Sustained Treatment-free Remission in BCR-ABL+ Chronic Myeloid Leukemia

The study will investigate in newly diagnosed CP-CML patients the efficacy of NIL frontline therapy vs IM followed by switch to NIL in the case of absence of optimal response as defined by the ELN criteria.

This is a prospective, interventional, randomized, two arms, phase IV study evaluating both the depth of the molecular response and the rate of treatment free remission rate in newly diagnosed CP-CML patients treated with NIL or IM followed by switch to NIL in absence of optimal response (defined according the ELN 2013 criteria) as per clinical practice.

The enrolled patients will be randomized 1:1 between NIL and IM. Patients will be stratified according to the Sokal risk score to high versus intermediate/low risk groups. Newly diagnosed patients will be treated according to the registered dose of NIL and IM for frontline chronic phase CML (300 mg BID and 400 mg OAD, respectively). The patients intolerant to IM and the patients without optimal response to IM at 3 months, at 6 months, at 12 months (except the patients with progression to accelerated or blastic phase) will be switched to NIL second line.

The absence of optimal response is defined by at least one of the following ELN criteria: a) Absence of Complete Hematologic Response at 3 months or thereafter; b) Absence of Partial Cytogenetic Response (\> 35% Ph+ metaphases) at 3 months; c) BCR-ABL transcript level \> 10% according to the IS at 3 months; d) Absence of Complete Cytogenetic Response (\> 1% Ph+ metaphases) at 6 months; e) BCR-ABL transcript level \> 1% according to the IS at 6 months; f) Absence of Major Molecular Response (MR3.0, transcript level \> 0.1% according to the IS) at 12 months.

Treatment choice for the patients with progression to advanced disease phase while on IM and for the patients intolerant to or resistant (including progressions to advanced phases) to NIL will be up to the principal investigator of the participating Center. However, information concerning the course and outcome of these patients will be collected and recorded for at least 5 years, and they could be enrolled in investigational studies promoted by GIMEMA or other sponsors.

After the induction of deep molecular remission phase of therapy, i.e. the first two years of the study, residual disease will be closely monitored (quarterly) by Q-PCR assays. All the patients who obtain a reduction greater than 4.0 logs of residual disease (MR4.0) within the first three years of treatment, and maintain this level of response in all the subsequent tests up to the end of the fourth years of therapy qualify for the discontinuation phase of the study. Therefore, all patients who are in MR4.0 after a four-year period of TKI treatment, that must include in its final part at least one years of maintained MR4.0, defined as 12-month period during which the MR4.0 never is lost in 4 consecutive MRD analyses at three-monthly intervals, will enter the treatment free remission (TFR) phase of the study. In case of loss of MR3.0, the last assumed TKI will be resumed at the same dose.

All patients, including those who do not match the criteria for discontinuation of TKI treatment, will continue the assigned treatment and will be followed for 5 years, starting from the date of enrolment.

Eligibility Criteria:
Inclusion Criteria:

* Patients with a confirmed diagnosis of BCR/ABL+ CML in chronic phase

Documented chronic phase CML must meet all the following criteria:

\< 15% blasts in peripheral blood \< 30% blasts plus promyelocytes in peripheral blood \< 20% basophils in the peripheral blood

* 100 x 109/L (≥ 100,000/mm3) platelets

  * Age ≥18
  * ECOG performance status of 0-2
  * Evidence of typical BCR-ABL transcripts which are amenable to standardized RQ-PCR
  * Adequate end organ function as defined by:

Total bilirubin \< 1.5 x ULN (ULN = upper limit of normal in a local institution lab).

Does not apply to patients with isolated hyperbilirubinemia (e.g., Gilbert's disease) grade \< 3 SGOT (AST) and SGPT (ALT) ≤ 3 x ULN Serum amylase and lipase ≤ 2 x ULN Alkaline phosphatase ≤ 2.5 x ULN Serum creatinine \< 1.5 x ULN

* Having completed the QoL baseline evaluation (i.e., before randomization)
* Written informed consent prior to any study procedures.

Exclusion Criteria:

* Expression of any atypical BCR-ABL transcripts, instead of the classical P210-encoding type with the e13a2 or the e14a2 junction at screening.
* Previous treatment with BCR-ABL inhibitors for a period longer than 1 month.
* Previous anticancer agents (hydroxyurea, anagrelide, interferon) for CML for a time longer than three months.
* Poorly controlled diabetes mellitus (defined as HbA1c \>8%).
* Prior documented history of coronary heart disease, including myocardial infarction, coronary bypass, coronary stent, and symptomatic angina:

LVEF \<45% or below the institutional lower limit of the normal range (whichever ishigher) Complete left bundle branch block Right bundle branch block plus left anterior or posterior hemiblock Use of a ventricular-paced pacemaker Congenital long QT syndrome or a known family history of long QT syndrome History of or presence of clinically significant ventricular or atrial tachyarrhythmias

* Atrial fibrillation or flutter
* Clinically significant resting bradycardia (\< 50 beats per minute)
* QTc \> 450 msec on the average of three serial screening ECGs (using the QTcF formula). If QTcF \> 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and the patient re-tested History or clinical signs of myocardial infarction within 12 months of study entry History of unstable angina within 12 months of study entry Other clinically significant heart disease (e.g. congestive heart failure)

  * Uncontrolled hypertension is not a heart disease.
  * History of peripheral arterial occlusive disease.
  * History of acute pancreatitis within 12 months of study entry, or a past medical history of chronic pancreatitis.
  * Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers which cannot be either discontinued or switched to a different medication prior to starting study drug.
  * Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and for which cannot be either safely discontinued or switched to a different medication prior to starting study drug.