Early Intervention With Acalabrutinib in Patients With High Risk CLL

Inclusion Criteria: * Subject must be able to voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures. * The time from diagnosis to consent should be ≤6 months. * Subject must be ≥ 18 years of age. * Subject must have diagnosis of CLL/SLL based upon 2018 iwCLL Guidelines. * Rai stage 0-2 disease without indication for treatment as defined by the 2018 iwCLL guidelines * Subject must have high risk CLL as defined by any one of the following: * NOTCH1 mutated (classic frameshift mutation only) * Unmutated V4-39 B cell receptor usage * Pathogenic c-MYC mutations * Complex karyotype, (by CpG/oligodeoxynucleotide stimulation) * Deletion 17p, or presence of TP53 mutation * Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2. * PT/PTT/INR within 1.5 x the ULN * Adequate renal function defined by serum creatinine less than 2 x ULN * Adequate hepatic function: * ALT/AST less than 2x ULN * Tbili less than 1.5 X ULN unless bilirubin elevation is due to Gilbert's syndrome (total bilirubin \<3) * Subject must have adequate bone marrow function. * Absolute neutrophil count ≥1.0 x103/μL * Hemoglobin ≥ 11.0 g/dL * Platelets ≥ 100 x 103/μL Exclusion Criteria: * Previous exposure to any systemic anti-cancer therapy as a treatment for CLL, including but not limited to chemotherapy, immunotherapy, radiotherapy, or investigational therapy. Note, patients treated with chemotherapy for a prior non-hematologic malignancy if more than 5 years earlier are eligible. * Subject with a history of malignancy except for non-melanoma skin cancers. Subjects treated with curative intent via methods of local resection and or locally targeted anticancer treatment and are free of malignancy for at least 5 years from treatment end will be allowed to enroll. * Subject requires chronic immunosuppressive therapy for any reason or was treated with immunosuppressive therapy within 6 months of study entry. * Subjects with a history of autoimmune hemolytic anemia or immune thrombocytopenia purpura. * Subject has prolymphocytic leukemia. * Active bleeding, or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease) * Subject requires warfarin or equivalent vitamin K antagonist * Uncontrolled or active significant infection, * History of or suspected or confirmed PML * Clinically significant cardiovascular disease such as uncontrolled or symptomatic 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. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study. * Patients with stroke or CNS hemorrhage within 6 months * Pregnant or breastfeeding * Women of childbearing potential (WCBP) who are sexually active with heterosexual partners must agree to use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib. * Major surgical procedure within 28 days of first dose of study drug. If a subject had surgery, they must have recovered adequately from any toxicity or complications before the first dose of study drug. * Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication. * Subject is known to be positive for human immunodeficiency virus (HIV) * Active hepatitis C, as confirmed by being positive for Hep C RNA by PCR * Active hepatitis B infection documented by a positive PCR for Hep B DNA. If hepatitis B serology is positive for hepatitis B core antibody, but Hep B DNA PCR is negative, patient is eligible to enroll. * Subject requires strong CYP 3A4/5 inhibitors or inducers (Appendix B). * Subject requires proton pump inhibitors. (Subjects that can transition to an H2 antagonist are allowed to enroll.)