cessation of Tyrosine Kinase Inhibitors in Patients With Chronic-phase Chronic Myelogenous Leukaemia Who Achieve Stable Deep Molecular Response
Actual Study Start Date : April 18, 2017
Estimated Primary Completion Date : March 30, 2019
Estimated Study Completion Date : March 30, 2019

Primary Outcome Measures :
  1. disease free survival [ Time Frame: 12 months ]
    molecular relapse-free survival without treatment

Secondary Outcome Measures :
  1. disease free survival [ Time Frame: 24 months ]
    molecular relapse-free survival without treatment

  2. Overall survival [ Time Frame: 24 months ]
    Overall survival without treatment

Biospecimen Retention:   Samples With DNA
For analysis by cytogenetic/ molecular methods for better understanding of the disease biology

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03131986

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Contact: Yuk Man Cheung, MBBS(HK) 85222555161
Contact: Crosby Lu, MMedSc 85222551654

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Hong Kong
The University of Hong Kong Recruiting
Hong Kong, Hong Kong
Contact: Yuk Man Cheung, MBBS(HK)    852-22554361 ext 1654   
Contact: Crosby Lu, MMedSc    852-22551654   
Sponsors and Collaborators
The University of Hong Kong
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Principal Investigator: Yuk Man Cheung, MBBS(HK) Queen Mary Hospital, Hong Kong
Publications of Results:

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Responsible Party: Professor Yok-lam Kwong, Prof Kwong Yok Lam, The University of Hong Kong Identifier: NCT03131986    
Other Study ID Numbers: QMH-CML-001
First Posted: April 27, 2017    Key Record Dates
Last Update Posted: June 11, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Neoplasms by Histologic Type
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases