Orelabrutinib Combined With Rituximab ± Lenalidomide in Response-Adapted Stratified Therapy for Untreated MZL

Orelabrutinib Combined With Rituximab ± Lenalidomide in Response-Adapted Stratified Therapy for Untreated MZL#a Prospective Single Arm Trial

This is a prospective, single-arm, phase II study aimed at evaluating the safety and efficacy of orelabrutinib combined with rituximab ± lenalidomide in response-adapted stratified therapy for untreated marginal zone lymphoma. The primary endpoint is the complete response rate (CRR).

Marginal zone lymphoma (MZL) is a type of lymphoma that comprises three main subtypes: extranodal mucosa-associated lymphoid tissue (MALT) lymphoma, nodal MZL, and splenic MZL. Accounting for approximately 7.8% of all non-Hodgkin lymphomas (NHL), MZL is the third most common subtype, following diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Although generally considered an indolent lymphoma with a favorable overall survival prognosis, some patients still face challenges such as disease relapse or transformation into aggressive large cell lymphoma, which leads to a poor prognosis.

This is a prospective, single-arm, phase II study designed to evaluate the safety and efficacy of orelabrutinib combined with rituximab ± lenalidomide in response-adapted stratified therapy for untreated marginal zone lymphoma. Eligible patients who meet the screening criteria will enter the treatment phase and receive orelabrutinib in combination with rituximab. After 6 cycles, patients who achieve complete response (CR) will continue with orelabrutinib and rituximab for an additional 6 cycles; patients with partial response (PR) or stable disease (SD) will receive orelabrutinib combined with rituximab and lenalidomide for an additional 6 cycles; patients with progressive disease (PD) will be withdrawn from the study.

Inclusion Criteria:

1. Aged ≥18 years, either sex.

2. Histopathologically confirmed CD20-positive marginal zone lymphoma (including MALT, SMZL, and NMZL) with at least 1 measurable lesion.

3. Stage III or IV disease with an indication for treatment.

4. No prior systemic therapy. Patients may have received prior local treatment (including surgery, radiotherapy, anti-Helicobacter pylori therapy, or anti-hepatitis C therapy) if they subsequently progressed, relapsed, or were unsuitable for local therapy.

5. ECOG performance status of 0-2.

6. Adequate organ function meeting the following criteria:

   1. Blood count: Absolute neutrophil count ≥1.5×10⁹/L, platelets ≥75×10⁹/L, hemoglobin ≥75 g/L. If bone marrow involvement is present: absolute neutrophil count ≥1.0×10⁹/L, platelets ≥50×10⁹/L, hemoglobin ≥50 g/L.
   2. Blood chemistry: Total bilirubin ≤1.5×ULN, AST or ALT ≤2×ULN; serum creatinine ≤1.5×ULN; serum amylase ≤ULN.

7. Coagulation: International normalized ratio (INR) ≤1.5×ULN.

8. Expected survival ≥12 months.

9. Voluntary provision of written informed consent before trial screening.

Exclusion Criteria:

1. Current or history of other malignancies, unless treated with curative intent and without evidence of recurrence or metastasis within the past 5 years.

2. Central nervous system involvement or transformation to high-grade lymphoma.

3. Uncontrolled or significant cardiovascular diseases, including:

   1. New York Heart Association (NYHA) Class II or higher congestive heart failure, unstable angina, myocardial infarction within 6 months prior to the first study drug dose, or arrhythmia requiring treatment at screening; left ventricular ejection fraction (LVEF) <50%.
   2. Primary cardiomyopathy (e.g., dilated, hypertrophic, arrhythmogenic right ventricular, restrictive, or unclassified cardiomyopathy).
   3. History of clinically significant QTc interval prolongation, or QTc interval >470 ms (female) or >450 ms (male) at screening.
   4. Symptomatic coronary artery disease or subjects requiring medication for it.
   5. Poorly controlled hypertension (defined as failure to achieve target blood pressure after ≥1 month of lifestyle modification combined with an adequate, tolerable regimen of ≥3 antihypertensive drugs including a diuretic, or requiring ≥4 antihypertensive drugs for control).

4. Active bleeding within 2 months prior to screening, current use of anticoagulants, or any condition deemed by the investigator to indicate a clear bleeding tendency.

5. History of deep vein thrombosis or pulmonary embolism within the past 6 months.

6. History of organ transplantation or allogeneic bone marrow transplantation.

7. Major surgery within 6 weeks or minor surgery within 2 weeks prior to screening. Major surgery requires general anesthesia (diagnostic endoscopy excluded). Insertion of vascular access devices is exempt.

8. Active infection or uncontrolled HBV (HBsAg positive and/or HBcAb positive with positive HBV DNA), HCV Ab positive, HIV/AIDS, or other serious infectious diseases. (Active infection is defined as requiring systemic antimicrobial therapy or associated with systemic signs/symptoms of inflammation.)

9. Current conditions severely impairing pulmonary function, such as pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, or drug-related pneumonia.

10. Prior treatment with BTK inhibitors, BCR pathway inhibitors (e.g., PI3K, Syk inhibitors), or BCL-2 inhibitors.

11. Pregnancy, lactation, or unwillingness to use effective contraception in subjects of childbearing potential.

12. Concomitant use of moderate/strong cytochrome P450 CYP3A inhibitors or strong inducers.

13. Any other condition considered by the investigator to make the subject unsuitable for trial participation.