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

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)