Acalabrutinib and Venetoclax Treatment of Newly Diagnosed Patients With CLL at High Risk of Infection or Early Treatment

Inclusion Criteria: 1. CLL diagnosed according to IWCLL criteria within one year prior to randomization 2. High risk of infection and/or progressive treatment within 2 years according to CLL-TIM 3. IWCLL treatment indication not fulfilled 4. Life expectancy \> 2 years 5. Age at least 18 years 6. Ability and willingness to provide written informed consent and adhere to study procedures and treatment 7. Adequate bone marrow function as indicated by platelets above 100 x 10E9, hemoglobin above 10 g/dL and neutrophils above 1 x 10E9 8. Creatinine clearance above 30 mL/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault 9. Adequate liver function as indicated by a total bilirubin≤ 2 x, AST/ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome. 10. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration. 11. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2. 12. Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 2 days after the last dose of investigational drugs. 13. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. 14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information Exclusion Criteria: 1. Prior CLL treatment (including monoclonal antibodies, chemotherapy, small molecules) 2. Transformation of CLL (Richter's transformation) 3. Previous autoimmune disease as AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura) treated with immune suppression or uncontrolled AIHA or ITP 4. History of PML 5. Uncontrolled or active infection 6. Malignancies other than CLL requiring systemic therapies (except anti-hormonal therapies) or considered to impact survival 7. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonists 8. History of bleeding disorders or current platelet inhibitors or anticoagulant therapy 9. History of clinically significant cardiovascular disease such as arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening. 10. History of stroke or intracranial hemorrhage within 6 months prior to registration. 11. Use of investigational agents which might interfere with the study drug within 28 days prior to registration. 12. Vaccination with live vaccines 28 days prior to registration. 13. Major surgery less than 30 days before start of treatment. 14. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial. 15. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly). 16. Fertile men or women of childbearing potential unless: surgically sterile or ≥ 2 years after the onset of menopause or willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index \<1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment. 17. Legal incapacity. 18. Persons who are in dependence to the sponsor or an investigator 19. Persons not considered fit for the trial by the investigator 20. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 21. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. 22. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 23. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) \> 2x ULN. 24. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study. 25. Major surgical procedure within 7 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. 26. Breastfeeding or pregnant.