Zanubrutinib, Bendamustine, Rituximab Prev. Untreated WM

Inclusion Criteria:

* Clinicopathological diagnosis of waldenström macroglobulinemia (WM) per the second international workshop on waldenström macroglobulinemia (IWWM2) criteria
* Presence of any MYD88 and CXCR4 mutation status, including MYD88 L265P mutation plus CXCR4 wild type, MYD88 L265P mutation plus CXCR4 mutation, or MYD88 wild type
* Meeting criteria for treatment per IWWM2 criteria. At least one of the following:

  * Constitutional Symptoms (at least one of the following)

    * Recurrent fever
    * Night sweats
    * Fatigue
    * Weight loss
  * Progressive or symptomatic lymphadenopathy or splenomegaly
  * Hemoglobin ≤ 10 g/dL
  * Platelet count ≤ 100 k/uL
  * Hyperviscosity syndrome
  * Symptomatic peripheral neuropathy
  * Systemic amyloidosis
  * Renal insufficiency
  * Symptomatic cryoglobulinemia or cold agglutinemia
* Treatment naive; must have not received any prior systemic therapy for WM
* Participants with suspected or symptomatic hyperviscosity (e.g. nosebleeds, headaches, blurred vision) must undergo plasmapheresis prior to treatment initiation.
* Adults age ≥18
* ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
* Women of childbearing potential: Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or practice complete abstinence1 from heterosexual intercourse during treatment and for at least 1 week after the last dose of zanubrutinib or at least 12 months after the last dose of rituximab, whichever is later. FCBP must be referred to a qualified provider of contraceptive methods if needed. Also, FCBP must have a pregnancy check with a negative serum pregnancy test obtained 28 days prior to and confirmed by C1D1.
* Men must agree to use a condom during sexual contact with a female of childbearing potential (FCBP) even if they have had a successful vasectomy 1) while participating in the study; and 2) for at least 1 week following the last dose of zanubrutinib.
* Participants must meet the following organ and marrow function as defined below:

  * Absolute neutrophil count ≥500/mcL believed to be caused by WM bone marrow involvement. Growth factors are not permitted \<14 days prior to C1D1.
  * Platelets ≥30,000/mcL believed to be caused by WM bone marrow involvement. Platelet transfusions are not permitted \<14 days prior to C1D1.
  * Hemoglobin ≥ 7 g/dL. RBC transfusions are not permitted \<14 days prior to C1D1.
  * Total bilirubin ≤ 1.5 X institutional ULN, or ≤3 x institutional ULN with documented liver metastases and/or Gilbert's Disease
  * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal, or ≤5 X institutional ULN with documented liver metastases
  * Creatinine clearance ≥30 mL/min using the Cockcroft-Gault formula
* Able to adhere to the study visit schedule and other protocol requirements.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, or psychiatric illness/social condition that would prevent the participant from signing the informed consent form
* Female participants who are pregnant, breastfeeding, or planning to become pregnant or breastfeed while enrolled in this study
* Participants with known CNS involvement by WM
* Participants with known history of Human Immunodeficiency Virus (HIV)
* Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:

  * Hepatitis B virus (HBV): Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (antiHBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before enrollment. Patients who are hepatitis B PCR positive will be excluded.
  * Hepatitis C virus (HCV): positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before enrollment. Patients who are hepatitis C RNA positive will be excluded.
* Concurrent systemic immunosuppressant therapy. Systemic steroids at doses \<20mg prednisone per day are permitted.
* Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura).
* Concurrent administration of warfarin or warfarin derivatives.
* Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
* Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the Investigator and the Sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required. Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the Investigator and the Sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required.
* Major surgery within 4 weeks of first dose of study drug.
* History of severe bleeding disorder such as hemophilia A, hemophilia B, or history of spontaneous bleeding requiring blood transfusion or other medical intervention. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
* Participants with inability to swallow pills.
* Inability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of the study participation.
* Any uncontrolled or significant cardiovascular disease defined as:

  * Unstable angina within 3 months before screening, or
  * History of myocardial infarction within 6 months prior to planned start of zanubrutinib, or
  * Previously documented left ventricular ejection fraction (LVEF) by any method of ≤ 45% in the 12 months prior to planned start of zanubrutinib; assessment of LVEF via echocardiogram or multigated acquisition (MUGA) scan during Screening should be performed in selected patients as medically indicated, or
  * Any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or
  * Uncontrolled or symptomatic arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
* Participants with a known hypersensitivity to any of the excipients of Zanubrutinib, Rituximab, or Bendamustine.
* Participants with a history of non-compliance to medical regimens, which will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs.
* Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score 6 prostate cancers.
* Severe or debilitating pulmonary disease.
* Ongoing alcohol or drug addiction or any psychiatric condition(s) which would compromise ability to comply with study procedures.
* Ongoing use of a strong CYP3A inducer.