• Patients with relapsed/refractory CLL who meet iwCLL criteria for requiring treatment.

• Patients with measurable disease as defined by at least one of: circulating lymphocytosis \> 5000 B cells/microliter, bone marrow involvement \> 30%, palpable splenomegaly or lymph nodes \> 1.5 cm. Computer tomography (CT) at screening must be performed and followed every 2 cycles (1 cycle = 28 days).

• Patients must have received at least two prior therapies for CLL including systemic therapy containing a covalent BTK inhibitor.

• Patients willing to undergo a pre-treatment and on treatment bone marrow biopsy.

• Age ≥18 years, at the time of signing the IRB approved informed consent. Because no dosing or adverse event data are currently available on the use of venetoclax in combination with roginolisib in participants \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.

• Participants must meet the following organ and marrow function as defined below:

‣ Platelet count ≥50 x 109/L\^\^\^

⁃ Total bilirubin ≤ 1.5 ×institutional upper limit of normal (ULN)\*

⁃ AST(SGOT)/ALT(SGPT) ≤3.0 × institutional ULN

⁃ Creatinine clearance ≥ 60 mL/min\*\*

⁃ \^\^\^Thrombocytopenia due to marrow involvement of CLL: \> 30 x 109/L for the safety run-in, and 20 x 109/L for the randomized portion of the study

⁃ \*unless increase attributed to leukemic organ involvement, hemolysis or Gilbert's syndrome. Patients who are \< 75 years may have bilirubin of ≤ 3.0 × ULN

⁃ \*\* calculated by the Cockcroft Gault formula or measured by 24 hours urine collection

• Patients with clinically inactive CNS disease or treated CNS disease that is no longer symptomatic, or who need corticosteroids or anticonvulsants may be enrolled in the study. For patients who have symptoms present, imaging and lumbar puncture must be performed to exclude a CNS condition that may impact the study conduct.

• Willingness to undergo a pre-treatment and on-treatment bone marrow to evaluate MRD.

• Willingness to use adequate contraception prior to study entry and for the duration of study participation.

‣ The effects of roginolisib on the developing human fetus are unknown.

⁃ Venetoclax may cause embryo fetal harm when administered to pregnant women. Anti-CD20 targeting agents are likely to cause fetal B-cell depletion. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Women of child-bearing potential will be required to have a negative serum pregnancy test during screening and a negative serum pregnancy test on Cycle 1 Day 1. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

⁃ Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of roginolisib or venetoclax administration. Contraception must be conducted up to 12 months after taking the last rituximab dose.

• Ability to understand and the willingness to sign a written informed consent document, which includes compliance with the requirements of this protocol.

• Eligible to receive infection prophylaxis and supportive care as per institutional guidelines.