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

This exploratory Phase II single-arm clinical trial is designed to evaluate the efficacy, safety, and immune reconstitution effects of a novel delayed fixed-duration BTK inhibitor (BTKi) induction followed by BCL-2 inhibitor combination regimen in previously untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients, with risk-stratified post-treatment management based on TP53/del(17p) status.Scientific RationaleCLL/SLL is a mature B-cell clonal proliferative neoplasm, where traditional chemoimmunotherapy has limited efficacy and high toxicity in high-risk populations with del(17p)/TP53 mutations. The current treatment paradigm has shifted to targeted therapies, with BTKi + BCL-2i combination as a first-line strategy. However, existing BCL-2i-based fixed-duration regimens have a grade ≥3 treatment-emergent adverse event (TEAE) incidence of 45%-80%, primarily hematological toxicities and infections. Prior clinical evidence shows that 12 cycles of BTKi monotherapy induction before combination therapy (the "brake" regimen) reduces infection risk compared to alternating chemoimmunotherapy + BTKi regimens, and 12 months of BTKi monotherapy increases T-cell receptor diversity, correlating with better clinical response and lower infection rates in relapsed/refractory CLL. This supports that extending BTKi induction before fixed-duration BCL-2i combination may optimize immune reconstitution, improving safety and long-term disease control.The study uses two investigational agents: zanubrutinib, a next-generation highly selective BTKi with higher BTK target selectivity and fewer off-target effects (e.g., lower cardiovascular adverse event risk vs. first-generation ibrutinib) compared to ibrutinib, approved in China for relapsed/refractory CLL/SLL and mantle cell lymphoma (MCL); and sonrotoclax, a highly selective BCL-2 inhibitor that restores mitochondrial apoptosis in CLL cells, with monotherapy showing 80.5% ORR and 26.8% CR/CRi rate in BTKi-pretreated high-risk relapsed/refractory CLL, and zanubrutinib + sonrotoclax combination achieving 92% 48-week uMRD rate and 100% 30-month PFS rate in treatment-naïve CLL/SLL. Study Design and PopulationThe study will consecutively enroll approximately 60 treatment-naïve CLL/SLL subjects meeting the 2025 Chinese CLL/SLL Diagnosis and Treatment Guidelines criteria, stratified into two groups:High-risk group (n=20): With 17p deletion (del17p) and/or TP53 mutationLow-risk group (n=40): Without del17p and/or TP53 mutationLow-risk group: Discontinue all treatment and enter observational follow-upHigh-risk group: Receive zanubrutinib monotherapy maintenance until disease progressionThis protocol is designed to systematically evaluate whether the delayed BCL-2i combination after extended BTKi induction improves MRD clearance, reduces toxicity, and optimizes long-term outcomes in treatment-naïve CLL/SLL, with tailored post-treatment management for high-risk populations to address their higher relapse risk.

Inclusion criteria

• Aged ≥18 years, no restriction on gender.
• 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).
• Meet at least one of the following indications for CLL treatment:

• Evidence of progressive bone marrow failure manifested by progressive reduction in hemoglobin and/or platelet counts.
• Massive splenomegaly (spleen palpable >6 cm below the left costal margin) or symptomatic splenomegaly.
• Bulky lymphadenopathy (maximum diameter >10 cm) or symptomatic lymphadenopathy.
• 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.
• Symptomatic organ dysfunction caused by CLL/SLL (involving skin, kidney, lung, spine and other organs).
• Autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) with inadequate response to corticosteroid therapy.
• 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.

• ECOG performance status ≤2.
• 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%).

• Male and female participants agree to use effective contraception throughout the study period and for a minimum of 4 weeks after treatment completion.
• Estimated life expectancy ≥6 months.
• 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.

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

• 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.

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

• 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.

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

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

• 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.

• 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.

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

• Systemic disorders that may impair patient compliance with trial requirements.