A PHASE II RANDOMIZED STUDY COMPARING IBRUTINIB AND RITUXIMAB VS. VENETOCLAX AND RITUXIMAB IN PREVIOUSLY UNTREATED WALDENSTROM'S MACROGLOBULINEMIA (WM) /LYMPHOPLASMACYTIC LYMPHOMA (LPL)

Step 1: Initial Registration/Randomization

-Confirmed diagnosis of WM/LPL w/ measurable disease by IgM w/in 28 days prior to reg.

-At least one of the criteria to require therapy for WM.

-No strong CYP3A inducer, moderate or strong CYP3A inhibitor, P-gp inihibitor w/in 7 days prior to the first dose or planned ongoing use.

-No prior systemic therapy. (except rituximab if last dose was at least 12 months prior to reg).

->/= 18 years.

-History and physical w/in 28 days prior to reg.

-Zubrod Performance Status </= 2.

-Not intolerant to rituximab.

-Creatinine clearance (CrCl) >/= 30 mL/min w/in14 days prior to reg.

-No hepatic dysfunction w/in 14 days prior to reg.

-Adequate bone marrow function w/out transfusion or growth factors w/in 14 days prior to reg (platelets >/= 50,000, hemoglobin >/= 7.0, ANC >/= 1,000)

-No active infection at study reg, or any major infection requiring IV antibiotics or hospitalization w/in 4 weeks prior to reg.

-HIV+: must be on effective anti-retroviral therapy and have undetectable viral load at most recent viral load test and w/in 6 months prior to reg

-No hepatitis C (except sustained virologic response

-Must be able to take and swallow oral meds. No known impairment of GI function or GI disease that may significantly alter the absorption of the study drug.

-No grapefruit, Seville oranges or starfruit w/in 3 days prior to the first dose of venetoclax.

-Must not be pregnant or nursing.

-No other prior malignancy (see exceptions)

-Must be offered specimen banking participation.

Step 2: Crossover

-Must have been registered and received treatment in the IR arm, and must show progression of disease during Cycles 3-24.

-No transformation to intermediate or high-grade lymphoma or development of Bing-Neel syndrome.

-Zubrod Performance Status </= 2 .

-Creatinine clearance (CrCl) >/= 30 mL/min w/in 14 days prior to reg.

-No hepatic dysfunction w/in 14 days prior to reg.

-Adequate bone marrow function w/out transfusion or growth factors w/in 14 days prior to reg (platelets >/= 50,000, hemoglobin >/= 8.0, ANC >/= 1,000)