Acalabrutinib in Combination With Venetoclax for the Treatment of Refractory or Recurrent Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma, The AVENUE-2 Trial

Inclusion Criteria: * Men and women \>= 18 years of age. * Diagnosis of CLL or small lymphocytic lymphoma (SLL) that meets the published diagnostic criteria. * Active disease per IWCLL 2018 criteria that require treatment. At least one of the following: * Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia * Massive (\> 6 cm below left costal margin), progressive, or symptomatic splenomegaly * Massive nodes (\> 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy * Progressive lymphocytosis with an increase of \> 50% over a 2-month period or lymphocyte-doubling time of \< 6 months. Lymphocyte-doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of \< 30 x 109/L lymphocyte-doubling time should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (e.g., infection) should be excluded. * Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs * Unintentional weight loss of \> 10% within the previous 6 months * Significant fatigue * Fevers \> 100.5 degrees Fahrenheit (F) or 38 degrees Celsius (C) for 2 weeks without other evidence of infection * Night sweats for \> 1 month without evidence of infection * Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. A line of therapy is defined as completing at least 2 cycles of treatment of standard regimen according to current National Comprehensive Cancer Network (NCCN) guidelines, or of an investigational regimen on a clinical trial. * Absolute neutrophil count (ANC) \>= 750 cells/microliter (0.75 x 10\^9/L); ANC \>= 500 cells/microliter (0.50 x 10\^9/L) in subjects with documented bone marrow involvement of CLL (independent of growth factor or transfusion support within 1 week of screening). * Hemoglobin \>= 10 g/dL (independent of growth factor or transfusion support within 1 week of screening). * Platelet count \>= 50,000 cells/microliter (50 x 10\^9/L); platelet count \>= 25,000 cells/microliter (25 x 10\^9/L) in subjects with documented bone marrow involvement of CLL (independent of growth factor or transfusion support within 1 week of screening). * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal (ULN) * Total bilirubin =\< 2 x ULN, unless directly attributable to Gilbert's syndrome * Estimated creatinine clearance of \>= 50 mL/min * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Women of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 30 days after the last dose of acalabrutinib or venetoclax, whichever occurs later * Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing tablets without difficulty * Ability to understand the purpose and the risks of the study and provide signed and dated informed consent and authorization to use protected health information Exclusion Criteria: * Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation (biopsy based on clinical suspicion may be needed to rule out transformation) * Prior disease progression while on a BTK inhibitor * Prior disease progression while on venetoclax * Prior intolerance to acalabrutinib or venetoclax * Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, low-grade prostate carcinoma (Gleason grade =\< 6) or other cancer from which the subject has been disease free for \>= 2 years or which will not limit survival to \< 3 years * 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 diseases as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study. * 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. Patients with history of such operations are eligible if in treating physician's opinion they have no absorption issues. * Known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib or venetoclax * Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease), or requires/is receiving anticoagulation with warfarin or equivalent vitamin K antagonists * Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastic time (aPTT) (in the absence of lupus anticoagulant) \> 2 x ULN * Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) * Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening * Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducers. The use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first dose of study drug is prohibited. * History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug * 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 * Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded. * Breastfeeding or pregnant * Concurrent participation in another therapeutic clinical trial * Known history of infection with human immunodeficiency virus (HIV) or any active significant infection (e.g,. bacterial, viral, or fungal) * History of or ongoing confirmed central nervous system (CNS) CLL * History of confirmed progressive multifocal leukoencephalopathy (PML)