Zanubrutinib Induction Followed by Delayed Fixed-Duration Combination With Sonrotoclax for CLL/SLL：Stop Trial 2.0

Inclusion Criteria:

1. Aged ≥18 years, no restriction on gender.
2. Newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) consistent with the Chinese Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (2025 Edition).
3. Meet at least one of the following indications for CLL treatment:

   1. Evidence of progressive bone marrow failure manifested by progressive reduction in hemoglobin and/or platelet counts.
   2. Massive splenomegaly (spleen palpable \>6 cm below the left costal margin) or symptomatic splenomegaly.
   3. Bulky lymphadenopathy (maximum diameter \>10 cm) or symptomatic lymphadenopathy.
   4. Progressive lymphocytosis: ≥50% increase in lymphocyte count within 2 months, or lymphocyte doubling time (LDT) \<6 months. LDT alone shall not serve as an indication for treatment if the baseline lymphocyte count is \<30×10⁹/L.
   5. Symptomatic organ dysfunction caused by CLL/SLL (involving skin, kidney, lung, spine and other organs).
   6. Autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) with inadequate response to corticosteroid therapy.
   7. At least one of the following disease-related B symptoms:

      * Unintentional weight loss ≥10% within the preceding 6 months without identifiable cause; ② Severe fatigue (ECOG performance status ≥2, inability to perform routine daily activities);

        ③ Unexplained fever \>38.0 °C lasting ≥2 weeks without confirmed infection;

        ④ Unexplained night sweats persisting for more than 1 month without confirmed infection.
4. ECOG performance status ≤2.
5. Major organ function meets the following criteria within 7 days prior to treatment initiation:

   ￮ Hematology: platelet count ≥30×10⁹/L;

   ￮ Biochemistry: total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN; creatinine clearance ≥30 mL/min;

   ￮ Cardiac Doppler echocardiography: left ventricular ejection fraction (LVEF) ≥lower limit of normal (50%).
6. Male and female participants agree to use effective contraception throughout the study period and for a minimum of 4 weeks after treatment completion.
7. Estimated life expectancy ≥6 months.
8. The patient voluntarily participates in the trial and signs the written informed consent form.

Exclusion Criteria:

* 1\. Previously received any systemic anti-tumor therapy for CLL/SLL. 2. Pathologically confirmed transformation to Richter's syndrome via biopsy. 3. Severe non-lymphoma-related hepatic or renal impairment defined as: ALT/AST \>3×ULN or TBIL \>2×ULN; creatinine clearance \<30 mL/min or serum creatinine \>2×ULN.

  4\. Significant pre-existing renal, neurological, psychiatric, pulmonary, endocrine, metabolic, immune, cardiovascular or hepatic disease judged by the investigator to compromise trial participation.

  5\. Other uncontrolled clinically significant medical conditions including but not limited to:

  a. Uncontrolled systemic infection (viral, bacterial, fungal); positive hepatitis B surface antigen with HBV-DNA \>1000 IU/mL; positive anti-HCV antibody or detectable HCV-RNA; positive anti-HIV antibody.

  b. Active uncontrolled autoimmune diseases other than autoimmune cytopenias. 6. Clinical signs of central nervous system (CNS) dysfunction or documented CNS infiltration by disease.

  7\. Received major surgery (excluding lymph node biopsy) within 14 days prior to enrollment or scheduled to undergo major surgery during trial treatment.

  8\. Inability to swallow capsules, malabsorption syndrome, or severe gastrointestinal disorders including prior gastrectomy, small bowel resection, symptomatic inflammatory bowel disease, ulcerative colitis, partial or complete intestinal obstruction.

  9\. Concurrent use of strong CYP3A inhibitors or inducers during study drug initiation and dose titration period.

  10\. Pregnant or breastfeeding females; females of childbearing potential without reliable contraceptive measures.

  11\. Clinically significant cardiovascular disease (NYHA cardiac functional class III/IV); history of myocardial infarction, malignant arrhythmia (including QTc ≥480 ms), inadequately controlled hypertension (systolic BP ≥150 mmHg, diastolic BP ≥100 mmHg) or unstable angina within 6 months before enrollment.

  12\. Coagulopathy-related exclusion: long-term treatment with multiple high-dose anticoagulants with no possibility of short-term discontinuation; persistent uncontrolled active bleeding; or prior life-threatening irreversible bleeding events.

  13\. History of severe hypersensitivity to any active ingredient or excipient of the investigational product.

  14\. Systemic disorders that may impair patient compliance with trial requirements.