Asciminib Frontline Risk Adapted

Inclusion Criteria: 1. Signed informed consent must be obtained prior to participation in the trial 2. Newly diagnosed patients with BCR::ABL1+ CML-CP up to 12 weeks after diagnosis 3. Evidence of any BCR::ABL1 transcript except transcripts lacking ABL1 exon a2. 4. Male or female patients ≥ 18 years of age 5. ECOG performance status of ≤2 * Diagnosis of CML-CP (ELN 2025 criteria) * Documented chronic phase CML will meet all the below criteria (Apperley et all 2025) with \<20% blasts in PB and BM * No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly. 6. Adequate end organ function prior to randomization as defined by: * Total bilirubin (TBL) \< 3 x ULN; participants with Gilbert's syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN * eGFR ≥ 30 mL/min/1.73m2 as calculated using the CKD-EPI 2021 equation * Serum lipase ≤ 1.5 x ULN. For serum lipase \> ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis 7. Participants must have the following laboratory values within normal limits or corrected to within normal limits with supplements prior to randomization: * Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with eGFR\* ≥ 90 mL/min/1.73m2) * Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with eGFR\* ≥ 90 mL/min/1.73m2) * Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with eGFR\* ≥ 90 mL/min/1.73m2) * For participants with mild to moderate renal impairment (eGFR\* ≥ 30 mL/min/1.73m2 and \< 90 mL/min/1.73m2) - potassium, total calcium (corrected for serum albumin) and magnesium should be ≥ LLN or corrected to within normal limits with supplements prior to randomization. * eGFR as calculated using CKD-EPI 2021 equation Exclusion Criteria: 1. Previous treatment for CML or any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea for a maximum of 12 weeks or any TKI for a maximum of 2 weeks. 2. BCR::ABL1 transcripts lacking ABL1 exon a2 (e.g., e13a3, e14a3, e1a3) 3. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required) 4. Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following: * History of myocardial infarction, angina pectoris, coronary artery bypass graft within 6 months prior to starting study treatment. * 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). * QTcF ≥ 450 ms on the average of three serial baseline ECG (using the QTcF formula). If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTcF. * Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: * Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia. * Concomitant medication(s) with a "Known risk of Torsades de Pointes" per crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study treatment by safe alternative medication. * Inability to determine the QTcF interval. 5. Severe and/or uncontrolled concurrent medical disease that in the opinion of the Investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes mellitus, active or uncontrolled infection; uncontrolled arterial or pulmonary hypertension, uncontrolled clinically significant hyperlipidemia) 6. History of significant congenital or acquired bleeding disorder unrelated to cancer. 7. Major surgery within 4 weeks prior to trial entry or patients who have not recovered from prior surgery. 8. History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis. 9. History of chronic liver disease leading to severe hepatic impairment or ongoing acute liver disease 10. Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. 11. History of Human Immunodeficiency Virus (HIV) infection unless well-controlled on a stable dose of anti-retroviral therapy at the time of screening. 12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery). 13. Participation in a prior investigational trial within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer. 14. Known hypersensitivity to the study treatment 15. Pregnant or nursing (lactating) women 16. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral salpingectomy at least six weeks before taking trial treatment. In the case of oophorectomy alone, the reproductive status of the woman needs to have been confirmed by follow-up hormone level assessment. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., hormonal profile confirming menopause and/or age-appropriate history of vasomotor symptoms). Women of childbearing potential are excluded unless they are using highly effective methods of contraception while taking study treatment and for a period of time after stopping study medication. Highly effective contraception methods include (according to the CTCG - Recommendations related to contraception and pregnancy testing in clinical trials version 1.2.): * Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. * Bilateral tubal occlusion, Bilateral tubal ligation (at least six weeks before taking study treatment). * Sterilization (vasectomy) of male partner(s) of the female participant at least 6 months prior to screening provided partner(s) has(have) received medical confirmation of surgical success * Combined (estrogen and progesteron containing) hormonal contraception associated with inhibition of ovulation; oral, intravaginal or transdermal. * Progesteron-only hormonal contraception associated with inhibition of ovulation: oral, injectable or implantable. * Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) In case of use of hormonal contraception, women should have been stable on the same method for a minimum of 3 months before taking trial treatment. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate history of vasomotor symptoms). Women are considered not of child bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on the trial. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered to be not of child bearing potential. Sexually active males taking trial treatment do not require contraception.