Zanubrutinib, Obinutuzumab, and Lenalidomide (ZGR) in the Treatment of Newly Diagnosed Splenic B-cell Lymphoma With Prominent Nucleoli (SBLPN): A Prospective, Open-label, Single-arm Clinical Trial

There is no consensus on optimal first-line therapy for splenic B-cell lymphoproliferative neoplasms (SBLPN). Existing regimens like cladribine/bendamustine plus rituximab face toxicity and resistance. Targeting Bruton's tyrosine kinase (BTK), the novel BTK inhibitor zanubrutinib (highly selective, low toxicity) combined with obinutuzumab (enhanced antibody-dependent cytotoxicity) and lenalidomide (immunomodulation) shows promise. This single-arm trial evaluates the ZGR regimen (zanubrutinib, obinutuzumab, lenalidomide) for untreated SBLPN, including 6-cycle induction and maintenance therapy (zanubrutinib-lenalidomide), aiming to enhance efficacy, survival, and tolerability, offering a novel approach for this rare disease.

Inclusion criteria

• Aged 18 to 80 years, male or female
• Histologically or cytologically confirmed SBLPN requiring active treatment;
• No prior systemic therapy for SBLPN received;
• ECOG performance status of 0-2;
• Anticipated life expectancy ≥6 months;
• Laboratory parameters (hematologic and biochemical) meeting the following criteria:
• a. Absolute neutrophil count (ANC) ≥1.0 × 10⁹/L, platelet count ≥50 × 10⁹/L;
• b. Total bilirubin (TBIL) ≤2.0 × upper limit of normal (ULN);
• c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN;
• d. Creatinine clearance ≥50 mL/min (calculated via Cockcroft-Gault formula or direct measurement).
• Men and women of childbearing potential must agree to use medically approved contraception throughout the study and for 4 weeks after treatment discontinuation;
• Participants must voluntarily enroll in the study and provide written informed consent.

Exclusion criteria

• History of central nervous system (CNS) disorders (including CNS lymphoma) diagnosed within 1 year prior to enrollment.
• Other primary malignancies within the past 3 years (excluding non-melanoma skin cancer, curatively treated localized prostate cancer, cervical carcinoma in situ, or squamous intraepithelial lesions on PAP smear).
• Exposure to any investigational drugs, antimicrobial agents, or participation in other interventional clinical trials within 4 weeks prior to enrollment.
• Major surgery (excluding lymph node biopsy) within 14 days before enrollment or anticipated requirement for major surgery during the study.
• Prior use of investigational agents targeting SBLPN.
• Active immunodeficiency, autoimmune diseases, prolonged systemic corticosteroid therapy (>10 mg/day prednisone equivalent) within 7 days prior to enrollment, or any immunosuppressive therapy.
• Severe hepatic dysfunction (e.g., severe jaundice, hepatic encephalopathy, refractory ascites, hepatorenal syndrome), cachexia, multiorgan failure, or severe renal impairment.
• Clinically significant cardiovascular comorbidities:

New York Heart Association (NYHA) class III/IV heart failure; Myocardial infarction within 6 months prior to enrollment; Uncontrolled arrhythmias (including QTc interval ≥480 ms); Poorly controlled hypertension (systolic ≥150 mmHg/diastolic ≥100 mmHg despite antihypertensives); Unstable angina.

• Bleeding diathesis or coagulation disorders; thrombotic events within 3 months prior to enrollment.
• Hypersensitivity to active ingredients or excipients of the investigational drugs.
• Pregnancy, lactation, or women of childbearing potential unwilling/unable to use contraception.
• Other conditions deemed unsuitable for participation by the investigator (e.g., compromised protocol compliance or safety risks).