Pirtobrutinib (LOXO-305) Consolidation for MRD Eradication in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) Treated With Venetoclax

Known or suspected Richter's transformation to diffuse large B cell lymphoma (DLBCL), prolymphocytic leukemia, or Hodgkin lymphoma at any time preceding enrollment

Known or suspected history of central nervous system (CNS) involvement by CLL

History of grade \>= 3 arrhythmia on prior covalent Bruton's tyrosine kinase (BTK) inhibitor

Patients who experienced a major bleeding event on a prior BTK inhibitor

\* NOTE: Major bleeding is defined as bleeding having one or more of the following features: life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g/dL; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome)

Active second malignancy. Patients with a treated second malignancy and with likelihood of requiring systemic therapy within the next 2 years of \< 10%, as determined by an expert in the field, will be eligible. Examples include:

* Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease

* Adequately treated cervical carcinoma in situ without current evidence of disease

* Localized (e.g., lymph node negative) breast cancer treated with curative intent with no evidence of active disease present for more than 3 years and receiving adjuvant hormonal therapy

* Localized prostate cancer undergoing active surveillance

* History of treated and cured Hodgkin's disease or non-Hodgkin lymphoma (NHL) \< 5 years from diagnosis

Major surgery within 4 weeks of planned start of study therapy

A significant history of renal, neurologic, psychiatric, endocrine, metabolic or immunologic disorder, that, in the opinion of the Investigator, would adversely affect the patient's participation in this study or interpretation of study outcomes

History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor (CAR)-T therapy within the past 60 days or presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing:

* Active graft versus host disease (GVHD)

* Need for anti-cytokine therapy for toxicity from CAR-T therapy

* Residual symptoms of neurotoxicity \> grade 1 from CAR-T therapy

Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\])

Significant cardiovascular disease, defined as any of the following:

* Unstable angina or acute coronary syndrome within the past 2 months

* History of myocardial infarction within 6 months prior to planned start of study treatment

* Documented left ventricular ejection fraction (LVEF) by any method of =\< 45% in the 12 months prior to planned start of study treatment

* \>= grade 3 New York Heart Association (NYHA) functional classification system of heart failure

* Uncontrolled or symptomatic arrhythmias

Prolongation of the QT interval corrected (QTc) for heart rate using Fredericia's Formula (QTcF) \> 470 msec on an electrocardiogram (EKG) during screening

* QTcF is calculated using Fredericia's Formula

* Correction of suspected drug-induced QTcF prolongation or prolongation due to electrolyte abnormalities can be attempted at the Investigator's discretion, and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation or electrolyte supplementation

* Correction of QTc for underlying bundle branch block (BBB) permissible

Hepatitis B or hepatitis C testing indicating active/ongoing infection based on screening laboratory tests as defined as:

* Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation. Patients who are hepatitis B PCR positive will be excluded

* Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before randomization. Patients who are hepatitis C RNA positive will be excluded

Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) or other clinically significant active disease process which in the opinion of the Principal Investigator may pose a risk for patient participation. Screening for chronic conditions is not required

Known human immunodeficiency virus (HIV) infection, regardless of CD4 count. Patients with unknown or negative status are eligible

Known active cytomegalovirus (CMV) infection. Patients with unknown or negative status are eligible

Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the oral administered study treatments

Investigational agent or anti-cancer therapy other than venetoclax, with the exception of hormonal therapy for breast or prostate cancer. Other agents must be discontinued for at least 4 weeks for monoclonal antibody therapy or 5 half lives for other agents

Use of \> 20 mg prednisone QD or equivalent dose of steroid per day at the time of cycle 1 day 1 (C1D1). Patients may not be on prednisone of any dose intended for anti-neoplastic use

Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist

Current treatment with strong cytochrome P450 (CYP) 3A4 (CYP3A4) inducers and/or strong P-glycoprotein (P-gp) inhibitors. Because of their effect on CYP3A4, use of any of the following within 3 days of study treatment start or planned use during study participation is prohibited:

* Grapefruit or products from grapefruit

* Seville oranges or products from Seville oranges

* Star fruit or products from star fruit

Vaccination with a live vaccine within 28 days prior to study start

Previous treatment with another non-covalent BTK inhibitor, such as nemtabrutinib

Pregnancy, lactation or plan to breastfeed during the study or within 30 days of the last dose of study treatment

Patients with known hypersensitivity to any component or excipient of LOXO-305 and venetoclax

Any unresolved toxicity from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) grade 2 at the time of starting study treatment, except for alopecia

What this study is about