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, skin (fat) biopsy, EMG, and CT C/A/P will be done within 90 days prior to Cycle1 Day 1.
* Presence of an IgM monoclonal paraprotein on serum immunofixation electrophoresis
* Diagnosis of IgM MGUS or Waldenstrӧm macroglobulinemia using the criteria from Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, et al.Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003. 30(2): 110-5.

* WM diagnostic criteria

* IgM monoclonal gammopathy of any concentration
* Bone marrow infiltration by small lymphocytes showing plasmacytoid/plasma cell differentiation
* Intertrabecular pattern of bone marrow infiltration
* Surface IgM+, CD5 +/-, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138- immunophenotype\* --- Variations from this immunophenotypic profile can occur. However, care should be taken to satisfactorily exclude other lymphoproliferative disorders. This is most relevant in CD5+ cases, for which chronic lymphocytic leukemia and mantle cell lymphoma require specific exclusion before a diagnosis of WM can be made.
* IgM MGUS diagnostic criteria

* IgM monoclonal gammopathy of any concentration
* No bone marrow infiltration
* Presence of predominantly sensory neuropathy with predominant demyelinating features on nerve conduction studies.
* Modified Rankin Scale score of ≥1 with progressing symptoms or a score ≥2
* ECOG ≤2
* Age \> 18 years
* Participants may not be on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin
* At the time of screening, participants must have acceptable organ and marrow function as defined below:

* Absolute neutrophil count≥1,000/uL (no growth factor permitted within previous 7 days)
* Platelets ≥100,000/uL (no platelet transfusions permitted within previous 7 days); patients may enroll below this threshold if not attributable to IgM MGUS or WM after consultation with Sponsor-Investigator.
* For participants with platelets \<100,000 uL deemed to be attributable to other causes than IgM MGUS or WM, platelets must be ≥50,000 uL (no platelet transfusions permitted)
* Hemoglobin ≥ 10 g/dL (transfusions permitted); patients may enroll below this threshold if not attributable to IgM MGUS or WM after consultation with Sponsor-Investigator.

-- For participants with hemoglobin \<10 g/dL deemed to be attributable to other causes than IgM MGUS or WM, hemoglobin must be ≥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
* International normalized ratio (INR) ≤ 2 x ULN and activated partial thromboplastin time (aPTT) ≤ 2 x ULN. Patients with INR and/or aPTT \>2 x ULN who have lupus anticoagulant may be enrolled.
* Females of childbearing potential (FCBP) must use highly effective contraception (see Appendix D) 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 1 week after last dose of acalabrutinib and 12 months from last dose of rituximab/biosimilar. 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 1 week after the last dose of acalabrutinib and 12 months after the last dose of rituximab during sexual contact with a FCBP
* Ability 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:

* Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study:
* Serum IgM ≥4,000 mg/dL
* Waldenstrӧm macroglobulinemia meeting criteria for treatment using consensus panel criteria from the Second International Workshop on WM besides symptomatic peripheral neuropathy.
* Prior exposure to chemotherapy, BTK inhibitors or other therapies used for WM treatment, except steroids, IVIG, or anti-CD20 antibodies that were administered \>90 days prior to first dose of study drug
* Concurrent participation in another therapeutic clinical trial.
* Participants with marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), IgM Myeloma or AL amyloidosis are excluded (Diagnosis based on WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues, S.H. Swerdlow, et al., Editors. 2017, IARC)
* Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP)
* Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months prior to screening
* Prior hypersensitivity, anaphylaxis, or intolerance to rituximab/biosimilar and ofatumumab, or acalabrutinib, including active product or excipient components
* Vaccination with a live vaccine within 4 weeks prior to first dose of rituximab.
* Prior or concurrent active malignancy within the past 2 years, except for curatively treated basal or squamous cell skin cancer, carcinoma in situ of the cervix or breast, or localized prostate cancer.
* Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study
* Known history of neuropathy attributed to an etiology other than IgM-mediated neuropathy
* Concurrent administration of medications that are moderate or strong inhibitors or inducers of CYP3A within 7 days prior to first dose of study drug
* Current, ongoing daily use of a proton pump inhibitor. Participants who switch to H2- receptor antagonists or antacids are eligible.
* Participants with chronic liver disease and hepatic impairment meeting Child-Pugh class C
* Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
* Peripheral neuropathy symptoms that have been present for \>5 years
* Known central nervous system lymphoma
* Active bleeding or history of bleeding diathesis (e.g., congenital von Willebrand's disease or hemophilia)
* History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months prior to the first dose of study drug
* 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 1 week of last dose of study drug acalabrutinib, or 12 months of last dose of rituximab/biosimilar.
* Male participants who plan to father a child while enrolled in this study or within 90 days after the last dose of study drug
* Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening
* New York Heart Association classification III or IV heart failure
* No active Human Immunodeficiency Virus (HIV) infection
* Active infection with Hepatitis B virus (HBV) or viral hepatitis C (HCV) as follows:

* Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Note: Patients with presence of HBcAb, but absence of HBsAg, are eligible if HBV DNA is undetectable and if they are willing to undergo monitoring for HBV reactivation throughout the study.
* Patients with presence of HCV antibody are eligible if HCV RNA is undetectable and if they are willing to undergo monitoring for HCV reactivation.
* No significant infection (eg bacterial, viral, or fungal) at study entry
* Inability to swallow pills
* 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
* Unwillingness or inability to comply with the protocol