Inclusion Criteria:
* Diagnosis of CLL or SLL according to WHO criteria
* Participants must require therapy according to iwCLL 2018 guidelines
* Participants must have ≥ 2 points (high or intermediate risk disease) according to the CLL
BALL Risk Model:
* Beta-2 microglobulin If ≥ 5 mg/L, assign 1 point
* Lactate dehydrogenase If \>institutional upper limit of normal, assign 1 point
* Hemoglobin If \<11 g/dL (female) or \<12 g/dL (male), assign 1 point
* Time from start of last therapy If \<24 months, assign 1 point, If 4 points, patient is high risk, If 2-3 points, patient is intermediate risk, If 0-1 points, patient is low risk
* Participants must have received prior systemic therapy for CLL
* Age over 18 years
* ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
* Participants must have adequate organ function as defined below:
* total bilirubin ≤2 × institutional upper limit of normal unless considered secondary to Gilbert's syndrome, in which case ≤3 x ULN
* AST(SGOT)/ALT(SGPT) ≤2 × institutional upper limit of normal
* creatinine within normal institutional limits OR
* creatinine clearance ≥30 mL/min according to the Cockcroft-Gault Equation for participants with creatinine levels above institutional normal.
* Participants must have adequate marrow function as defined below (unless clearly due to disease under study per investigator discretion)
* absolute neutrophil count ≥1,000/mcL
* platelets ≥75,000/mcL OR
* \> 20,000/mcL if thrombocytopenia is clearly due to disease under study (per investigator discretion).
* For females of childbearing potential, a negative serum pregnancy test within 7 days of study treatment
* For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate \[\<1% per year\] when used consistently and correctly) and to continue its use for 90 days after the last dose of acalabrutinib or venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later)
* The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
* Willingness to not donate sperm or oocytes during the entire study treatment period and after treatment discontinuation
* Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* Prior therapy with a BTK inhibitor (e.g. acalabrutinib) or BCL2 inhibitor (e.g. venetoclax), with the following exception:
* Patients with undetectable MRD by flow cytometry at 10 (peripheral blood or bone marrow) or CR from prior treatment with BCL2 inhibitor (with or without BTK inhibitor) are eligible. Note: Patients who received prior BTK inhibitor therapy alone are not eligible.
* Known hypersensitivity (IgE-mediated) reaction to obinutuzumab or to any of its excipients
* Participants who are receiving any other investigational agents unless authorized by the overall study principal investigator
* Known active histological transformation from CLL to an aggressive lymphoma (i.e., Richter's transformation)
* Active malignancy or systemic therapy for another malignancy within 3 years; local/regional therapy with curative intent such as surgical resection or localized radiation within 3 years of treatment is permitted; active prostate cancer that is considered low-risk and appropriate for continued active surveillance strategy is permitted.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 2 weeks prior to Cycle 1, Day 1
* Known bleeding diathesis
* Pregnant women are excluded from this study because the study agents have potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study agents, breastfeeding should be discontinued if the mother is treated with study therapy.
* Prior major surgical procedure within 4 weeks of study, or anticipation of need for a major surgical procedure during the course of the study
* Known CNS hemorrhage or stroke within 6 months of the study
* History of progressive multifocal leukoencephalopathy (PML)
* History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection
* Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody \[HBcAb\] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to take appropriate anti-viral prophylaxis as indicated and undergo monthly DNA testing.
* Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
* Congestive heart failure, New York Heart Association classification III/IV
* Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
* Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment
* Known condition or other clinical situation that would affect oral absorption
* Psychiatric illness/social situations that would interfere with study compliance
* Receipt of therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9 and CYP2C19, within 7 days prior to the first dose of study drug administration
* Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study drug administration.
* Requires dual antiplatelet therapy or anticoagulation with warfarin
