Study of Venetoclax in Combination With Azacytidine in AML Patients Selected Using Ex Vivo Drug Sensitivity Screening

Inclusion Criteria:

1. Written informed consent

2. Patients who present with one of the following (except acute promyelocyticleukemia):

• De novo or secondary AML patients who are non-fit for standard inductiontherapy (see below)

• Relapsed or refractory AML patients following at least 1 line of priortherapies (see below)

3. Ex vivo sensitivity testing performed to assess venetoclax sensitivity

4. Validation cohort: All participants are treated with venetoclax+azacitidineirrespective of the ex vivo screening results.

5. Study cohort: Only the participants exhibiting ex vivo sensitivity tovenetoclax are included to study therapy.

6. Participant must have ECOG Performance status ≤ 2 for participants ≥ 75 years of ageOR ≤ 3 for participants ≥ 18 to 74 years of age

7. Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.

8. Participant must have adequate renal function as demonstrated by a calculatedcreatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.

9. Participant must have adequate liver function as demonstrated by

10. alanine aminotransferase (ALT) ≤ 4.0 × ULN

11. bilirubin ≤ 1.5 × ULN

12. Specific inclusion criteria for participants non-fit for standard chemotherapy Participant must be:

≥ 70 years of age OR ≥ 18 to 69 years of age and ineligible for intensivechemotherapy meeting at least one of the criteria following:

• Clinically significant comorbidities, reflected at least 1 of:

• Left ventricular ejection fraction (LVEF) < 50%.

• Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected.

• Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected.

• Chronic stable angina or congestive heart failure controlled withmedication.

• Alanine aminotransferase (ALT) 3.0-4.0 × ULN

• Other contraindication(s) to anthracycline therapy (must be documented)

• Adverse risk karyotype associated with poor outcome with standard chemotherapy

• Patient's refusal from intensive chemotherapy

9. Specific inclusion criteria for relapsed patients Participant must be ≥ 55 years of age with non-CBF AML relapse OR ≥ 18 of age andmeeting at least one of the criteria following:

• Not candidate for intensive chemotherapy (see the criteria 8.)

• The duration of remission < 12 months.

• Relapse after allogeneic transplantation.

• 2nd (or higher) relapse.

10. Specific inclusion criteria for refractory patients The patients who fail to achievea complete or partial remission after induction chemotherapy (two cycles ofchemotherapy containing cytarabine or clofarabine, in compilation with topoisomeraseII inhibitor (e.g. anthracycline or mitoxantrone)

Exclusion Criteria:

1. Participant has acute promyelocytic leukemia (APL)

2. The leukemic cell content (blast percentage) in bone marrow/peripheral blood (depending which is used for drug sensitivity testing) is ≤ 10 %

3. ECOG >3 (see also inclusion criteria 4)

4. Participant has known CNS involvement with AML (note: CSF or radiologicalinvestigations are not required without clinical suspicion)

5. Participant with known HIV infection or active hepatitis B virus (HBV), or hepatitisC virus (HCV) infection that is not controlled with anti-viral medication.

6. Participant has cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which participants are comfortable atrest but ordinary physical activity results in palpitations, fatigue, dyspnea, oranginal pain.

7. Evidence of clinically significant condition(s) that in the opinion of theinvestigator would adversely affect his/her participation in this study (includingbut not limited to):

8. Participant has a chronic respiratory disease that requires continuous oxygenuse

9. Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal)

10. Malabsorption syndrome or other condition that precludes enteral route ofadministration.

11. Uncontrolled GVHD.

12. Participant has a history of other malignancies prior to study entry, with theexception of previous malignancy treated with curative intent.