An Early Phase Study of Venetoclax, Lenalidomide, and Rituximab/Hyaluronidase in Slow-Growing Lymphomas That Have Come Back After Treatment or Have Not Responded to Treatment

Signed informed consent form

Ability and willingness to comply with the requirements of the study protocol

Able to swallow oral medications whole

Patients must have received at least one prior systemic therapy

Histologically confirmed indolent B-cell non-Hodgkin's lymphoma (NHL) of any of the following subtypes recognized by the World Health Organization (WHO) classification: Follicular lymphoma and marginal zone lymphoma. Patients with indolent non-Hodgkin's Lymphoma (iNHL) should have received at least 1 previous prior therapy

Patients must have an indication for treatment by Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria in the opinion of the investigator

Radiographically measurable disease by computed tomography (CT) scan, defined as at least one node \> 1.5 cm in size

All study participants must be registered into the mandatory lenalidomide risk evaluation and mitigation strategy (REMS) program, and be willing and able to comply with the requirements of the REMS program

Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the lenalidomide REMS program

Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. Patients intolerant to aspirin (ASA) may use low molecular weight heparin or equivalent. Inability to take any form of prophylaxis excludes participation

Eastern Cooperative Oncology Group performance status of 0, 1, or 2

Hemoglobin \>= 9 g/dL (unless caused by underlying disease, as established by extensive bone marrow involvement or as a result of hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator)

Absolute neutrophil count \>= 1.0 x 10\^9/L (unless caused by underlying disease, as established by extensive bone marrow involvement or as a result of hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator)

Platelet count \>= 75 x 10\^9/L (unless caused by underlying disease, as established by extensive bone marrow involvement or as a result of hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator)

International normalized ratio \> 1.5 x upper limit of normal (ULN) for patients not receiving therapeutic anticoagulation

Partial thromboplastin time (PTT) or activated PTT (aPTT) =\< 1.5 x ULN

Creatinine clearance \>= 60 mL/min, calculated with the use of the 24-hour creatinine clearance or modified Cockcroft-Gault equation

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 2.5 x ULN

Total bilirubin =\< 1.5 x ULN (or =\< 3 x ULN for patients with documented Gilbert syndrome)

Women of childbearing potential must have a negative serum or urine pregnancy test result within 14 days prior to registration

For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of \< 1% per year during the treatment period and for at least 30 days after the last dose of venetoclax and lenalidomide or 12 months after the last dose of rituximab, whichever is longer \* Women must refrain from donating eggs during this same period

\* A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (\>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus) \* Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices \* The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: \* With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for at least 6 months after the last dose of rituximab and for at least 30 days after the last dose of venetoclax and lenalidomide whichever is longer. Men must refrain from donating sperm during this same period \* With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose of rituximab to avoid exposing the embryo \* The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

What this study is about