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Inclusion Criteria:

1. Men and women ≥ 18 years of age, at the time of signing the informed consent.
2. Eastern Cooperative Oncology Group performance status of 0 to 3
3. Meet at least one of the following cardiovascular inclusion criteria: - Left ventricular ejection fraction (LVEF) \< 50% as assessed by local ECHO at screening. - History of heart failure or meeting Universal Definition of Heart Failure at screening, regardless of current LVEF. - History of ischaemic heart disease (IHD) including acute coronary syndrome, myocardial infarction, or coronary revascularization (percutaneous coronary intervention/stent or coronary artery bypass surgery). - Diagnosis of cardiomyopathy - Ongoing clinically significant (symptomatic or requiring intervention) cardiac arrhythmia, including atrial fibrillation or other arrhythmias. - History of moderate or severe cardiac valvular diseases as documented per cardiac imaging
4. Diagnosis of CLL
5. Treatment naïve or relapsed/refractory patients who have received no more than 2 prior lines of systemic anti-CLL treatment.
6. Active disease per iwCLL 2018 criteria that requires treatment.
7. Meet the following laboratory parameters:

   1. Absolute neutrophil count (ANC) ≥ 500 cells/μL (0.50 × 109/L).
   2. Platelet count ≥ 30,000 cells/μL (30 × 109/L).
   3. Serum aspartate aminotransferase and ALT ≤ 3.0 × ULN.
   4. Total bilirubin ≤ 1.5 × ULN unless directly attributable to Gilbert's syndrome.
   5. Estimated creatinine clearance (ie, estimated glomerular filtration rate \[eGFR\] using Cockcroft-Gault) ≥ 40 mL/min, or serum creatinine ≤ 2 × ULN.
8. Women and men who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib.
9. Patients must be willing and able to adhere to the study visit schedule, understand, and comply with other protocol requirements, and provide written informed consent and authorisation to use protected health information (in accordance with national and local patient privacy regulations). Note: vulnerable patients, as defined in the ICH GCP, are not allowed on this protocol (eg, prisoners or institutionalised patients).

Exclusion Criteria:

1. Known active CNS leukaemia, leptomeningeal disease or spinal cord compression. In case of R/R patients with prior history of CNS localisation of leukaemia who received treatment are eligible provided that there is no evidence of CNS involvement at study entry as documented by cerebrospinal fluid (CSF) cytology and/or brain MRI.
2. Ongoing Richter's transformation.
3. Prior exposure to a BTKi.
4. Major surgery within 30 days before first dose of study treatment.
5. Uncontrolled haemolytic anaemia.
6. Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study treatment.
7. Received a live virus vaccination within 28 days of first dose of study treatment.
8. History of or ongoing confirmed PML.
9. History of prior malignancy except for the following:

   1. Prior history of malignancy with no evidence of active disease present for more than

3 years before screening or felt to be at low risk for recurrence by treating physician.

(b) Adequately treated lentigo maligna melanoma without current evidence of disease or adequately resected non-melanomatous skin cancer (ie, basal cell carcinoma or squamous cell carcinoma of the skin). (c) Curatively treated in situ carcinoma of the cervix or carcinoma in situ of the prostate at any time prior to study without current evidence of disease. 10 Unable to swallow tablets or malabsorption syndrome, or disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

11 Active uncontrolled systemic infection (bacterial, fungal, viral or other) or clinically significant localised infection. 12 Known history of infection with human immunodeficiency virus (HIV). 13 Serologic status reflecting active HepB or HepC infection.

(a) Patients with HepB core antibody positive who are surface antigen negative or who are HepC antibody positive will need to have a negative polymerase chain reaction (PCR) result before randomisation and must be willing to undergo deoxyribonucleic acid (DNA) PCR testing during the study. (b) Patients who are HepB surface antigen positive or HepB PCR positive and those who are HepC PCR positive will be excluded. 14 History of stroke or intracranial haemorrhage within 6 months prior to randomisation.

15 History of bleeding diathesis (eg, haemophilia, von Willebrand disease). 16 Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study treatment. Direct anti-X (DOACs) or low molecular weight heparins (LMWH, eg, enoxaparin) on stable dosing schedule is allowed. 17 Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor/inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study treatment is prohibited. 18 Breastfeeding or pregnant. 19 Concurrent participation in another therapeutic clinical trial. 20 Uncontrolled cardiac/cardiovascular disease including the following:

1. Baseline cardiac troponin (cTnI or cTnT or hs-cTn) levels greater than the upper limit of normal (per the local laboratories reference range) that is due to an acute coronary event and cannot be fully explained by non-ischaemic conditions.
2. Uncontrolled cardiac tachyarrhythmias (sinus, atrial or ventricular) that require new/additional therapy within the last month.
3. Clinically significant QT prolongation defined as QT interval corrected by Fridericia's formula (QTcF) values; QTcF \> 500 ms.
4. Any of the following within the last 3 months:

i. Unstable IHD: percutaneous coronary intervention, coronary artery bypass surgery, or an episode of acute coronary syndrome including acute myocardial infarction and unstable angina pectoris. ii. Major cardiac surgery/procedures or valvular surgery. iii. Hospitalization due to heart failure. 21 Uncontrolled hypertension despite optimal management 22 Current life-threatening illness, medical conditions, organ system dysfunction or lifestyle habits which, in the investigator's opinion, could compromise the patient's safety or ability to adhere to the study protocol.

• Charlotte, North Carolina, United States
• Columbus, Ohio, United States
• Philadelphia, Pennsylvania, United States
• Brno, Czechia
• Hradec Králové, Czechia
• Prague, Czechia
• Cagliari, Italy
• Florence, Italy
• Milan, Italy
• Milan, Italy
• Pavia, Italy
• Perugia, Italy
• Krakow, Poland
• Poznan, Poland
• Barcelona, Spain
• Madrid, Spain
• Seville, Spain
• Bournemouth, United Kingdom
• Oxford, United Kingdom
• Plymouth, United Kingdom
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• Stockton, United Kingdom
• Sutton Coldfield, United Kingdom