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 inaccordance with ICH/GCP regulations before registration and prior to anytrial-specific procedures.

• Confirmed diagnosis of SMZL, including Matutes immunophenotype score <3. Evaluationof the following features is desirable: absence of CD103 expression by flowcytometry, absence of Cyclin D1, BCL6, and CD10 expression by immunohistochemistry,and absence of the MYD88 L265P mutation. Patients with prominent splenomegaly andinvolvement of the splenic hilar and/or extra hilar lymph nodes are eligible

• Previously untreated disease. Patients with prior hepatitis C virus (HCV) infectionwho underwent HCV eradication and have persistent SMZL after 3 monthspost-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 > 7.5g/dl. Values below such thresholds are allowed if attributable to the underlyinglymphoma. 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 bladdercancer, carcinoma in situ of the cervix or breast, or localized Gleason score ≤ 6prostate cancer.

• Clinically significant cardiovascular disease

• History of cerebrovascular accident or intracranial hemorrhage within 6 monthsbefore registration and known bleeding disorders (eg, von Willebrand's disease orhemophilia).

• History of confirmed progressive multifocal leukoencephalopathy (PML).

• Concomitant diseases that require anticoagulant therapy with warfarin orphenprocoumon or other vitamin K antagonists and patients treated with dualanti-platelet therapy. Patients being treated with factor Xa inhibitors (eg,rivaroxaban, apixaban, edoxaban), direct thrombin inhibitors (e. dabigatran) lowmolecular weight heparin (LMWH), or single anti-platelet agents (eg. aspirin,clopidogrel) can be included but must be properly informed about the potential riskof bleeding.

• Malabsorption syndrome or other condition that precludes the enteral route ofadministration.

• Any uncontrolled active systemic infection requiring intravenous antimicrobialtreatment.

• Known human immunodeficiency virus (HIV) infection.

• Active COronaVIrus Disease 19 (COVID-19) infection or non-compliance with theprevailing 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 orequivalent.

• 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 laboratoryabnormality that in the opinion of the investigator may increase the risk associatedwith trial participation or investigational product administration or may interferewith the interpretation of trial results and/or would make the patient inappropriatefor enrolment into this trial.

• Pregnancy or breastfeeding.

• Concurrent participation in another therapeutic clinical trial.