A Phase II Study Using Rituximab Plus Venetoclax in the Front Line Treatment of Marginal Zone Lymphoma

Inclusion Criteria:

* Age greater than or equal to 18 years
* Histologically confirmed Marginal Zone Lymphoma
* Patients must have measurable disease as defined by at least one lymph node ≥1.5 cm or spleen \>13 cm.

  °Patients with intestinal MALT lymphoma must have disease that is detectable by EGD or colonoscopy with biopsy
* Patients with gastric MALT lymphoma must be h. pylori negative

  °Patients who are h. pylori positive are allowed if they have failed a trial of h.pylori eradication
* Patients with gastric MALT lymphoma who are h. pylori negative or who have relapsed/refractory disease after h. pylori eradication must be ineligible for, have refused or failed gastric radiation therapy
* ECOG performance status ≤ 1
* Life expectancy of greater than 2 years
* Patients must have normal organ function as defined below:

  * Platelet count ≥ 50,000 cells/mm\^3
  * Hemoglobin ≥ 8.0 g/dL
  * Absolute neutrophil count ≥ 1000 cells/mcL. If there is documented bone marrow involvement, ANC must be \>/= 500 cells/mcL
  * Total bilirubin \< 1.5 x upper normal institutional limits. In patients with Gilbert's disease or documented liver involvement, total bilirubin up to 3x ULN will be allowed
  * AST(SGOT)/ALT(SGPT) \<3 x institutional upper limit of normal unless elevation is caused by liver involvement with MZL
* AST(SGOT)/ALT(SGPT) \<3 x institutional upper limit of normal unless elevation is caused by liver involvement with MZL

  °OR Creatinine clearance \>60 mL/min for patients with creatinine levels above institutional normal (by Cockcroft-Gault estimate or 12-24h creatinine clearance measurements).
* Ability to understand and the willingness to sign a written informed consent document.
* Able to swallow pills
* HIV-positive patients on combination antiretroviral therapy are eligible if their HIV is under adequate control with an antiretroviral regimen that has been stable for \> 4 weeks, as long as the CD4 count is \> 300. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
* Patients with Hepatitis B surface antibody serum positivity due to prior immunization, as well as those with Hepatitis B core antibody positivity with negative PCR on antiviral therapy will be eligible.

Exclusion Criteria:

* Patients who have had prior systemic therapy, including rituximab
* Patients who have had prior radiation therapy, with the following exception:

  °Palliative radiotherapy RT is allowed but must be completed at least 1 week prior to treatment on this study, and prior baseline imaging studies or biopsies. Patients must meet criteria for measurable/assessable disease as outlined above after completion of RT
* Prior treatment with ibrutinib or other BTK inhibitor
* Patients with h. pylori-associated gastric MALT or stage I/II MZL will be excluded unless they are deemed to be unfit for radiation therapy with curative intent.
* Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

  °Patients with Hep B core ab positivity are allowed provided Hep B PCR is undetectable
* Lactating or pregnant women
* Participants unwilling to adhere to institutional guidelines for highly effective contraception for 12 months after the last dose of rituximab
* Patients who received moderate or strong CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of venetoclax.
* Patients who received moderate or strong CYP3A inducers (such as rifampin, carbamazepine, phenytoin, St. John's Wort) within 7 days prior to the first dose of venetoclax.