Inclusion Criteria:
\- Inclusion Criteria For all patients
1. Diagnosis of CLL according to the IwCLL criteria or SLL according to the World Health Organization (WHO) criteria. This includes previous documentation of:
* Biopsy-proven small lymphocytic lymphoma OR
* Diagnosis of CLL according to the IWCLL criteria as evidenced by Peripheral blood lymphocyte count of greater than 5 x109/L .
* Immunophenotype consistent with CLL defined as the predominant population of lymphocytes share both B cell antigens (CD19, CD20 (typically dim expression), or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc).
2. On therapy with acalabrutinib for a minimum of 3 months without evidence of progression as per IWCLL 2018 criteria.
3. Relapsed or Refractory CLL who have received at least one prior therapy before initiation of acalabrutinib
4. Presence of measurable residual disease in the peripheral blood or bone marrow aspirate by NGS based clonoseq test.
5. Adequate organ function as defined below unless attributed to disease involvement:
* Liver function (bilirubin ≤ 1.5 × ULN, AST and/or ALT \<3 x ULN). Patients with Gilbert Disease are permitted irrespective of bilirubin values.
* Kidney function (crcl \> 30ml/min using Cockroft-Gault, based on actual weight).
* ANC ≥ 1,000/µL, Hgb \> 8, Platelet Count ≥ 50,000/ µL. Use of G-CSF is not permitted for up to 7 days prior to enrollment.
Exclusion Criteria:
* Exclusion Criteria For all patients
1. Current evidence of central nervous system involvement.
2. Unable to generate clonoseq ID specimen for measurable residual disease tracking.
3. Completion of an autologous hematopoietic stem cell transplantation within 3 months prior to first dose of study drug.
4. Prior allogeneic stem cell transplant within 6 months. The patient should not have any active Graft vs. Host disease (GVH) or should be on immune suppressive agents.
5. Completion of treatment with any radiotherapy, chemotherapy, antibody, immunoconjugates and/or another investigational drug ≤4 weeks (or 5 half-lives of the drug, whichever is shorter) prior to the first dose of study drug. Patients may be enrolled after a minimum of 2 weeks of radiation if radiation was for palliative intent.
6. Progression of disease on BTK inhibitor.
7. Unable to tolerate full dose of acalabrutinib at 100 mg twice a day.
8. Inability to swallow and retain oral medications.
9. Pregnant women are excluded from this study.
10. Any active, concurrent, significant illness or disease (other underlying lymphoma) or clinically significant findings including psychiatric and behavioral problems, medical history and/or physical examination findings that would preclude the patient from participation in the study such as:
* active infection requiring systemic therapy ≤10 days before the first dose of study drug
* unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association \[NYHA\] II, III, IV;), myocardial infarction ≤6 months prior to first study drug, uncontrolled cardiac arrhythmia e.g., atrial fibrillation/flutter, cerebrovascular accidents ≤6 months before first dose of study drug
* Significant (as defined by study doctor) pulmonary disease or disorder
* any severe or uncontrolled other disease or condition which might increase the risk associated with study participation
11. Vaccination with live, attenuated vaccines within 28 days prior to the first dose of study medication.
12. Receiving systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents). The use of inhaled corticosteroids is permitted.
13. Corticosteroids ≥ 10 mg of prednisone within the last 7 days.
14. Has had a solid organ transplant within the last 3 years. Note: Patients who have had a Solid organ transplant \>3 years ago are eligible if there are no signs/symptoms of graft versus host disease (GvHD) and off immunosuppressive medications as per above.
15. Known history of hypersensitivity to loncastuximab tesirine
16. Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath)
17. Breastfeeding or pregnant
18. Any other malignancy known to be active, with the exception of
* Cervical carcinoma of Stage 1A (1A1,1A2) and 1B (1B1,1B2,1B3)
* Non-invasive basal cell or squamous cell skin carcinoma
* Non-invasive, superficial bladder cancer
* Prostate cancer with a current PSA level \< 0.1 ng/mL
* Any curable or localized cancer with a CR of \> 2 years' duration.
