Leukemia, Myelogenous, Chronic Phase Clinical Trial
Official title:
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.
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
;