* INCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
1. Stated willingness to comply with all study procedures
2. Age \>=18 years
3. Confirmed diagnosis of CLL or SLL according to International Workshop on CLL (iwCLL) guidelines
1. Coexpression of CD5, CD19, CD20, and CD23 expression and light-chain restriction; CD23 dim or negative expression is acceptable as long as other parameters are consistent with a diagnosis of CLL.
2. CLL: clonal B-lymphocytosis \>=5,000 cells/mL
OR
SLL: lymphadenopathy with the tissue morphology of CLL but that are not leukemic, \<5,000 cells/mL
4. Active disease requiring treatment according to iwCLL guidelines
5. Measurable disease characterized by \>=1 of the following:
1. Lymphadenopathy: \>=1 lymph node measuring \>=1.5 cm in the greatest diameter
2. Splenomegaly: spleen measuring \>13 cm in craniocaudal length
3. Lymphocytosis: \>=5,000 B cells/microL
4. Bone marrow infiltration: CLL comprising \>= 30% of all cells
6. Previously untreated CLL with \>=1 LN amenable to core-needle biopsy
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
8. The patient has adequate organ function for all of the following criteria, as defined below:
* System: Hepatic
* Laboratory Value: ALT or AST: \<= 3 x the ULN or \<= 5 x ULN with documented liver involvement
* Laboratory Value: Total bilirubin: \<= 1.5 x ULN or \<= 3 x ULN with documented liver involvement and/or Gilbert s Disease
* System: Renal
--Laboratory Value: Serum creatinine: Calculated creatinine clearance \>= 30 ml/min according to Cockcroft/Gault Formula: \[(140-age) x body weight (kg) x 0.85 (if female)\]/ \[serum creatinine (mg/dL) x 72\]
* System: Hematologic
* Laboratory Value: Hemoglobin: \>= 8 g/dL (\>= 80 g/L)
* Laboratory Value: ANC: \>= 0.75 x 10\^9/L
* Laboratory Value: Platelets: \>= 50 x 10\^9/L
Notes:
Hgb and platelets: independent of transfusions within 7 days of Screening assessment.
ANC: independent of growth factor support within 7 days of Screening assessment.
Criteria must be met on C1D1 without transfusion/G-CSF within 7 days of assessment.
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST =aspartate aminotransferase; ULN = upper limit of normal.
9. Adequate coagulations, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or international normalized ratio (INR) not greater than 1.5 X ULN.
10. Willingness of WOCBP and their partners to observe highly effective birth control methods for the duration of treatment and for 1 month following the last dose of study treatment.
11. Ability to take oral medication and be willing to adhere to the study drug regimen
12. Agreement to adhere to Lifestyle Considerations throughout study duration
13. Able to understand and willing to sign a written informed consent document.
EXCLUSION CRITERIA:
1. Diagnosis of Richter Transformation
2. Documented CNS involvement
3. Pregnancy or plan to become pregnant during the study or within 1 month of the last dose of study treatment. WOCBP must have a negative serum pregnancy test.
4. Lactation or plan to breastfeed during the study or within 1 week of the last dose of study treatment.
5. Known active cytomegalovirus (CMV) infections. Unknown or negative status are eligible.
6. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:
1. Patients with positive hepatitis B surface antigen (HBsAg) are excluded.
2. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require a negative hepatitis B polymerase chain reaction (PCR) evaluation before randomization.
3. Patients who are HBV DNA PCR positive will be excluded.
7. 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.
8. Patients who have tested positive for Human Immunodeficiency Virus (HIV) and have a detectable viral load and/or a CD4 count \<350 are excluded due to risk of opportunistic infections with both HIV and BTK inhibitors. Eligible patients with HIV must be stable on antiretroviral therapy \>=4 weeks prior to study entry. For patients with unknown HIV status, HIV testing will be performed at Screening and result must be negative for enrollment.
9. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug. (e.g., gastric bypass surgery, gastrectomy).
10. Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation. Screening for chronic conditions is not required.
11. Stroke or intracranial hemorrhage within 6 months of screening
12. Hypertensive urgency or emergency
13. Active, clinically significant cardiovascular disease including:
* Unstable angina or acute coronary syndrome within the past 2 months prior to screening
* Documentation of LVEF by any method of \<= 40% in the 12 months prior to screening
* Uncontrolled or symptomatic arrhythmias
* Class 3 or 4 congestive heart failure as defined by New York Heart Association Functional Classification
* Myocardial infarction, unstable angina or acute coronary syndrome within 3 months of screening.
* Prolongation of the QT interval corrected for heart rate (QTcF) \> 470 msec. QTcF is calculated using Fridericia s Formula (QTcF): QTcF=QT/(RR\^0.33)
Correction of suspected drug-induced QTcF prolongation 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.
\- Correction for underlying bundle branch block (BBB) allowed.
Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
14. Known allergy/sensitivity to pirtobrutinib or any of the excipients (hydroxypropyl methylcellulose acetate succinate, microcrystalline cellulose, mannitol, sodium starch glycolate, and magnesium stearate.).
15. History of bleeding diathesis (e.g. von Willebrand disease or hemophlia)
16. Has received a live vaccine or live-attenuated vaccine within 28 days before the first dose of pirtobrutinib. Administration of killed vaccines are allowed.
17. Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist are excluded. Direct oral anticoagulants (DOACs) are allowed.
18. Diagnosis of primary immunodeficiency or is receiving chronic systemic steroid therapy (in dosing \>20 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
19. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid)
20. 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 the 4 weeks prior to study enrollment to maintain adequate blood counts.
21. Active second malignancy unless in remission and with life expectancy \>2 years.
Note: Participants are eligible if they have prostate cancer under active surveillance or observation.
22. Has not adequately recovered after 4 weeks from major surgery or has ongoing surgical complications.
23. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
24. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
