Comparison Between Rituximab Plus Zanubrutinib Versus Rituximab Monotherapy in Untreated SMZL Patients

Inclusion Criteria: * Ability to understand and willingness to sign a written informed consent in accordance with ICH/GCP regulations before registration and prior to any trial-specific procedures. * Confirmed diagnosis of SMZL, including Matutes immunophenotype score \<3. Evaluation of the following features is desirable: absence of CD103 expression by flow cytometry, absence of Cyclin D1, BCL6, and CD10 expression by immunohistochemistry, and absence of the MYD88 L265P mutation. Patients with prominent splenomegaly and involvement of the splenic hilar and/or extra hilar lymph nodes are eligible * Previously untreated disease. Patients with prior hepatitis C virus (HCV) infection who underwent HCV eradication and have persistent SMZL after 3 months post-eradication can be included. * Treatment needs according to the ESMO guideline criteria * Measurable lesions * Age ≥ 18 years. * European Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. * Absolute neutrophil count (ANC) ≥ 1.0 x 109/L, platelet count ≥ 50 x 109/L, Hb \> 7.5 g/dl. Values below such thresholds are allowed if attributable to the underlying lymphoma. Transfusions are allowed if clinically indicated during screening. * Adequate hepatic and renal function and coagulation parameters * Patient able and willing to swallow trial drugs as whole tablet/capsule Exclusion Criteria: * Previous splenectomy. * Any systemic therapy for SMZL. * Patients with central nervous system (CNS) involvement. * Prior malignancy (other than the disease under study) within the past 2 years, except for curatively treated basal or squamous skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score ≤ 6 prostate cancer. * Clinically significant cardiovascular disease * History of cerebrovascular accident or intracranial hemorrhage within 6 months before registration and known bleeding disorders (eg, von Willebrand's disease or hemophilia). * History of confirmed progressive multifocal leukoencephalopathy (PML). * Concomitant diseases that require anticoagulant therapy with warfarin or phenprocoumon or other vitamin K antagonists and patients treated with dual anti-platelet therapy. Patients being treated with factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban), direct thrombin inhibitors (e. dabigatran) low molecular weight heparin (LMWH), or single anti-platelet agents (eg. aspirin, clopidogrel) can be included but must be properly informed about the potential risk of bleeding. * Malabsorption syndrome or other condition that precludes the enteral route of administration. * Any uncontrolled active systemic infection requiring intravenous antimicrobial treatment. * Known human immunodeficiency virus (HIV) infection. * Active COronaVIrus Disease 19 (COVID-19) infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic. * Active chronic hepatitis C or hepatitis B virus infection * Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune. thrombocytopenia) requiring steroid therapy with \> 20 mg daily of prednisone dose or equivalent. * Known hypersensitivity to trial drugs or any component of the trial drugs. * Concomitant treatment with strong CYP3A inducers or inhibitors * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and/or would make the patient inappropriate for enrolment into this trial. * Pregnancy or breastfeeding. * Concurrent participation in another therapeutic clinical trial.