Venetoclax and Eprenetapopt for the Treatment of Relapsed of Refractory Mantle Cell Lymphoma

Inclusion Criteria:

* Confirmed diagnosis of mantle cell lymphoma in tissue biopsy and chromosome translocation t(11;14), (q13;q32) and/or overexpress cyclin D1 in tissue biopsy, cyclin D1 negative MCL (confirmed by hematopathology's are allowed and blastoid/pleomorphic morphology, complex karyotype are allowed)
* Patients must have relapsed or refractory MCL (irrespective of prior BTK inhibitor or anti CD19 chimeric antigen receptor T cell \[CART\] exposure)
* Prior exposure to venetoclax is allowed as long as the patients had clear evidence of disease progression on venetoclax (alone or in combination with other therapy) and the maximum dose of venetoclax was =\< 400 mg. Doses \> 400 mg and progression on venetoclax are excluded
* Patients with known TP53 status (positive or negative) - confirmed by a pre-treatment biopsy a pre-treatment biopsy to be sent for TP53 sequencing and TP53 testing by fluorescence in situ hybridization (FISH) and TP53 by immunohistochemistry (IHC) from hem-path to the hem-pathology and get the TP53 status before starting the study as a part of screening. To send bone marrow (BM) for TP53 assessment if it is involved by MCL \> 10% instead
* TP53 mutation positive by IHC (\>= 50%) in MCL cells and/or TP53 deletion by FISH in bone marrow (BM) or in tissues and/or del17p in karyotype or TP53 deletion positive by FISH in BM/involved tissue with MCL or presence of somatic TP53 mutations by next generation sequencing (NGS) or whole exome sequencing (WES) and TP53 wild type or mutation-negative status are allowed
* High risk MCL (blastoid/pleomorphic histology, high Ki-67 \[\>= 50%\], TP53/NOTCH1/2, NSD2, CYCLIN D1, BIRC3 mutated, complex karyotype, Bulky disease \> 5 cm, FISH positive for TP53 or MYC from involved tissues, high risk Mantle Cell Lymphoma International Prognostic Index \[MIPI\] score)
* Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form
* Age from \>= 18 years at the time of signing the informed consent
* Patients must have bi-dimensional measurable disease
* Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
* Absolute neutrophil count (ANC) \> 1,000/mm\^3

  * If bone marrow and spleen are involved, the counts of ANC will not be limited
* Platelet count \>= 100,000/mm\^3

  * If bone marrow and spleen are involved, the counts of platelets will not be limited
* Prothrombin time (or international normalized ratio) and partial thromboplastin time not to exceed 1.2 times the institution normal range (patients with an elevated prothrombin time and known lupus anticoagulant may be eligible for participation after consulting the medical monitor)
* Platelet count \>= 100, 000/mm\^3
* Absolute neutrophil count (ANC) \>= 1000/mm\^3 unless cytopenia is clearly due to marrow involvement from MCL
* Total hemoglobin \>= 9 g/dL (without transfusion support within 2 weeks of screening);

  * If any of the above-mentioned cytopenias (a-c) are present due to significant BM involvement (requiring transfusion or granulocyte colony-stimulating factor \[G-CSF\] support) MCL patients may proceed with enrollment after discussion with the PI or designee. Cytopenias may not be due to evidence of myelodysplastic syndrome (MDS) or hypoplastic BM
* Creatinine clearance \>= 30 mL/min (by Cockcroft-Gault method)
* Total serum bilirubin =\< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome, non-Hodgkin lymphoma (NHL) organ involvement, controlled immune hemolysis or considered an effect of regular blood transfusions
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 x ULN, unless due to NHL organ involvement
* Projected life expectancy of \> 12 weeks
* Female patients must be surgically sterile, postmenopausal (for at least 1 year), or have confirmed negative results for a pregnancy test at screening, on a blood or urine sample obtained within 7 days prior to initiation of study treatment
* Women of childbearing potential and men with female partners of childbearing potential must be willing to use an effective form of contraception
* Patient enrolled into the eprenetapopt + venetoclax study should use an effective form of contraception for up to 30 days after the last dose of eprenetapopt in combination with venetoclax, whichever time period is longer. Recommended methods of highly effective birth control are:

  * Hormonal contraception (birth control pills, patches, or rings)
  * Intrauterine device (IUD)
  * Birth control injections
  * Double barrier methods (diaphragm with spermicidal gel or condoms with birth control foam)
  * Sterilization of participant or partner ("tubes tied" or vasectomy)
* Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated, with a life expectancy \> 3 years. Principal investigator (PI) could use judgment in the best interests of patients

Exclusion Criteria:

* Known central nervous system (CNS) involvement by lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease (as shown by magnetic resonance imaging \[MRI\] brain and/or cerebrospinal fluid \[CSF\] or clinical exam by neurologists may be eligible if a compelling clinical rationale is provided to Aprea pharma which is the supporting company and the institution is the investigational new drug \[IND\] sponsor)
* Any serious uncontrolled medical condition including but not limited to, uncontrolled hypertension, diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active infection, active hemorrhage, laboratory abnormality, or psychiatric illness that places the patient at unacceptable risk and would prevent the subject from signing the informed consent form
* Pregnant or lactating females
* Known human immunodeficiency virus (HIV) infection
* Patients with active hepatitis B infection (not including patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody. Active hepatitis B/C. Patients with prior exposure to hepatitis B (i.e. positive anti-hepatitis B CORE antibody) must demonstrate hepatitis B polymerase chain reaction (PCR) to be negative during screening period and undergo prophylaxis and monitoring for hepatitis B according to institutional guidelines. Known hepatitis C infection is allowed as long as there is no active disease and is cleared by gastrointestinal (GI) consultation
* Clinically significant cardiovascular diseases as determined after cardiology consultation, including uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months of screening or any class 3 (moderate) or 4 (severe) cardiac disease following the New York Heart Association classification, known left ventricular ejection fraction (LVEF) \< 40%, history of familial long QT syndrome, Symptomatic atrial or ventricular arrhythmias not controlled by medications. Otherwise, significant screening electrocardiogram (ECG) abnormalities and/or pacemaker may be allowed after discussion with the PI and the cardiologist clearance
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of venetoclax
* With known allergies to xanthine oxidase inhibitors and/or rasburicase
* Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that, in the opinion of the investigator, may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
* No concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy. No major surgery within 3 weeks prior to first dose of study treatment. Washout period for chemotherapy is 14 days. Washout period for targeted agents is 2 weeks or 5 half-lives (t1/2) (whichever is shorter). Washout period for antibody-based immunotherapies or cellular therapies is 4 weeks. Washout period for radiotherapy is 7 days (limited field) and 28 days (extended field that includes BM). Washout period must be completed prior to any treatment administration
* Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia
* Consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting study treatment
* Concomitant steroids for disease related pain control are allowed at any dose but must be discontinued prior to any study treatment initiation. Chronic use of corticosteroids is allowed up to 20 mg prednisone daily for non-cancer related conditions at the time of study start
* History of allogeneic or autologous stem cell transplant (SCT) or CAR-T therapy within the last 30 days or with any of the following:

  * Active uncontrolled graft versus host disease (GVHD)
  * Cytopenias from incomplete blood cell count recovery post-transplant;
  * Need for anti-cytokine therapy for residual symptoms of neurotoxicity \> grade 1 from CAR-T therapy
* Ongoing immunosuppressive therapy
* Known neurologic disorder or residual neurologic toxicities that may put patients at increased risk of neurologic toxicity in the opinion of the investigator
* Concomitant malignancies or previous malignancies with less than a 1-year disease-free interval at the time of signing consent. Subjects with adequately treated basal or squamous cell carcinoma of the skin, or adequately treated carcinoma in situ (e.g. cervix) may enroll irrespective of the time of diagnosis. Patients with controlled, advanced prostate cancer (not on active chemotherapy) are permitted
* Active uncontrolled systemic infection
* Received an investigational agent within 30 days or within 5 T1/2, whichever is shorter prior to the first dose of study treatment
* Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong P-glycoprotein (P-gp) inhibitors