Orelabrutinib Combined With Zebetuzumab and Lenalidomide for the Treatment of Newly Diagnosed MZL

Inclusion Criteria:

• 1. Age 18-75 years, gender not restricted;
• 2. Histopathologically confirmed CD20-positive marginal zone lymphoma includes MALT,SMZL, and NMZL; at least one measurable lesion;
• 3. Indication for treatment

• 3.1. Initial diagnosis II 2 or IIE or IV stage gastric MALT treatmentindications. Including: ① Meeting the inclusion criteria for clinical trials; ②Presence of lymphoma-related clinical symptoms; ③ Gastrointestinal bleeding (bleeding condition controlled or assessed by the investigator for suitabilityof inclusion); ④ End-organ damage; ⑤ Large mass; ⑥ Persistent or rapid diseaseprogression; ⑦ Patient's willingness;

• 3.2. Recommendations for treatment indications of newly diagnosed stage III-IVnon-gastric MALT and NMZL. The GELF criteria, similar to those used forfollicular lymphoma, include: ① The presence of ≥3 distinct regions of involvedlymph nodes, with each involved lymph node having a diameter of ≥3 cm; ② Thepresence of any lymph node or extranodal lesion with a diameter >7 cm; ③ Thepresence of B symptoms; ④ Splenomegaly; ⑤ Symptoms of organ compression,pleural or peritoneal effusion; ⑥ Cytopenia caused by the disease; ⑦ Persistentor rapid disease progression, with tumor size increasing by 20%-30% within 2-3months or approximately 50% within 6 months; ⑧ Meeting the inclusion criteriafor clinical trials;

• 3.3. Recommended indications for the treatment of newly diagnosed SMZL.Including: ① Progressive or painful splenomegaly; ② Symptomatic or progressivecytopenia such as HB<100g/L, PLT<80×10^9/L, absolute neutrophil count (ANC)<1.0×10^9/L (note to differentiate from cytopenia caused by autoimmunefactors);

• 4. Without prior systemic treatment, may include MZL (marginal zone lymphoma) thathas progressed, relapsed, or is unsuitable for local treatment after previous localtherapy (local treatment includes surgery, radiotherapy, anti-Helicobacter pyloritherapy for at least 12 months, or anti-hepatitis C therapy);
• 5. ECOG performance status score 0-2 points
• 6. The main organ functions meet the following criteria (except for SMZL, which isjudged separately by the investigator to meet treatment requirements): Completeblood count: Absolute neutrophil count ≥1.5×10^9/L, platelets ≥75×10^9/L, hemoglobin ≥75g/L; if accompanied by bone marrow involvement, absolute neutrophil count ≥1.0×10^9/L, platelets ≥50×10^9/L, hemoglobin ≥50g/L; Blood biochemistry: Totalbilirubin ≤ 1.5 times ULN, AST or ALT ≤ 2 times ULN; serum creatinine ≤ 1.5 timesULN; serum amylase ≤ ULN; creatinine clearance rate ≥ 60 mL/min;
• 7. Coagulation function: International Normalized Ratio (INR) ≤1.5 times ULN;
• 8. Expected survival time ≥ 12 months;
• 9. Voluntarily sign a written informed consent before trial screening.

Exclusion Criteria:

• 1. Currently or previously diagnosed with other malignancies, unless radicaltreatment has been performed and there is evidence of no recurrence or metastasiswithin the past 5 years, excluding cured cervical carcinoma in situ, basal cellcarcinoma of the skin, and localized squamous cell carcinoma of the skin;
• 2. Lymphoma involving the central nervous system or transforming to a higher grade;
• 3. Uncontrolled or significant cardiovascular diseases, including: a) Occurrence ofNew York Heart Association (NYHA) Class III-IV congestive heart failure, unstableangina, myocardial infarction within 6 months prior to the first administration ofthe investigational drug, or the presence of treatable arrhythmias at screening,with left ventricular ejection fraction (LVEF) <50%; b) Primary cardiomyopathies (such as dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic rightventricular cardiomyopathy, restrictive cardiomyopathy, unclassifiedcardiomyopathy); c) A clinically significant history of QTc interval prolongation,or QTc interval during the screening period >470ms for females and >450ms for males;d) Subjects with symptomatic or medication-requiring coronary heart disease; e)Suffering from uncontrolled hypertension (blood pressure remains uncontrolled aftermore than one month of using a reasonable and tolerable dosage of three or moreantihypertensive drugs (including diuretics) based on lifestyle improvements, orblood pressure can only be effectively controlled by taking four or moreantihypertensive drugs);
• 4. Active bleeding within 2 months prior to screening, or currently takinganticoagulants, or deemed by the investigator to have a clear bleeding tendency;
• 5. History of deep vein thrombosis or pulmonary embolism in the past six months;
• 6. Underwent major surgery within 6 weeks prior to screening or minor surgery within 2 weeks prior to screening. Major surgery refers to procedures performed undergeneral anesthesia, but endoscopic examinations for diagnostic purposes are notconsidered major surgery. The insertion of vascular access devices is exempt fromthis exclusion criterion;
• 7. Active infection or uncontrolled HBV (HBsAg positive and/or HBcAb positive withHBV DNA titer positive), HCV RNA positive, HIV/AIDS, or other severe infectiousdiseases;
• 8. Currently, there are subjects with severe pulmonary function impairment due toconditions such as pulmonary fibrosis, interstitial pneumonia, pneumoconiosis,radiation pneumonitis, and drug-related pneumonia: FEV1% or DLCO (or DLCO/VA) %pred < 40% (with severe pulmonary ventilation and gas exchange dysfunction);
• 9. Pregnant, lactating women and childbearing age subjects unwilling to usecontraception;
• 10. Need to continuously take medications with moderate to strong inhibitory orstrong inducing effects on cytochrome P450 CYP3A;
• 11. The investigator considers other conditions unsuitable for participating in thistrial.