Ibrutinib Followed by BR (Bendamustine and Rituximab) as a Time-Limited Therapy for Waldenström Macroglobulinemia

Inclusion criteria

• Patient fully understands the study, voluntarily participates, and signs the Informed Consent Form (ICF).
• Patient of any gender, aged ≥18 years and ≤75 years.
• Patient must meet diagnostic criteria for Waldenström Macroglobulinemia (WM) and be MYD88 L265P mutation positive.
• Patient has documented baseline IgM levels and disease assessment parameters (including liver, spleen, lymph nodes; if extramedullary lesions exist, include assessment of other extramedullary sites) prior to ibrutinib use, to facilitate subsequent efficacy evaluation.
• ECOG performance status score of 0-1.
• Patient has received ≥12 cycles of ibrutinib monotherapy, achieved a treatment response (but not Complete Response (CR) ), and is currently on a treatment plateau.
• Patient has maintained good treatment tolerance (experienced no Grade ≥3 adverse reactions during ibrutinib therapy) and is still receiving ibrutinib.
• Patient has no prior treatment with Bendamustine combined with Rituximab (BR) regimen.
• Laboratory values:

• Neutrophils ≥1.0 × 10⁹/L
• Platelets ≥50 × 10⁹/L
• Hemoglobin ≥70 g/L
• Total bilirubin ≤2 × Upper Limit of Normal (ULN)
• Alanine aminotransferase (ALT) / Aspartate aminotransferase (AST) ≤3 × ULN
• Creatinine clearance (CrCl) ≥30 mL/min (calculated by Cockcroft-Gault formula).
• Patient has an estimated life expectancy ≥6 months.

Exclusion criteria

• Diagnosis or treatment for a malignancy other than B-cell Non-Hodgkin Lymphoma (B-NHL) within the past year (including active Central Nervous System lymphoma). Received other anti-tumor therapies (including chemotherapy, targeted therapy, hormonal therapy, anti-tumor Chinese herbs with activity) within 4 weeks prior to study drug administration (excluding ibrutinib) or participated in other clinical trials receiving investigational drugs.
• Clinical evidence of transformation to large cell lymphoma.
• Non-lymphoma related liver or kidney impairment:

• ALT >3 × ULN
• AST >3 × ULN
• Total bilirubin (TBIL) >2 × ULN
• Serum creatinine clearance <30 mL/min.
• Other severe medical conditions that could interfere with the study (e.g., uncontrolled diabetes, gastric ulcer, other severe cardiopulmonary diseases), as determined by the investigator.
• Cardiac function or disease meeting any of the following:

• Long QTc syndrome or QTc interval >480 ms;
• Complete left bundle branch block, second- or third-degree atrioventricular block;
• Severe, uncontrolled arrhythmias requiring drug therapy;
• New York Heart Association (NYHA) classification ≥ Class III;
• Left ventricular ejection fraction (LVEF) <50%;
• History within 6 months prior to enrollment: myocardial infarction, unstable angina, severe unstable ventricular arrhythmias, or any other arrhythmia requiring treatment; history of clinically significant pericardial disease; or ECG evidence of acute ischemia or active conduction system abnormalities.
• Known history of Human Immunodeficiency Virus (HIV) infection, or active Hepatitis B Virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics.

Note: Active HBV infection is defined as meeting ALL THREE criteria: a. HBV DNA quantification ≥2000 IU/mL; b. ALT ≥2 × ULN; c. Hepatitis not attributable to other causes (e.g., disease itself, drugs). Patients initially diagnosed with active HBV infection who convert to inactive HBV status after anti-HBV therapy may be enrolled provided they receive adequate anti-HBV prophylaxis.

• Major surgery within 14 days prior to enrollment (excluding lymph node biopsy) or anticipated need for major surgery during the study.
• History or current diagnosis of another malignancy (except adequately controlled non-melanoma skin basal cell carcinoma, carcinoma in situ of the breast/cervix, and other malignancies effectively controlled without treatment for the past five years).
• Pregnant or lactating women, or women of childbearing potential not using contraception.
• Hypersensitivity to any of the study drugs or their components.
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, gastrectomy, extensive small bowel resection potentially affecting absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restriction/bariatric surgery (e.g., gastric bypass).
• History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.
• History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).
• Requirement for or ongoing anticoagulation therapy with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days prior to the first dose of study drug.
• Diagnosis of gastrointestinal ulcer by endoscopy within 3 months prior to the first dose of study drug.