Venetoclax After TKI to Target Persisting Stem Cells in CML

Inclusion Criteria:

1. Patients with diagnosis of chronic phase CML with cytogenetic confirmation of thePhiladelphia (Ph) chromosome

2. Ph negative cases or patients with variant translocations who are BCR::ABL1 positivein multiplex PCR are also eligible

3. Typical b2a2 and/or b3a2 BCR::ABL1 transcripts

4. Subject must be ≥ 18 years of age

5. Stored DNA from initial diagnosis (prior TKI treatment) for BCR::ABL1 breakpointanalysis

6. BCR::ABL1 transcript level according to the international scale (IS) of MR4 orbetter which has been confirmed three times within the past 13 months and wasassessed by an IS-certified reference laboratory, such as of the University Jena oranother MR4-certified laboratory in Germany

7. At least 3 years of TKI therapy

8. Patients who failed to discontinue TKI in a prior discontinuation attempt are stilleligible if they fulfill criteria 6 after retreatment with TKI

9. WHO performance status 0-2

10. Adequate end organ function as defined by:

• Total bilirubin (TBL) < 3 x Upper Limit of Normal (ULN); patients withGilbert's syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN,

• Creatinine Clearance (CrCl) ≥ 30 millilitres per minute (mL/min) as calculatedusing Cockcroft-Gault formula, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN 1.5 x ULN, value must be considered not clinically significant and notassociated with risk factors for acute pancreatitis.

11. Patients must have the following laboratory values within normal limits or correctedto within normal limits with supplements:

• Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associatedwith CrCl ≥ 90 mL/min),

• Total calcium (corrected for serum albumin); (calcium increase of up to 12.5mg/dl or 3.1 mmol/L is acceptable if associated with CrCl ≥ 90 mL/min),

• Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associatedwith CrCl ≥ 90 mL/min),

• For patients with mild to moderate renal impairment (CrCl ≥ 30 mL/min and <90mL/min) - potassium, total calcium (corrected for serum albumin) and magnesiumshould be within normal limits or corrected to within normal limits withsupplements.

12. Women of childbearing age must use a highly effective method of contraception whileusing venetoclax. Women using hormonal contraceptives should also use a barriermethod.

13. Negative pregnancy test in women of childbearing potential

14. Subject must voluntarily sign and date an informed consent

Exclusion Criteria:

1. Concomitant use of strong CYP3A-Inhibtors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, clarithromycin, ritonavir) is contraindicated

2. Concomitant use of moderate CYP3A-Inhibitors (e.g., ciprofloxacin, diltiazem,erythromycin, fluconazole, verapamil) should be avoided.

3. Grapefruit products, Seville oranges, and starfruit (carambola) should be avoidedduring treatment with venetoclax as they contain inhibitors of CYP3A

4. Concomitant use of venetoclax with P-gp and BCRP inhibitors

5. Concomitant use of venetoclax with strong CYP3A inducers (e.g., carbamazepine,phenytoin, rifampin) or moderate CYP3A inducers (e.g., bosentan, efavirenz,etravirine, modafinil, nafcillin) should be avoided

6. Concomitant use of preparations containing St. John´s wort

7. Patients with severe renal impairment (Crea-Clearance < 30 ml/min) or on dialysis

8. Patients with severe hepatic impairment

9. Patients who are pregnant or breast feeding, or females of reproductive potentialnot employing an effective method of birth control. Female patients must agree toemploy an effective barrier method of birth control throughout the study and for andfor at least 30 days after ending venetoclax treatment

10. Known impaired cardiac function

11. Impaired gastrointestinal function or disease that may alter the absorption of studydrug

12. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug orwho have not recovered from side effects of such therapy

13. Active or uncontrolled infections at the time of enrolment

14. Known HIV sero-positivity or known active hepatitis B or C infection (HIV testing isnot required)

15. Participation in another clinical study with other investigational drugs within 14days prior to enrolment

16. Any medical, mental, psychological or psychiatric condition that in the opinion ofthe investigator would not permit the patient to complete the study or understandthe patient information

17. Subject has acute leukemia

18. Subject has known active CNS involvement.

19. Hypersensitivity to venetoclax or any component of the formulation