PONAZA : A COMBINATION OF PONATINIB AND 5-AZACITIDINE IN CHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE OR IN MYELOID BLAST CRISIS

Inclusion Criteria:

1. Patient aged 18 years or more

2. Signed informed consent

3. Patient with Philadelphia chromosome positive CML in first blast crisis or firstaccelerated phase:

• AP-CML is defined by the presence of any of the following features:

• 15-29% blasts in peripheral blood (PB) or bone marrow (BM)

• ≥ 20% basophils in PB

• ≥ 30% blasts plus promyelocytes (with blasts <30%) in PB or BM,

• <100 x10(9)/L platelets unrelated to therapy, or by clonal cytogeneticsevolution (i.e., the presence of cytogenetic abnormalities other than thePhiladelphia chromosome);

• MBC-CML is defined by the presence of ≥ 30% blasts in the bone marrow and/orperipheral blood or the presence of extramedullary disease.

4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 3

5. Have adequate renal function as defined by the following criterion: Serum creatinine ≤ 1.5 × upper limit of normal (ULN) for institution

6. Have adequate hepatic function as defined by the following criteria:

7. Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome or CML

8. Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltrationof the liver is present

9. Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemicinfiltration of the liver is present

10. Have normal pancreatic status as defined by the following criterion: Serum lipase andamylase ≤ 1.5 × ULN

11. Have normal QTcF interval on screening electrocardiogram (ECG) evaluation, defined asQTcF of ≤ 450 ms in males or ≤ 470 ms in females.

12. Have a negative pregnancy test documented prior to enrollment (for females ofchildbearing potential).

13. Agree to use an effective form of contraception with sexual partners throughout studyparticipation (for female and male patients who are fertile).

14. Have fully recovered (≤ grade 1, returned to baseline, or deemed irreversible) fromthe acute effects of prior cancer therapy before initiation of study drug

Exclusion Criteria:

1. Pregnant or lactating women,

2. Participation in another clinical trial with any investigative drug within 30 daysprior to study enrolment,

3. Prior history of hematopoietic stem cell transplantation

4. Cardiovascular disease:

• Stage II to IV congestive heart failure (CHF) as determined by the New York HeartAssociation (NYHA) classification system for heart failure.

• Myocardial infarction within the previous 6 months

• Symptomatic cardiac arrhythmia requiring treatment

5. Individuals with another active malignancy

6. Patients at high risk or very high risk of arterio-veinous occlusive disease definedby European CVD score

7. Previous treatment with azacitidine,

8. Diagnosis of malignant disease within the previous 12 months (excluding base cellcarcinoma, "in-situ" carcinoma of the cervix or breast or other local malignancyexcised or irradiated with a high probability of cure)

9. Known active viral infection with Human Immunodeficiency Virus (HIV) or Hepatitis typeB or C