Ibrutinib and Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia After Ibrutinib Resistance

Inclusion Criteria:

* Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL).
* Currently taking ibrutinib and first took ibrutinib \> 12 months ago.
* At high risk for the development of ibrutinib resistance. Patients are considered at high risk for ibrutinib resistance if they have had \>= 2 prior therapies for CLL prior to ibrutinib and have either del(17p)(13.1) and/or a complex CLL karyotype.
* Able to continue taking ibrutinib.
* Willing to enter the intervention cohort if clinical disease progression as defined by IWCLL 2018 criteria develops.
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2.
* Absolute neutrophil count (ANC) \>= 1000/mm\^3 independent of growth factor support.
* Platelets \>= 100,000/mm\^3 or \>= 50,000/mm\^3 if bone marrow involvement independent of transfusion support in either situation.
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x upper limit of normal (ULN).
* Total bilirubin =\< 1.5 x ULN unless bilirubin rise is due to Gilbert?s syndrome or of non-hepatic origin.
* Creatinine clearance (CLcr) \>30 ml/min.
* Able to take an absorb pill form oral medications.
* Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
* Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[beta-hCG\]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
* Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
* CRITERIA FOR ENTERING THE INTERVENTION COHORT: Clinical disease progression as defined by IWCLL 2018 criteria AND presence of an ibrutinib resistance mutation as defined.
* CRITERIA FOR ENTERING THE INTERVENTION COHORT: No evidence of a non-CLL/small lymphocytic lymphoma (SLL) lymphoma (Richter?s syndrome).
* CRITERIA FOR ENTERING THE INTERVENTION COHORT: No contraindication to taking venetoclax.
* CRITERIA FOR ENTERING THE INTERVENTION COHORT: Able to continue taking ibrutinib.

Exclusion Criteria:

* Inability to continue taking ibrutinib for any reason.
* Presence of a known ibrutinib resistance mutation as defined.
* Clinical disease progression while taking ibrutinib as defined by IWCLL 2018 criteria.
* Major surgery or a wound that has not fully healed within 4 weeks of randomization.
* Known central nervous system lymphoma.
* Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon).
* Requires chronic treatment with strong CYP3A inhibitors.
* 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 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
* Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection.
* Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator?s opinion, could compromise the subject?s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
* Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
* History of lymphoma (Richter?s syndrome) unless in complete remission \> 2 years without relapse.
* History of active malignancies other than CLL within the past 3 years prior to study entry, with the exception of:

  * Adequately treated in situ carcinoma or the cervix or breast
  * Basal cell or localized squamous cell carcinoma of the skin
  * Previous malignancy treated with curative therapy and not expected to relapse.
* Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease, etc.).
* Prior allogeneic stem cell transplant with Day 0 \< 12 months prior and/or with chronic graft versus host disease (GVHD) requiring current use of immunosuppression. Patients with prior allogeneic stem cell transplant with Day 0 \> 12 months prior who do not require immunosuppression for GVHD will be eligible.
* Patients in the observation cohort who develop clinical disease progression and do NOT have a known ibrutinib resistance mutation will be taken off study and may not enter the intervention cohort.