This is a multicenter, prospective, single-arm phase II study designed to evaluate the safety and efficacy of lisaftoclax (APG-2575), an oral selective BCL-2 inhibitor, in patients with indolent B-cell lymphomas. The study will enroll adult patients with chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), or marginal zone lymphoma (MZL) who are either treatment-naïve but considered ineligible for Bruton tyrosine kinase (BTK) inhibitor therapy due to significant comorbidities, or who are intolerant to prior BTK inhibitor treatment.

Eligible patients will receive oral lisaftoclax once daily with a dose ramp-up to a target dose of 600 mg in 28-day cycles. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or completion of the planned treatment period. The primary objective is to evaluate the safety and tolerability of lisaftoclax monotherapy, while secondary objectives include assessment of antitumor activity, including overall response rate (ORR), complete response (CR) rate, minimal residual disease (MRD) negativity, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Quality of life will also be assessed using the EORTC QLQ-C30 questionnaire.

Inclusion Criteria:

1. Age ≥ 18 years at the time of signing the informed consent form (ICF).

2. Histologically confirmed diagnosis of an indolent lymphoma (CLL/WM/MZL), meeting one of the following conditions:

   Cohort A: Previously untreated and ineligible for Bruton's Tyrosine Kinase inhibitor (BTKi) therapy due to severe comorbidities (e.g., uncontrolled hypertension, cardiac disease, or active infection, etc.).

   Cohort B: Received only one prior line of BTKi as first-line treatment, did not achieve a partial response (PR), and discontinued BTKi due to intolerable treatment-related adverse events (e.g., atrial fibrillation, hemorrhage, infection, rash, etc.).

3. Adequate bone marrow function, defined as:

   1. Hemoglobin (Hb) ≥ 70 g/L (without transfusion support within 7 days prior to the first dose of study drug).
   2. Absolute neutrophil count (ANC) ≥ 0.5 × 10⁹/L (independent of growth factor support within 7 days prior to the first dose of study drug).
   3. Platelet count ≥ 50 × 10⁹/L (without transfusion support within 7 days prior to the first dose of the study drug. If the patient has documented bone marrow involvement, a platelet count ≥ 30 × 10⁹/L is acceptable, provided the investigator ensures adequate supportive care).

4. Adequate hepatic and renal function, defined as:

   1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN).
   2. Creatinine clearance (Ccr) ≥ 40 ml/min (estimated by the Cockcroft-Gault formula).
   3. Total bilirubin < 1.5 × ULN.

5. Left ventricular ejection fraction (LVEF) ≥ the lower limit of normal (LLN, 50%).

6. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 3.

7. Life expectancy ≥ 3 months.

8. Men, women of childbearing potential (WOCBP, defined as premenopausal women capable of becoming pregnant), and their partners must agree to use highly effective contraception methods (e.g., condoms, implants/injections/oral contraceptives, intrauterine devices [IUD], abstinence, or a sterilized partner) during the treatment period and for 90 days after the last dose of the study drug. Postmenopausal women (at least 12 months of spontaneous amenorrhea) or surgically sterile women are not considered WOCBP.

9. No other active malignant disease within the past 3 years, except for currently treated basal cell

Exclusion Criteria:

1. Prior treatment with any B-cell lymphoma 2 (BCL-2) inhibitor.
2. Patients with active infection (including active hepatitis B virus [HBV] or hepatitis C virus [HCV] infection, or human immunodeficiency virus [HIV] positivity) or any other serious uncontrolled medical condition (Patients who are hepatitis B surface antigen (HBsAg) positive or hepatitis B core antibody (HBcAb) seropositive are eligible if their HBV DNA is below the lower limit of detection/quantification and they are willing to undergo monthly HBV reactivation monitoring. Patients who are HCV antibody positive are eligible if their HCV RNA is below the lower limit of detection/quantification).
3. Presence of other concurrent malignancies (except for those specified in the inclusion criteria) that may affect the interpretation of study results or treatment with the investigational drug, or patients with severe coagulation disorders, or severe impairment of cardiac, cerebral, pulmonary, hepatic, or renal function.
4. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 12 months prior to the first dose of the study drug.
5. Administration of any live vaccine within 28 days prior to the first dose of the study drug.
6. Women of childbearing potential (WOCBP) or men with partners of childbearing potential who are unwilling to use highly effective contraception; pregnant or breastfeeding women.
7. Inability to swallow tablets, or presence of malabsorption syndrome, any disease significantly affecting gastrointestinal function, gastrectomy/small bowel resection, symptomatic inflammatory bowel disease or ulcerative colitis, or partial/complete bowel obstruction.
8. Known hypersensitivity to the active pharmaceutical ingredient, excipients of the study drug, or its analogs.
9. Requirement for concomitant treatment with strong inhibitors or inducers of cytochrome P450 (CYP) 3A.
10. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's judgment, could compromise the patient's safety or pose an undue risk for study participation.