orelabrutinib combined with rituximab as first-line systemic treatment for marginal zone lymphoma

Conditions: Marginal Zone Lymphoma(MZL)

Summary: this is a single-arm, prospective clinical study to evaluate the efficacy and safety of orelabrutinib combined with rituximab as first-line systemic treatment for marginal zone lymphoma.

marginal zone lymphoma (mzl) is a relatively common type of b-cell non-hodgkin lymphoma (b-nhl), with an incidence rate second only to diffuse large b-cell lymphoma (dlbcl) and follicular lymphoma (fl). the bruton tyrosine kinase (btk) signaling pathway plays a significant role in b-cell malignancies. most b-cell malignancies require activation of the b-cell receptor (bcr), and btk, located downstream of the bcr, plays a crucial role in b-cell proliferation, apoptosis, differentiation, and migration induced by antigens. currently, there is no unified treatment regimen with high-level evidence for the treatment of newly diagnosed mzl. as mentioned above, although high-intensity immunochemotherapy regimens achieve high response rates and durable remission, they also bring higher treatment-related safety risks (with a rate of grade 3 or higher adverse events of about 80%), including treatment-related deaths. therefore, exploring effective chemotherapy-free regimens for mzl patients is a scientifically valuable and clinically meaningful attempt. drugs such as btk inhibitors and cd20 monoclonal antibodies have shown good therapeutic activity and clinical data as single agents. this is a single-arm, prospective clinical study to evaluate the efficacy and safety of orelabrutinib combined with rituximab as first-line systemic treatment for marginal zone lymphoma. all subjects will receive induction treatment with the orelabrutinib and rituximab regimen. the treatment cycle is 28 days, with a total of 6 cycles. patients who achieve a partial response (pr) or better will enter a 2-year maintenance period with orelabrutinib.

Eligibility criteria:
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.