First-line treatment with orelabrutinib plus rituximab for marginal zone lymphoma

Inclusion Criteria:

* Age ≥ 18 years, regardless of gender;
* Histologically confirmed CD20-positive marginal zone lymphoma, including MALT, SMZL, and NMZL, with at least one lesion outside the spleen measuring more than 1.5 cm in any axis;
* MZL that has progressed or relapsed after prior local therapy (including surgery, radiotherapy, anti-Helicobacter pylori treatment, and anti-hepatitis C treatment), or is not suitable for local therapy;
* ECOG performance status of 0-2;
* Presence of an indication for treatment as judged by the investigator (symptomatic, cytopenia, risk of end-organ damage, bulky disease, ongoing progression, or patient's desire for treatment);
* Adequate function of major organs, as follows:
* Hematology: Absolute neutrophil count ≥ 1.5×109/L, platelets ≥ 75×109/L, hemoglobin ≥ 75 g/L; if there is bone marrow involvement, absolute neutrophil count ≥ 1.0×109/L, platelets ≥ 50×109/L, hemoglobin ≥ 50 g/L;
* Biochemistry: Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), AST or ALT ≤ 2 times ULN; serum creatinine ≤ 1.5 times ULN; serum amylase ≤ ULN;
* Coagulation: International normalized ratio (INR) ≤ 1.5 times ULN.
* Life expectancy of ≥ 3 months;
* Voluntary written informed consent obtained before screening for the trial.

Exclusion Criteria:

* Currently or previously having other malignancies, unless there is evidence of no recurrence or metastasis within the past 5 years after curative treatment;
* Lymphoma involvement of the central nervous system or transformation to high-grade lymphoma;
* Non-hematological toxicities from prior anti-cancer treatments not recovered to ≤ Grade 1 (excluding alopecia);
* Presence of uncontrolled or significant cardiovascular disease, including:
* New York Heart Association (NYHA) Class II or higher congestive heart failure, unstable angina, myocardial infarction within 6 months before the first administration of the study drug, or arrhythmias requiring treatment at screening, left ventricular ejection fraction (LVEF) \< 50%;
* Primary cardiomyopathy (such as dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy);
* History of clinically significant QTc interval prolongation, or QTc interval \> 470 ms for females, \> 450 ms for males during the screening period;
* Symptomatic or medically treated coronary artery disease;
* Uncontrolled hypertension (defined as blood pressure not reaching target levels despite a reasonable and tolerable full dose of three or more antihypertensive drugs (including diuretics) for more than one month, or requiring four or more antihypertensive drugs to effectively control blood pressure).
* Active bleeding within 2 months before screening, or currently taking anticoagulant drugs, or deemed by the investigator to have a clear tendency to bleed;
* Urine protein ≥ 2+, and 24-hour urine protein quantification ≥ 2 g/24 hours;
* History of deep vein thrombosis or pulmonary embolism within the past six months;
* History of organ transplantation or allogeneic bone marrow transplantation;
* Major surgery within 6 weeks before screening or minor surgery within 2 weeks before screening. Major surgery is defined as surgery using general anesthesia, but diagnostic endoscopy is not considered major surgery. Insertion of a vascular access device will be exempt from this exclusion criterion;
* Active infection or uncontrolled HBV (HBsAg positive and/or HBcAb positive with positive HBV DNA titer), HCV Ab positive, HIV/AIDS, or other severe infectious diseases;
* Currently having pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, or other conditions that significantly affect pulmonary function;
* Previous treatment with BTK, BCR pathway inhibitors (such as PI3K, Syk), or BCL-2 inhibitors;
* Suitable and preparing for stem cell transplantation;
* Any psychiatric or cognitive impairment that may limit their understanding, execution of the informed consent form, and compliance with the study;
* Subjects with drug abuse or alcoholism;
* Pregnant, breastfeeding women, and fertile subjects unwilling to use contraception;
* Need to continuously take drugs with moderate to severe inhibitory or strong inducing effects on cytochrome P450 CYP3A;
* Any other condition deemed by the investigator as unsuitable for participation in this trial.