Nemtabrutinib for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) Refractory to Covalent Bruton Tyrosine Kinase Inhibitor or Pirtobrutinib and Previously Treated With a BCL2 Inhibitor

Background: Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) are diseases in which the body makes too many white blood cells that do not work properly. Because white cells play a role in immune function, people with CLL/SLL may be at greater risk of infections. CLL/SLL can be controlled with drugs, but many people develop resistance, and the treatments stop working. Objective: To test a new drug (nemtabrutinib) in people with CLL/SLL. Eligibility: People aged 18 years or older with CLL/SLL that persists despite treatment. Design: Participants will be screened. They will have imaging scans, blood and urine tests, and a test of their heart function. They will have a bone marrow biopsy: a sample of tissue and fluids will be drawn from inside their hip bone. They may also have a sample cut from a swollen lymph node, if one is safe to access. Nemtabrutinib is a tablet taken by mouth. Participants will take the drug once a day at home in 4-week cycles. They will have clinic visits at least every 4 weeks for the first 6 months and then every 3 months after that. Biopsies, imaging exams, and other tests may be repeated at these visits. Participants may also undergo lymphapheresis: Blood will be drawn from a tube inserted into a vein. The blood will pass through a machine that separates out cancer and immune cells. The remaining blood will be returned to the body through a different tube. Participants may stay in the study as long as the drug is helping them.

* INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. Age \>=18 years. CLL/SLL is extremely rare in patients \< 18 years old. 2. Ability to comprehend the investigational nature of the study and provide informed consent 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 2. CLL: clonal B-lymphocytosis \>=5,000 cells/mL OR SLL: lymphadenopathy with the tissue morphology of CLL but that are not leukemic, \=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 8. A female participant is eligible to participate if not pregnant or breastfeeding, and \>=1 of the following conditions applies: Is not a person of childbearing potential (POCBP) OR Is a POCBP and * Uses a contraceptive method * Has a negative highly sensitive serum pregnancy test within 7 days before the first dose of study intervention. 9. The participant has provided documented informed consent for the trial. 10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days prior to the first dose of study intervention. 11. The ability to swallow and retain oral medication Note: Administration of nemtabrutinib is not permitted through a PEG-J tube. 12. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for \>=4 weeks and have undetectable HBV viral load prior to study entry. Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Hepatitis B screening tests should include HBsAg, HBcAb, HBsAb . Hepatitis B screening tests are not required unless: * Known history of HBV infection * As mandated by local health authority 13. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. Note: Participants must have completed curative anti-viral therapy \>=4 weeks prior to nemtabrutinib initiation. 14. Participants with HIV are eligible if they meet ALL of the following criteria: * The CD4 count is \>350 cells/microL at screening * The HIV viral load is below the detectable level as per locally available testing * Are on a stable ART regimen for \>=4 weeks prior to study entry Note: ART includes drugs, which are NOT strong CYP3A4 inducers (participants receiving ART that are strong CYP3A4 inducers are not eligible to be included in the study). * Are compliant with their ART Note: If the participant has had an AIDS defining opportunistic infection in the past 12 months prior to screening, they are not eligible to be included in the study. 15. Adequate organ function as defined in the following table. Specimens must be collected within 7 days prior to drug initiation. Organ Function Laboratory Values: * Hematological --Absolute neutrophil count (ANC) \>=750/microL (or \>=500/mircoL in participants with documented bone marrow involvement)\* * Platelets \>=50,000/mircoL\* * Hemoglobin \>=8 g/dL\* * Renal * Creatinine \=30 mL/min for participant with creatinine levels \>1.5 x institutional ULN * Hepatic * Total bilirubin \