Asciminib as Initial Therapy with Addition of Lower Dose Tyrosine Kinase Inhibitors for Patients with Chronic Myeloid Leukemia who do not Achieve Optimal Response or a Deep Molecular Remission (ALERT CML)

• AST and ALT < 3 times the institutional upper limit of normal (ULN)
• eGFR ≥ 30 mL/min as calculated using the 2021 chronic kidney disease epidemiology (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 institutional ULN with Gilbert Syndrome (unless direct bilirubin is within normal limits)

1. Postmenopausal for at least one year before the screening visit,
2. Surgically sterile
3. If they are of childbearing potential, agree to practice two effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug,
4. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
5. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable contraception methods.)

1. Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose
2. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
3. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

1. History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
2. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
3. QTcF at screening greater than or equal to 450 msec (male patients), greater than or equal to 460 msec (female patients) unless patient has a pacemaker
4. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
1. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ii. Concomitant medication(s) with a "Known risk of Torsades de Pointes" per wwwcrediblemeds.org/ that cannot be discontinued or replace 7 days prior to starting study drug by safe alternative medication.

iii. Inability to determine the QTcF interval