2nd or 3rd TKI-stop After 2 Years Nilotinib Pre-treatment in CML-patients

Multicenter Prospective Trial After 1st or 2nd Unsuccessful Treatment Discontinuation in Chronic Myeloid Leukemia ( CML) Estimating the Efficacy of Nilotinib in Inducing the Persistence of Molecular Remission After Stopping TKI a 2nd or 3rd Time

The main goal of the study is the assessment of duration of major molecular response (MMR) or better at 12 and 36 months after stopping tyrosine kinase inhibitors (TKI) therapy a second or third time in patients with at least three years prior TKI treatment comprising at least two years of nilotinib treatment within this trial and maintained stable MR4 (BCR-ABL ratio <0,01% on international Scale (IS) for at least one year and MR4.5 (BCR-ABL ratio <0,0032% on IS) for at least 6 months:

• who failed a first stop in the EURO-SKI study (standardized criteria)
• who failed a first or second stop outside the EURO-SKI study but would have had fulfilled same eligible criteria and were stopped according to EURO-SKI rules
• who failed a first or second stop outside the EURO-SKI study without fulfilling EURO-SKI rules

The proposal is to re-treat patients with a minimum of two years with nilotinib 2x300 mg/d resulting in total of at least three years TKI treatment who show recurrent disease after unsuccessful first or second stop after TKI treatment in or outside the EURO-SKI study.

If MR4 or better is re-achieved and maintained for at least one year and MR4.5 or better is re-achieved and maintained for at least 6 months, patients will be eligible for a second stop attempt within this study. For MR4, three consecutive PCRs with MR4 or deeper should be measured within one year and for MR4.5, two PCRs during 6 months should demonstrate a MR4.5.

Patients who exhibited hematological relapse after the first stop attempt will not be eligible for a second stop attempt within this study.

After inclusion, 3 monthly monitoring will be performed under nilotinib treatment within the trial. Patients fulfilling the criteria mentioned above will then enter the screening phase.

After verification of MR4.5, TKI treatment will be stopped and patients followed in the same manner as described in EURO-SKI (monthly PCRs for 6 months, 6-weekly PCRs 7-12 months after stopping, thereafter 3-monthly). If MMR is lost (BCR-ABL >0.1% (IS)), TKI treatment will once again be restarted; here the same TKI (nilotinib) is recommended.

It is assumed that after failure of first (or second) stop a switch to treatment with 2GTKI may increase the chance of stopping a second (or third) time [Legros et al. Blood 2012; Rea et al. Blood 2014] It is expected that the rate of a successful second (or third) stop at 12 and 36 months is more than 25%.

Inclusion Criteria:

• Age ≥ 18 years
• Patients with Ph chromosome and/or the BCR-ABL (either b3a2 and /or b2a2) fusion gene positive CML
• CML in CP having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not
• Pretreatment at least one year with any TKI after 1st stop
• Written informed consent

Exclusion Criteria:

• Previous hematological relapse after first stop of TKI.
• Failure to any TKI at any time during CML treatment according to current ELN criteria
• Previous planned or performed allo SCT
• Previous AP/BC at any time in the history of the disease
• High cardiac risk according to ESC score (≥ 10 Points)
• Impaired cardiac function including any of the following:
• Use of a ventricular paced pacemaker; congenital long QT syndrome or family history of; history or presence of significant ventricular or atrial tachyarrhythmias; clinically significant resting bradycardia (<50 bpm); QTcF >450 msec at baseline, myocardial infarction before baseline; other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension).
• Treatment with inhibitors of CYP3A4 or medications that have been well documented to prolong the QT interval is contraindicated.
• History of acute pancreatitis within one year of study entry or medical history of chronic pancreatitis.
• Positive hepatitis B virus serology test or HBV infection
• Any other malignancy except if neither clinically significant nor requires active intervention.
• Severe or uncontrolled medical conditions (i.e., uncontrolled diabetes, acute or chronic liver disease, pancreatic, or severe renal disease unrelated to tumor, active or uncontrolled infection).
• Women who are pregnant, breast feeding, or of childbearing potential without a negative serum pregnancy test at baseline. Male or female patients of childbearing potential unwilling to use an effective barrier contraceptive method