The purpose of the study is to investigate whether the combination of rituximab and high dose methylprednisolone can be given together, can reduce the amount of cancer cells that are present prior to starting venetoclax, and therefore make it safer to take venetoclax. Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) will be treated in this study. Subjects will be assessed for their risk of tumor lysis syndrome (TLS), a potentially serious side effect associated with venetoclax and rituxan. TLS is caused by the fast breakdown of cancer cells. TLS can lead to kidney failure or abnormal heart rhythm. Depending on their TLS risk, patients will be assigned to one of two treatment arms. Patients who are at high risk for TLS at baseline will receive HDMP/Rituximab for 1 cycle before beginning venetoclax. Patients who are at low risk for TLS at baseline will not receive HDMP/Rituximab and will instead start directly with venetoclax. Once the proper dose of venetoclax is reached, both arms will continue venetoclax for up to 2 years and receive rituximab for 5 cycles. The purpose is to determine if HDMP/Rituximab prior to venetoclax is efficient at reducing tumor burden and lowering the risk of developing TLS. Although all of these drugs are approved by the FDA for the treatment of patients with CLL or SLL, and although the combination of rituximab and venetoclax is approved by the FDA for the treatment of patients with CLL or SLL, the combination and dosing schedule in this trial are considered experimental.

Objectives:

Primary:

1. To determine the percentage of patients who have a reduction of lymphadenopathy (from greater than to less than 5 cm in largest diameter) and/or absolute lymphocyte count (from greater than to less than 25k/uL) following 1 or 2 cycles of HDMP + rituximab.

Secondary:

1. To determine the rate of laboratory or clinical TLS with this strategy.
2. To determine the safety (CTCAE4) of this approach.
3. To determine the overall efficacy (iwCLL) of this overall strategy.
4. To determine the percentage of patients who have undetectable minimal residual disease in the bone marrow.

Endpoints:

Primary:

1. Percentage of patients that have a decrease in tumor burden from levels of disease that meet "Medium/High-tumor burden" criteria to meet "Low tumor burden" criteria for disease burden following 1 or 2 cycles of HDMP + Rituximab.

Secondary:

1. Percentage of patients that have a decrease in tumor burden from levels of disease that meet "Medium/High-tumor burden" c criteria to meet "Low tumor burden" criteria for disease burden following 1 cycle of HDMP + Rituximab.
2. Percentage of patients that have a decrease in tumor burden from levels of disease that meet "Medium/High-tumor burden" criteria to meet "Low tumor burden" criteria for disease burden following 2 cycles of HDMP + Rituximab.
3. Rate of laboratory TLS (from start of treatment until completion of venetoclax ramp-up)
4. Rate of clinical TLS (from start of treatment until completion of venetoclax ramp-up)
5. Adverse events by CTCAE4 definitions
6. Overall Response rate, Partial Response rate, and Complete response rate per iwCLL criteria after 9 months of venetoclax and at completion of treatment.
7. Undetectable minimal residual disease (MRD) rate based on bone marrow biopsy after 9 months of venetoclax, and at completion of treatment.

Single center, open-label, pilot/feasibility study to determine the feasibility of HDMP/R as a debulking approach prior to venetoclax.

Patients with CLL/SLL who require therapy, and have disease burden meeting criteria for Medium or High Risk Tumor Burden (based on: lymph nodes >/= 5 cm in diameter and/or absolute lymphocyte count >/= 25k/uL) are enrolled.

• Patients will receive HDMP + Rituximab for 1 cycle, followed by reassessment of Tumor Burden,
• If Tumor Burden classification is low after HDMP + Rituximab (lymph nodes < 5cm in diameter AND absolute lymphocyte count < 25k/uL), patients will initiate venetoclax dose ramp-up, with ramp-up schedule according to venetoclax package insert.
• Patients who still have a disease burden (lymphadenopathy > 5 cm or ALC > 25k/iL) that meets criteria for medium or high risk of TLS after 1 cycle of HDMP + Rituximab are given the option to repeat a 2nd cycle of HDMP + Rituximab prior to venetoclax dose ramp-up.

Upon completion of ramp-up (venetoclax to 400 mg), all patients will continue Venetoclax 400 mg (or highest tolerated dose) for up to 2 years. Patients will also continue rituximab 500 mg/m2 q 28 days through Cycle 6.

Endpoint Assessment:

1. Assessment of the disease burden after a maximum of 2 cycles of HDMP + Rituximab is the primary endpoint.
2. Assessment of the disease burden after 1 cycle of HDMP + Rituximab.
3. Assessment of the disease burden after 2 cycles of HDMP + Rituximab (for the subset of patients that do not meet criteria for low tumor burden after 1 cycle).
4. Clinical and laboratory TLS events between start of treatment and the completion of venetoclax dose-ramp up (Cycle 2, Day 1)
5. Presence or absence of detectable MRD in the marrow will be assessed after approximately 9 months of venetoclax and completion of treatment.
6. Radiology assessment after approximately 9 months of venetoclax and completion of study (unless prior imaging studies are without measurable disease)

Inclusion Criteria:

Patients must meet the following criteria for study entry:

1. Subjects must be age 18 or older.

2. Both men and women of all races and ethnic groups are eligible for this trial.

3. Ability to understand and willingness to sign a written informed consent.

4. Diagnosis: CLL or SLL, as documented in the medical record

5. Disease Status/ Prior Therapy:

   • Must have had treatment for CLL/SLL with at least 1 line of prior therapy. (There is not requirement nor restriction for specific type of previous therapy, with the following exceptions: prior treatment with venetoclax within 6 months, prior progressive disease on venetoclax, or prior grade 3 or 4 toxicity (not including TLS) that directly lead to discontinuation of venetoclax; Prior HDMP/Rituximab is allowed unless there was no response (Stable Disease or Progressive Disease) or was within 3 months.)
   • Indication for CLL or SLL therapy based on international working group (iwCLL) guidelines, which include: constitutional symptoms, bulky or symptomatic lymphadenopathy, bulky or symptomatic splenomegaly, rapid doubling of the ALC (approximately 6 months or less), or Rai stage 3 or 4 disease.
   • Disease burden meets criteria for Medium or High Tumor Burden, based on Absolute lymphocyte count >/= 25k/uL or any lymph node 5 cm or greater in diameter. The ALC criteria must be met during the screening period. The imaging criteria may be based on radiologic study within 30 days of Cycle 0, Day 1.

6. Has recovered from the toxic effects of prior therapy to their clinical baseline.

7. Women of child-bearing potential (not postmenopausal for at least one year or not surgically incapable of bearing children) must agree to not become pregnant for the duration of the study. Both men and women must agree to use a barrier method of contraception for the duration of the study and until 5 half-lives after the final dose of venetoclax (approximately 1 week), and at least 5 half-lives of final dose of Rituximab.

8. ECOG performance status of 0-2

9. Adequate hematologic function: Platelet count >/= 30k/uL, hemoglobin > 7 g/dL, AND ANC > 500/uL. (Values may be lower if due to marrow infiltration by CLL).

10. Adequate renal function: creatinine clearance based on 24 hr collection >/= 40 ml/min; OR Calculated Creatinine clearance (CrCl) ≥ 40 mL/min (based upon the Cockcroft-Gault Equation [CrCl = (140-age) * actual wt (in kg) * (0.85 if female) / (72 * Cr)].

11. Adequate hepatic function:

    • Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN
    • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Subject is known to be positive for HIV. (HIV testing is not required.)

2. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

   • Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
   • Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.

3. Treatment with any of the following within 7 days prior to the first dose of venetoclax:

   • Steroid therapy for anti-neoplastic intent
   • moderate or strong cytochrome P450 3A (CYP3A) inhibitors (see Appendix C for examples)
   • moderate or strong CYP3A inducers (see Appendix C for examples)

4. Administration or consumption of any of the following within 3 days prior to the first dose of venetoclax:

   • grapefruit or grapefruit products
   • Seville oranges (including marmalade containing Seville oranges)
   • star fruit

5. Prior CLL therapy:

   • Biologic agent (monoclonal antibody) within 30 days for anti-neoplastic intent.
   • Chemotherapy (purine analog or alkylating agent) or target small molecule agent within 14 days or 5 half-lives (whichever is shorter), or has not recovered to less than CTC grade 2 clinically significant adverse effect(s)/toxicity(s) of previous therapy.

6. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy

7. Known hypersensitivity to any of the study drugs

8. History of other malignancy that could affect compliance with the protocol or interpretation of results (example: patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are generally eligible. Patients with a malignancy that has been treated, but not with curative intent, will also be excluded, unless the malignancy has been in remission without treatment for 2 years prior to enrollment.)

9. Known active bacterial, viral, fungal, mycobacterial, or other infection (excluding fungal infections of nail beds); or any major episode of infection requiring treatment with IV antibiotics or hospitalization (related to the completion of the course of antibiotics) within 4 weeks before the start of Cycle 0

10. Major surgery (within 4 weeks prior to the start of Cycle 0), other than for diagnosis

11. Women who are pregnant or lactating

12. Uncontrolled diabetes mellitus (related to high dose steroid risk)

13. Myocardial infarction within 6 months of starting study drug or other clinically significant heart disease (NYHA class 3 heart failure, uncontrolled hypertension)