Rituximab + High-Dose Methylprednisolone Debulking Prior to Venetoclax for CLL & SLL Patients

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)