Pirtobrutinib (LOXO-305) and Venetoclax for the Treatment of Patients With CLL or SLL Resistant to Covalent BTKi

Inclusion Criteria: * Diagnosis of CLL or SLL according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines * Detectable CLL on flow cytometry of the blood or marrow at time of enrollment * Age ≥ 18 years old * Eastern Cooperative Oncology Group (ECOG) performance 0-2 * Currently taking ibrutinib, acalabrutinib, or zanubrutinib at any daily dose and tolerating it for \> 4 weeks * Evidence of progressive disease by iwCLL 2018 criteria for progressive disease or doubling of absolute lymphocyte count (ALC) in ≤ 6 months while on BTK inhibitor provided ALC is \> 5 k/uL * Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) or ≤ 5 x ULN with documented liver involvement * Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or Gilbert's disease * Creatinine clearance (CrCl) ≥ 30 according to modified Cockcroft-Gault equation * Absolute neutrophil count (ANC) ≥ 0.75 k/uL * Without transfusion or growth factor administration in the 7 days prior to screening * Any values if cytopenias are due to bone marrow involvement with disease * Hemoglobin ≥ 8 g/dL * Without transfusion or growth factor administration in the 7 days prior to screening * Any values if cytopenias are due to bone marrow involvement with disease * Platelets ≥ 50 k/uL * Without transfusion or growth factor administration in the 7 days prior to screening * Any values if cytopenias are due to bone marrow involvement with disease * Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x ULN * No known inherited qualitative platelet defect (e.g. delta granule storage pool deficiency) * Willing and able to complete study activities and treatment * Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol * Willingness of men and women of reproductive potential and their partners to observe conventional and highly effective or acceptable birth control methods for the duration of treatment and for 6 months following the last dose of pirtobrutinib or 30 days from the last dose of venetoclax * ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Discontinued initial study treatment ≤ 12 months ago * ELIGIBILITY FOR RE-TREATMENT WITH PIRTOBRUTINIB: Meets iwCLL 2018 criteria for progressive disease Exclusion Criteria: * Inability to tolerate 2 Liters of oral or intravenous (IV) hydration * Prior venetoclax exposure \> 13 months or known resistance to venetoclax * Known hypersensitivity to any of the excipients of pirtobrutinib or venetoclax * Need for treatment with warfarin or other vitamin K antagonist during study treatment * History of bleeding diathesis * Patients who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor. Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome) * History of stroke or intracranial hemorrhage within 6 months * Inability to take pills or oral medications * Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of either pirtobrutinib or venetoclax * Current known central nervous system involvement with CLL or SLL. Patients with previous treatment for central nervous system (CNS) involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the investigator and with documented approval by the principal investigator * Treatment with the following: * Targeted agents, investigational agents, therapeutic monoclonal antibodies, or cytotoxic chemotherapy within 5 half-lives or 2 weeks, whichever is shorter * Treatment with immunoconjugated antibody treatment within 10 weeks * Receipt of broad field radiation ( ≥ 30% of the bone marrow or whole brain radiotherapy) within 14 days or palliative limited field radiation within 7 days prior to study enrollment * Note: Treatment with ibrutinib, acalabrutinib, or zanubrutinib is allowed. Treatment with topical chemotherapy agents for precancerous skin conditions or skin cancers is allowed * Unresolved adverse events from prior treatment not resolved to grade ≤ 1 with the exception of alopecia or grade 2 peripheral neuropathy * History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T cell (CAR-T) therapy within 60 days. Patients with a history of allogeneic stem cell transplant must be stable off all immunosuppression for at least 2 months prior to study screening. Presence of any of the following, regardless of prior SCT and/or CAR-T therapy timing will be exclusionary: * Active graft versus host disease (GVHD) * Cytopenia from incomplete blood cell count recovery post-transplant * Need for anti-cytokine therapy for toxicity from CAR-T therapy and/or residual symptoms of neurotoxicity \> grade 1 from CAR-T therapy * Ongoing immunosuppressive therapy * Active second malignancy unless in remission and with life expectancy \> 2 years. Adjuvant endocrine therapy for breast or prostate cancer that is expected to be cured is allowed. Non-melanoma skin cancers are permitted if adequately treated * Psychiatric illness, or social situations that would limit compliance with study requirements * Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within th