The aim of this study is to investigate whether some patients, with excellent responses to treatment of white blood cell cancer [chronic myeloid leukaemia (CML)], are being over-treated and can remain well on either a lower dose of treatment or without treatment at all. The dose of drugs, imatinib (Glivec), nilotinib (Tasigna) or dasatinib (Sprycel), will initially be cut to half the standard dose for 12 months and then treatment will be stopped completely for a further two years. This study will also help to develop a treatment decrease and stopping strategy for future patients.
Patients who have been treated with imatinib, dasatinib or nilotinib for at least 3 years from original diagnosis and whose BCR-ABL1 levels (measure of a gene fusion product) have been at or below 0.1% on all tests for the past 12 months.
Two groups are studied: those in whom BCR-ABL1 has been undetectable for at least 12 months in at least three samples (molecular remission at the 4-log level, abbreviated as the MR4 group) and those in whom BCR-ABL1 is detectable on some or all tests in the past 12 months, but always below a level of 0.1% (major molecular response, abbreviated to the MMR group). Both groups are treated identically though analysed separately, by initially decreasing treatment to half of the standard dose for 12 months. If the BCR-ABL1 level remains at or below 0.1%, treatment is then completely stopped and observation continues for a further 24 months.
It is estimated that DESTINY will bring substantial savings to the NHS. Dose decrease or discontinuation of treatment might improve quality of life. Imatinib has several mild but persistent side effects such as rash, oedema and stomach upset. Similarly, dasatinib may cause fluid accumulation in lungs and hypertension and nilotinib may be associated with an increased late risk heart diseases.
The DESTINY trial will evaluate the feasibility of de-escalation and then stopping treatment in chronic myeloid leukaemia patients with excellent responses to prior treatment. DESTINY is conceived as a pilot for including this strategy in the next phase III study for the UK (to be known as SPIRIT3). Patients are eligible if in first chronic phase; have been treated with imatinib, dasatinib or nilotinib for at least 3 years from original diagnosis; and whose BCR-ABL1 levels have been at or below 0.1% on all tests for the past 12 months. Two groups will be studied; those in whom BCR-ABL1 has been undetectable for at least 12 months in at least 3 samples, all of which have at least 104 control transcripts (molecular remission at the 4-log level, abbreviated as the MR4 group), and those in whom BCR-ABL1 is detectable on some or all tests in the past 12 months, but always below a level of 0.1% (major molecular response, abbreviated to the MMR group). Both MR4 and MMR groups will be treated identically though analysed separately, by initially de-escalating treatment to 50% of the standard dose for 12 months. If the BCR-ABL1 level remains at or below 0.1%, treatment is then completely stopped, and observation continues for a further 24 months.
The objective of DESTINY is to determine the safety and efficacy of initially de-escalating and then stopping tyrosine-kinase inhibitor (TKI) treatment, in CML patients with either undetectable disease or with stable MMR.
Dasatinib, imatinib or nilotinib; de-escalated to half the standard dose for 12 months. If on imatinib, the dose should be decreased to 200mg daily, if on nilotinib, to 200mg twice daily (which is half the standard dose for second line use, since it is anticipated that the vast majority of nilotinib entrants will be receiving 400mg twice daily because of prior imatinib intolerance) and if on dasatinib then to 50 mg daily. Follow Up Length: 37 month(s).
5.2. (MMR group) some or all BCR-ABL1 molecular results are in MMR (BCRABL1/ ABL1 ratio of 0.1% or less, but not zero, with at least 10,000 ABL1 control transcripts). If the results over the preceding 12 months are a mix of MMR and undetectable BCR-ABL1, then the patient is eligible for the MMR but not the MR4 group.
*Patients who are Philadelphia chromosome (Ph) negative (or whose Ph status is not known) are eligible. Patients who do not have a standard BCR-ABL1 fusion transcript (i.e. other than e13a2 or e14a2, also known as b2a2 and b3a2) are eligible, but before screening the patient, contact should be made with Prof Foroni at Imperial College (see contacts) since specialised quantitative molecular assessment will be required.
Planned Sample Size: 168; UK Sample Size: 168; Description: 84 patients will be recruited from both the 'MR4' and 'MMR' groups of patients.
10. Previous treatment with ponatinib or bosutinib. Patients who received interferon prior to commencing TKI (even if resistant to their interferon) are eligible, provided their response to TKI fits the entry criteria.