* 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, \<5,000 cells/mL
4. Cohort A: refractoriness to cBTKi defined as lack of response or progressive disease while on therapy
Cohort B: refractoriness to pirtobrutinib defined as lack of response or progressive disease while on therapy
5. Prior treatment with a BCL2i
6. Active disease requiring treatment or progressive disease during or after therapy according to iwCLL guidelines
7. 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
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 as described in Section 5.5.2 Contraceptive Requirements
* 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 \<=1.5 x ULN OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) \>=30 mL/min for participant with creatinine levels \>1.5 x institutional ULN
-Hepatic
* Total bilirubin \<=1.5 x ULN OR direct bilirubin \<= ULN for participants with total bilirubin levels \>1.5 x ULN
* AST (SGOT) and ALT (SGPT) \<=2.5 x ULN
-Coagulation
* PT, aPTT \<=1.5 x ULN unless participant is receiving anticoagulant therapy
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);
ULN=upper limit of normal; INR=international normalized ratio; PT=prothrombin time; aPTT=activated partial thromboplastin time
\*Growth factor and/or transfusion support is permissible to meet this requirement if cytopenia is due to bone marrow involvement of CLL
EXCLUSION CRITERIA:
The participant must be excluded from the study if the participant meets any of the following criteria:
1. Documented CNS involvement
2. Active HBV/HCV infection. See Inclusion Criteria 10 (HBV) and 11 (HCV) for requirements.
3. Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
4. Gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy).
5. Active, uncontrolled infection requiring systemic therapy, including IV antibiotics during screening. Participants may be rescreened followed completion of IV antibiotic course.
6. Stroke or intracranial hemorrhage within 6 months of screening
7. Hypertensive urgency or emergency
8. Active, clinically significant cardiovascular disease including:
* 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 6 months of screening.
* History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.
9. QTcF \>450 milliseconds based on Fridericia s formula (NOTE: QTcF value may be calculated as the numerical average of up to 3 separate readings for eligibility).
10. Known allergy/sensitivity to nemtabrutinib or any of the excipients (hypromellose acetate succinate, microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, and may include film coat).
11. History of severe bleeding disorders defined as an ongoing congenital or acquired condition that leads to an increased likelihood of bleeding.
12. Known additional malignancy that is progressing or has required active treatment within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk, early-stage prostate cancer (T1-T2a, Gleason score \<=6, and PSA \<10 ng/mL), either treated with definitive intent or untreated in active surveillance with stable disease, are not excluded.
13. Currently being treated with the following drugs:
* P-gp substrates with a narrow therapeutic index
* CYP3A strong inducers
* CYP3A strong inhibitors
Note: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a participant to be eligible for study enrollment.
14. Has received prior systemic anti-CLL therapy within 3 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) of start of nemtabrutinib.
15. Has received prior radiotherapy within 2 weeks of start of nemtabrutinib or radiation-related toxicities requiring corticosteroids.
Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week washout, is permitted.
16. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of nemtabrutinib. Administration of killed vaccines are allowed.
17. Patients requiring ongoing treatment with warfarin within 7 days of start of nemtabrutinib
18. Enrolled on another therapeutic clinical trial for CLL/SLL at the start of nemtabrutinib. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anticancer therapy is prohibited.
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. Has not adequately recovered after 4 weeks from major surgery or has ongoing surgical complications.
Note: Biopsy and placement of central venous access devices are not considered major surgery.
21. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
