Bendamustine, Rituximab and Acalabrutinib in Waldenstrom's Macroglobulinemia

This is a multi-centre, open label, single-arm, phase II clinical trial in untreated patients with Waldenstrom's Macroglobulinemia. Symptomatic, previously untreated patients will receive SOC bendamustine and rituximab for 6 28-day cycles. Bendamustine will be given intravenously at 90 mg/m2 on days 1 and 2 of each cycle. Rituximab will be given on day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures)). Concomitantly, participants will receive 100 mg of the investigational product, Acalabrutinib, orally for 1 year (365 days) at 100 mg BID.

Inclusion Criteria: 1. Have biopsy proven Waldenstrom's macroglobulinemia, (biopsy from within 3 months (+/- 7 days) prior to Day 1). 2. Have not received any systemic treatment for the disease (plasmapheresis, involved field radiation or corticosteroids (for contrast enhanced studies and to acutely control disease-related symptoms or as chemotherapy premedication)) are allowed. 3. Be willing and able to provide written informed consent for the trial. 4. Male or female \>=18 years of age on day of signing informed consent and of any racial or ethnic group. 5. Have at least one measurable site of disease based on Cheson Criteria (Appendix C) using standard CT imaging or a quantifiable IgM paraprotein that is two times the upper limit of normal. 6. Have symptomatic or impending symptomatic disease or evidence of hematologic or biochemical compromise related to the lymphoma. 7. Have a performance status of 0-2 on the ECOG Performance Scale. 8. Demonstrate adequate organ function as defined in Table 2. Adequate organ function must be confirmed within 72 hours prior to start of treatment. Patients with abnormal liver enzymes of up to 5 times the upper limit of normal and/or reduced glomerular filtration rate (GFR) or estimated glomerular filtration rate (eGRF) of ≥ 30 mL/min/1.73 m2can be considered for enrolment. 9. A life expectancy \> 6 months in the opinion of the investigator. 10. Female subject of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication (day 1). 11. Female subjects of childbearing potential should be willing to use 2 highly effective methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study until 2 days post-last dose of acalabrutinib, 4 weeks post-last dose of bendamustine, and 12 months post-last dose of rituximab. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year. 12. Male subjects should agree to use a highly-effective method of contraception starting with the first dose of study therapy until 2 days post-last dose of acalabrutinib, 6 months post-last dose of bendamustine, and 12 months post-last dose of rituximab. 13. Ability to comply with protocol requirements. Exclusion Criteria: 1. Previous systemic therapy for WM (other than described in the inclusion criteria). 2. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 21 days of the first dose of treatment (SD1). 3. Patient is being planned for consolidative autologous stem cell transplant (ASCT). 4. Is on warfarin anti-coagulation 5. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids 7 days prior to the start of treatment are eligible. 5\. Has clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac diseases as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study. 6\. Has clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac diseases as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study. 7\. Has hypertension that cannot be controlled with anti-hypertensives. 8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 35 days prior to the first dose of trial treatment (SD1), except that used as pre-medication for chemotherapy or contrast-enhanced studies are eligible. Subjects may be on physiologic doses of replacement prednisone or equivalent doses of corticosteroid (\