Venetoclax Plus R-ICE Chemotherapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Inclusion Criteria: * Histological confirmation of relapsed/refractory diffuse large B-cell lymphoma after prior rituximab and anthracycline-containing systemic treatment regimen such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride), R-HyperCVAD (rituximab, cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone) etc. A biopsy immediately before enrollment is not required. * Subjects must have received no more than 2 prior systemic therapies for lymphoma. Prior therapy with systemic rituximab monotherapy or conventional chemotherapy (i.e. bendamustine, CVP (Cyclophosphamide, Vincristine Sulfate, Prednisone) or other) ± rituximab for indolent non-Hodgkin's lymphoma (NHL) ± maintenance/extended-use rituximab will count as 1 line of systemic therapy. * Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2 * Subjects must have normal organ and marrow function as defined below: * Hemoglobin ≥ 8.0 g/dl * Absolute neutrophil count ≥ 1,000/mcL * Platelet count ≥ 75,000/mcL * Total bilirubin ≤ 1.5 X the upper limit of normal (ULN) unless a known history of impaired bilirubin conjugation such as Gilbert's, for whom the maximum will be 2.5 ULN. * Aspartate transaminase (AST) (SGOT) ≤ 2.5 X institutional ULN * Alanine transaminase (ALT) (SGPT) ≤ 2.5 X institutional ULN * International normalized ratio (INR) ≤ 1.5 ×ULN * Patients must have a calculated serum creatinine clearance \> 50 mL/min using Cockcroft-Gault calculation or based on 24-hour urine collection performed within 7 days prior to treatment. * Specific guidelines will be followed regarding inclusion of relapsed/refractory DLBCL based on Hepatitis B serological testing as follow: * HBsAg negative, HBcAb negative, HBsAb negative patients are eligible. * HBsAg negative, HBcAb negative, HBsAb positive patients are eligible. * Patients who test positive for HBsAg are ineligible * Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status) should have a HBV DNA testing performed and protocol eligibility determined as follow: * If HBV DNA is positive, the subject is ineligible. * If HBV DNA is negative, the subject may be included but must undergo HBV DNA PCR testing monthly x 3 months beginning from the start of treatment * Subjects must have the ability to understand and the willingness to sign a written informed consent document. * 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 or 18 months after the last dose of rituximab, whichever is longer. 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). * 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. 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. Exclusion Criteria: * Prior treatment toxicities have not resolved to ≤ Grade 2 according to NCI CTCAE Version 4.0 (except clinically insignificant toxicities such as alopecia). * Subjects receiving any other investigational agents. * Patients with active tumor lysis syndrome (TLS) either from laboratory or clinical changes. * Patients with active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma. * History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to rituximab or other agents used in this study. * Subjects with uncontrolled intercurrent illness . * HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Venetoclax. In addition, these subjects are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in subjects receiving combination antiretroviral therapy when indicated. HIV testing prior to enrollment is not required for screening but strongly encouraged for patients with no documented prior HIV assessment. * Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody. * Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation * Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody \[HBcAb\] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to undergo monthly DNA testing. * Women who are pregnant or lactating * Malabsorption syndrome or other condition that precludes enteral route of administration * Chemotherapy or radiation within 3 weeks of the first scheduled study treatment. * Less than 2-year disease free from another primary malignancy (other than squamous or basal cell carcinoma of the skin, "in-situ" carcinoma of the cervix or breast, superficial bladder carcinoma, or previously treated localized prostate cancer with normal prostate specific antigen (PSA) levels). Patients who have had completed all anti-cancer treatment for another primary malignancy more than 2 years prior to screening are eligible if they are not considered to have a "currently active" malignancy based on having less than a 30% risk of relapse. * Major surgery, other than diagnostic surgery, within 2 weeks. * Medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent). Brief (\<15 days) treatment with glucocorticoids (prednisone 100 mg by mouth daily, or equivalent) is acceptable. * Known allergy to both xanthine oxidase inhibitors and rasburicase. * Use of warfarin is prohibited. Anticoagulation with low-molecular weight heparin (i.e. enoxaparin) or direct thrombin inhibitors is permitted. * The following concomitant medications are not allowed from 7 days prior to the first dose of study drug and during venetoclax administration: Strong CYP3A4 inhibitors including but not limited to fluconazole, ketoconazole, and clarithromycin or strong CYP3A4 inducers included but not limited to rifampin, carbamazepine. * Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment. * Concomitant medications that fall into the categories below could potentially lead to adverse reactions and should be considered with caution. * Moderate/Weak CYP3A inducers such as efavirenz and oxcarbazepine * CYP2C8 substrates such as thiazolidinediones (glitazones) and select statins (because of expected inhibition of the metabolism of CYP2C8 substrates) by venetoclax * CYP2C9 substrates such as tolbutamide (because of expected inhibition of the metabolism of CYP2C9 substrates by venetoclax. It is recommended to exclude CYP2C9 substrates with a narrow therapeutic index such as phenytoin.