Zanubrutinib and Sonrotoclax for the Treatment of Relapsed Chronic Lymphocytic Leukemia /Small Lymphocytic Leukemia, ZeuS-2 Trial

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative.

  * Assent, when appropriate, will be obtained per institutional guidelines
* Age: ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) ≤ 2
* Histological or flow cytometry confirmed diagnosis of B-CLL/SLL as documented by medical records and with histology based on criteria established by the World Health Organization (WHO)
* CLL has progressed at least 6 months after completion of first-line fixed-duration novel drug (non-chemotherapy) regimen, including but not limited to venetoclax (V) + CD20 monoclonal antibody (monoclonal antibody \[mAb\], e.g., obinutuzumab (O); BTK inhibitor (zanubrutinib or acalabrutinib or ibrutinib) + V ± CD20 mAb
* Active disease meeting criteria for requiring treatment per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines (one of the following):

  * A minimum of any one of the following constitutional symptoms:

    * Unintentional weight loss \> 10% within the previous 6 months prior to screening.
    * Extreme fatigue (unable to work or perform usual activities).
    * Fevers of greater than 100.5°F for ≥ 2 weeks without evidence of infection.
    * Night sweats without evidence of infection.
  * Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia.
  * Massive (i.e., \> 6 cm below the left costal margin), progressive or symptomatic splenomegaly.
  * Massive nodes or clusters (i.e., \> 10 cm in longest diameter) or progressive lymphadenopathy.
  * Progressive lymphocytosis with an increase of \> 50% over a 2-month period, or an anticipated doubling time of less than 6 months.
  * Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids.
  * Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine)
* Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
* Without bone marrow involvement: absolute neutrophil count (ANC) ≥ 1,000/mm\^3, with bone marrow involvement: ANC ≥ 500/mm\^3

  * NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement.

Neupogen or biosimilar may be administered for patients with ANC \< 1000 with risk for development of febrile neutropenia as determined by treating physician. Dosing will be at 5 mcg/kg rounded to the nearest vial size

* Without bone marrow involvement: Platelets ≥ 50,000/mm\^3, with bone marrow involvement: platelets ≥ 30,000/mm\^3

  * NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement
* Hemoglobin ≥ 7 g/dL

  * NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment unless cytopenia is secondary to disease involvement
* Total bilirubin ≤ 2 X upper limit of normal (ULN) (unless has Gilbert's disease or compensated hemolysis directly attributable to CLL)
* Aspartate aminotransferase (AST) ≤ 2.5 x ULN
* Alanine aminotransferase (ALT) ≤ 2.5 x ULN
* Creatinine clearance of ≥ 30 mL/min/ per 24-hour urine test or the Cockcroft-Gault formula
* Fridericia's corrected QT interval (QTcB) ≤ 480 ms

  * Note: To be performed within 28 days prior to Day 1 of protocol therapy
* Seronegative for hepatitis C virus (HCV), active hepatitis B virus (HBV) (Surface antigen negative) OR

  * If seropositive for HCV or HBV, nucleic acid quantitation must be performed. Viral load must be undetectable
* Meets other institutional and federal requirements for infectious disease titer requirements

  * Note: Infectious disease testing to be performed within 28 days prior to Day 1 of protocol therapy
* Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

  * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Agreement by females and males of childbearing potential\* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 1 week after the last dose of protocol therapy

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

Exclusion Criteria:

* Chronic use of corticosteroids in excess of 20 mg/day prednisone
* Major surgery (under general anesthesia) ≤4 weeks of the first dose of study drug
* Prior chemotherapy
* Refractory to prior BTK or BCL2 inhibitor (defined as relapsed within/\< 6 months after completion of initial fixed duration regimen)
* Vaccination with a live vaccine within 35 days prior to the first dose of study drug or at any time during planned study treatment
* Requires ongoing treatment with a strong CYP3A inducer
* Requires ongoing treatment with inhibitors of P-gp and BCRP
* Requires ongoing treatment with warfarin or warfarin derivatives
* Concurrent participation in another therapeutic clinical trial
* Use of the following substances prior to the first dose of study drug:

  * ≤ 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug: strong and moderate inhibitors or inducers of CYP3A
  * ≤ 7 days before the first dose of study drug: corticosteroid (\> 20 mg prednisone or equivalent) given with antineoplastic intent
* Known current central nervous system involvement by lymphoma/leukemia
* Known Richter's transformation
* Any uncontrolled or clinically significant cardiovascular disease including the following:

  * Myocardial infarction (MI) within 6 months before screening
  * New York Heart Association (NYHA) (New York Heart Association) heart failure class III-IV
  * Unstable angina within 3 months before screening
  * History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes).
  * History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
* Prior malignancy except:

  * Malignancy treated with curative intent and no known active disease present for ≥ 2 years prior to initiation of therapy on current study
  * Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease
  * Adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without evidence of disease
  * Asymptomatic prostate cancer managed with "watch and wait" strategy
* Uncontrolled immune hemolysis or thrombocytopenia
* Significant bleeding disorder (stable therapeutic anticoagulation acceptable)
* History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
* Severe or debilitating pulmonary disease
* Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
* Active fungal, bacterial and/or viral infection requiring systemic therapy
* Underlying medical conditions that, in the investigator's opinion, will render the administration of study drugs hazardous or obscure the interpretation of toxicity or adverse events (AEs)
* Known active infection with HIV
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study agents
* Uncontrolled autoimmune anemia and/or autoimmune thrombocytopenia (e.g., idiopathic thrombocytopenia purpura)
* Any condition which in the discretion of the investigator would compromise the ability to comply with study procedures
* Females only: Pregnant or breastfeeding
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)