Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase

Inclusion Criteria:

1. Age ≥18 years old

2. Willing and able to give informed consent

3. Newly diagnosed with CML in chronic phase within 6 months from confirmed diagnosisvia bone marrow biopsy/aspirate and have either the b3a2 (e14a2) or b2a2 (e13a2)variants that give rise to the p210 BCR::ABL1 protein. Subtype classificationwhether b3a2 (e14a2) or b2a2 (e13a2) is not required for study eligibility.

4. Minimal prior CML therapy with a TKI for less than or equal to 30 days. Treatmentwith hydroxyurea, busulfan, anagrelide or other non-specific chemotherapy agents isallowed with no time restrictions within the eligible time from diagnosis.

5. ECOG performance status 0-2 (appendix 1)

6. Adequate organ function:

• AST and ALT < 3 times the institutional upper limit of normal (ULN)

• eGFR ≥ 30 mL/min as calculated using the 2021 chronic kidney diseaseepidemiology (CKD-EPI) creatinine equation (https://www.kidney.org/professionals/kdoqi/gfr_calculator)

• Total bilirubin < 1.5 times the institutional ULN or < 3.0 x the institutionalULN with Gilbert Syndrome (unless direct bilirubin is within normal limits)

7. Adequately controlled blood pressure, defined as systolic blood pressure of <140mmHq and diastolic of <90 mmHg, at the time of enrollment.

8. Lipase ≤ 1.5 x ULN. For lipase > ULN - ≤ 1.5 x ULN, value should be considered notclinically significant and not associated with risk factors for acute pancreatitis.

9. Creatine phosphokinase < 2.5 x ULN

10. Female patients must meet one of the following:

11. Postmenopausal for at least one year before the screening visit,

12. Surgically sterile

13. If they are of childbearing potential, agree to practice two effective methodsof contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug,

14. Must also adhere to the guidelines of any treatment-specific pregnancyprevention program, if applicable

15. Agree to practice true abstinence when this is in line with the preferred andusual lifestyle of the subject. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, postovulation methods] and withdrawal are notacceptable contraception methods.)

16. Male patients, even if surgically sterilized (i.e., status post vasectomy), mustagree to one of the following:

17. Practice effective barrier contraception during the entire study treatmentperiod and through 90 days after the last study drug dose

18. Must also adhere to the guidelines of any treatment-specific pregnancyprevention program, if applicable

19. Agree to practice true abstinence when this is in line with the preferred andusual lifestyle of the subject. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, postovulation methods] and withdrawal are notacceptable methods of contraception.)

Exclusion Criteria:

1. Patients with accelerated or blast phase CML (refer to appendix 4)

2. Active second malignancy requiring active treatment

3. History of recent (within 12 months) acute pancreatitis or chronic pancreatitis

4. Subjects who have previously received treatment with asciminib.

5. Subjects with PLT count < 50,000 mm3 or ANC of < 500 mm3 or Hemoglobin < 8 g/dL

6. Cardiac or cardiac repolarization abnormality, including any of the following:

7. History within 6 months prior to starting study treatment of myocardialinfarction (MI), angina pectoris, coronary artery bypass graft (CABG)

8. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),complete left bundle branch block, high-grade AV block (e.g., bifascicularblock, Mobitz type II and third degree AV block)

9. QTcF at screening greater than or equal to 450 msec (male patients), greaterthan or equal to 460 msec (female patients) unless patient has a pacemaker

10. Long QT syndrome, family history of idiopathic sudden death or congenital longQT syndrome, or any of the following: i. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia orhypomagnesemia, history of cardiac failure, or history of clinicallysignificant/symptomatic bradycardia ii. Concomitant medication(s) with a "Known riskof Torsades de Pointes" per wwwcrediblemeds.org/ that cannot be discontinued orreplace 7 days prior to starting study drug by safe alternative medication. iii. Inability to determine the QTcF interval

11. Pregnant or lactating

12. Taking a strong inhibitors or inducers of CYP3A4 or CYP3A4 substrates with narrowtherapeutic index (refer to appendix 6) at time of enrollment

13. Unable to comply with lab appointment schedule and PRO assessments

14. Another investigational drug within 4 weeks of enrollment

15. Any serious medical or psychiatric illness that could, in the investigator'sopinion, interfere with the completion of treatment according to this protocol

16. Patient has undergone a prior allogeneic stem cell transplant

17. Known clinical history of active HBV infection