The purpose of the present study is to determine the rate of successful treatment-free
remission (TFR) within the first 52 weeks following cessation of ponatinib treatment in
patients who achieved MR4. Eligible patients had been previously treated with TKI and when
patients achieved an optimal molecular response, TKI treatment was discontinued. After loss
of response, patients were treated again with a TKI treatment and have documented MR4 for one
year at the time of switch to ponatinib to study entry. MR4 is defined as BCR-ABL transcript
level ≤ 0.01% IS or undetectable BCR-ABL levels with sample sensitivity of at least 4 log.
1. Male or female patients ≥ 18 years of age.
2. ECOG Performance Status of 0, 1, or 2.
3. Patient with diagnosis of BCR-ABL positive and Ph+ CML-Chronic Phase.
4. Patients who failed the first attempt of TKI discontinuation and after TKI
reintroduction they achieve again MR4 and it is maintained and confirmed for more than
5. Patients who are able to take oral therapy
6. Adequate end organ function as defined by:
1. Direct bilirubin ≤ 1.5 x ULN except for i) patient with documented Gilbert's
syndrome for whom any bilirubin value is allowed and ii) for patients with
asymptomatic hyperbilirubinemia (liver transaminases and alkaline phosphatase
within normal range),
2. SGOT(AST) and SGPT(ALT) ≤ 2.5 x ULN,
3. Serum lipase and amylase ≤ 1.5 x ULN,
4. Alkaline phosphatase ≤ 2.5 x ULN,
5. Serum creatinine ≤ 1.5 x ULN.
7. Patients must have the following electrolyte values ≥ LLN limits or corrected to
within normal limits with supplements prior to the first dose of study medication:
3. Total calcium (corrected for serum albumin)
8. Patients must have normal marrow function as defined below:
1. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L,
2. Platelets ≥ 100 x 109/L.
3. Hemoglobin > 9 g/dL.
9. Patients with preexisting, well-controlled diabetes can be included.
10. Have normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in
males or ≤ 470 ms in females.
11. Have a negative pregnancy test documented prior to enrollment (for females of
12. Be willing and able to comply with scheduled visits and study procedures.
13. Patients with the ability to comprehend and sign the informed consent.
14. Written informed consent obtained prior to any screening procedures.
1. Prior accelerate phase, blast crisis or autologous or allogenic transplant.
2. Patients with known atypical transcript. An atypical transcript is defined by the
presence of any transcript in the absence of the major transcripts b3a2 (e14a2) and
b2a2 (e13a2) or p210 protein.
3. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if a
testing was done in the past (there is no requirement to perform mutation testing at
study entry if it was not done in the past).
4. Are taking medications with a known risk of torsades de pointes (Annex 5).
5. Patient ever attempted to permanently discontinue TKI treatment.
6. Severe and/or uncontrolled concurrent medical disease that in the opinion of the
investigator could cause unacceptable safety risks or compromise compliance with the
protocol (e.g., uncontrolled diabetes (defined as HbA1c > 9%), uncontrolled
7. Have clinically significant, uncontrolled, or active cardiovascular disease,
specifically including, but not restricted to:
1. Any history of MI, unstable angina, cerebrovascular accident, or TIA.
2. Any history of peripheral vascular infarction, including visceral infarction.
3. Any revascularization procedure, including the placement of a stent.
4. Congestive heart failure (NYHA class III or IV) within 6 months prior to
enrollment, or LVEF less than lower limit of normal, per local institutional
standards, within 6 months prior to enrollment.
5. History of clinically significant (as determined by the treating physician)
atrial arrhythmia or any history of ventricular arrhythmia.
6. Venous thromboembolism, including deep venous thrombosis or pulmonary embolism,
within 6 months prior to enrollment.
8. Have uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 150
mmHg). Patients with hypertension should be under treatment on study entry to effect
blood pressure control.
9. Have a history of alcohol abuse.
10. History of acute pancreatitis within 1 year prior to study entry or past medical
history of chronic pancreatitis.
11. Have malabsorption syndrome or other gastrointestinal illness that could affect oral
absorption of study drug.
12. Known presence of a significant congenital or acquired bleeding disorder unrelated to
13. Have a history of another malignancy, other than cervical cancer in situ or no
metastatic basal cell or squamous cell carcinoma of the skin; the exception is if
patients have been disease-free for at least 5 years, and are deemed by the
investigator to be at low risk for recurrence of that malignancy.
14. Have undergone major surgery (with the exception of minor surgical procedures, such as
catheter placement) within 14 days prior to first dose of ponatinib.
15. Treatment with other investigational agents (defined as not used in accordance with
the approved indication) within 4 weeks of Day 1.
16. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and
the treatment cannot be either discontinued or switched to a different medication
prior to study entry. See Annex 6 for a list of these medications. This list may not
17. Patients actively receiving therapy with herbal medicines that are strong CYP3A4
inhibitors and/or inducers, and the treatment cannot be either discontinued or
switched to a different medication prior to study entry. These herbal medicines may
include Echinacea (including E. purpurea, E. angustifolia and E. pallida), Piperine,
Artemisinin, Hyperico, and Ginkgo.
18. Patients who are currently receiving treatment with any medications that have the
potential to prolong the QT interval and the treatment cannot be either safely
discontinued or switched to a different medication prior to study entry.
19. Have an ongoing or active infection; this includes, but is not limited to, the
requirement for intravenous antibiotics.
20. Have a known history of human immunodeficiency virus infection; testing is not
required in the absence of prior documentation or known history.
21. Have hypersensitivity to the ponatinib active substance or to any of its inactive
22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test.
23. Patients must not have a contraindication or a known hypersensitivity to ASA.
24. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption.
25. Patients with previous or current hepatitis B virus infection.