Ibrutinib + Venetoclax in Untreated WM

Inclusion Criteria:

* Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy \& aspirate, and CT C/A/P will be done within 90 days prior to Cycle 1 Day 1.
* Clinicopathological diagnosis of Waldenström macroglobulinemia \[28\].
* Known tumor expression of mutated MYD88 performed by a CLIA certified laboratory.
* Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenström macroglobulinemia \[29\].
* Participants with symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred vision) must undergo plasmapheresis prior to treatment initiation.
* Age ≥ 18 years
* ECOG performance status ≤2 (see Appendix A)
* Measurable disease, defined as presence of serum immunoglobin M (IgM) with a minimum IgM level of \>2 times the upper limit of normal of each institution is required
* At the time of screening, participants must have acceptable organ and marrow function as defined below:

  * Absolute neutrophil count ≥500/uL (no growth factor permitted)
  * Platelets ≥50,000/uL (no platelet transfusions permitted)
  * Hemoglobin ≥ 7 g/dL (transfusions permitted)
  * Total bilirubin \< 1.5 x institutional ULN
  * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN
  * Estimated GFR ≥30 mL/min
* Females of childbearing potential (FCBP) must use one reliable form of contraception or have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 90 days after discontinuation from the study. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening.
* Men must agree to use a latex condom during treatment and for up to 90 days after the last dose of ibrutinib or venetoclax during sexual contact with a FCBP
* Ability to understand and the willingness to sign a written informed consent document.
* Exclusion Criteria
* Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study:
* Participants who have one or more prior systemic therapies for WM.
* Participants who are receiving any other investigational agents.
* Participants with known CNS lymphoma.
* Participants with known history of Human Immunodeficiency Virus (HIV), chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring active treatment. Note: Participants with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, and anti-HBs+ and anti-HBC-) and positive anti-HBc from IVIG may participate.
* Concurrent administration of medications or foods that are moderate or strong inhibitors or inducers of CYP3A within 7 days prior to first dose of study drug.
* Participants with chronic liver disease and hepatic impairment meeting Child-Pugh class C (Appendix B).
* Concurrent administration of warfarin.
* Concurrent systemic immunosuppressant therapy within 21 days of the first dose of study drug.
* Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
* Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of the study drug.
* Known bleeding disorders (e.g., congenital von Willebrand's disease or hemophilia)
* History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
* Major surgery within 4 weeks of first dose of study drug.
* Malabsorption syndrome or other condition that precludes enteral route of administration.
* Female participants who are pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 90 days of last dose of study drug.
* Male participants who plan to father a child while enrolled in this study or within 90 days after the last dose of study drug
* Participants with known history of alcohol or drug abuse.
* Participants with inability to swallow pills.
* On any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin.
* 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.
* Participants with a history of non-compliance to medical regimens.
* Participants who are unwilling or unable to comply with the protocol.