A Study of MRD-Guided Zanubrutinib Plus Sonrotoclax in Treatment-Naïve, High-Risk CLL/SLL Patients

A Prospective Study of MRD-Guided, Time-Limited Therapy With Zanubrutinib Plus Sonrotoclax in Treatment-Naïve, High-Risk Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Patients

This study is a prospective, multicenter, open-label, single-arm phase II clinical trial evaluating the efficacy and safety of an MRD-guided, time-limited therapy with zanubrutinib combined with sonrotoclax in previously untreated high-risk CLL/SLL patients.

Inclusion Criteria:

• Patients must meet all of the following inclusion criteria to be enrolled in this study:

Age between 18 and 75 years, inclusive. Diagnosis of CLL/SLL according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria.

Meeting iwCLL 2018 treatment indications and carrying at least one high-risk factor, including CLL-IPI high-risk/very high-risk, del(11q), del(17p)/TP53 mutation, unmutated IGHV, or complex karyotype.

Measurable disease: presence of measurable lymphadenopathy by computed tomography (CT) scan.

ECOG performance status of 0 to 2.

Adequate major organ function meeting the following criteria:

1. Hematologic function: without transfusion or hematopoietic growth factor support for at least 7 days prior to enrollment (at least 14 days for pegylated G-CSF such as pegfilgrastim), and meeting the following criteria: absolute neutrophil count (ANC) > 0.75 × 10⁹/L, platelet count (PLT) > 30 × 10⁹/L, hemoglobin (Hb) > 80 g/L.
2. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN).
3. Creatinine clearance (CrCl) ≥ 60 mL/min (estimated by Cockcroft-Gault formula).
4. Total bilirubin (TBIL) ≤ 1.5 × ULN (unless due to Gilbert's syndrome or other non-hepatic causes).
5. Coagulation function: prothrombin time (PT)/international normalized ratio (INR) < 1.5 × ULN, activated partial thromboplastin time (APTT) < 1.5 × ULN (exceptions may be considered on a case-by-case basis if clearly unrelated to coagulopathy or bleeding disorders).

Life expectancy ≥ 6 months. Female subjects of non-childbearing potential (e.g., postmenopausal for ≥ 1 year with amenorrhea, history of hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) are eligible. Female subjects of childbearing potential must have a negative serum pregnancy test at enrollment.

Able to understand and voluntarily sign a written informed consent form.

Exclusion Criteria:

• Patients meeting any of the following criteria will be excluded from this study:

Any prior treatment for CLL or SLL (including but not limited to chemotherapy, targeted therapy, immunomodulatory therapy, radiotherapy, and/or monoclonal antibody therapy).

History of other malignancies, unless:

1. The malignancy has been cured with no known active disease for at least 3 years prior to the first dose and is considered by the treating physician to carry a low risk of recurrence.
2. Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease.
3. Adequately treated carcinoma in situ with no evidence of disease. Known or suspected history of Richter's transformation. Uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia. Subjects with a decline in hemoglobin level or platelet count due to autoimmune destruction within 4 weeks prior to first dose, or requiring > 20 mg prednisone daily (or equivalent) to treat or control autoimmune disease.

Use of > 20 mg/day prednisone within 7 days prior to first dose of study drug (unless used for prophylaxis or treatment of allergic reactions, such as to contrast media).

Known allergic reaction to any of the study drugs. Known hypersensitivity to xanthine oxidase inhibitors and/or rasburicase. Subjects with hypersensitivity to xanthine oxidase inhibitors who cannot receive rasburicase will be excluded.

Receipt of a live attenuated vaccine within 4 weeks prior to first dose of study drug.

Active infection requiring systemic therapy that is ongoing or completed within 14 days prior to first dose, or any uncontrolled active systemic infection.

Known bleeding disorders (e.g., von Willebrand disease or hemophilia). History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

Known history of HIV infection, or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Subjects who are positive for HBV core antibody, hepatitis B surface antigen (HBsAg), or HCV antibody must have a negative PCR result prior to enrollment. Subjects with a positive PCR result will be excluded.

Major surgery within 4 weeks prior to first dose. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's judgment, could compromise the subject's safety or pose an undue risk to the study results.

Current active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia, New York Heart Association (NYHA) Class 3 or 4 congestive heart failure, or history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months.

Inability to swallow capsules/tablets, or presence of malabsorption syndrome, disease significantly affecting gastrointestinal function, history of partial or total gastrectomy or small bowel resection, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

Concurrent use of warfarin or other vitamin K antagonists. Requirement for treatment with strong cytochrome P450 (CYP) 3A inhibitors. Current active, clinically significant hepatic impairment meeting Child-Pugh Class B or C criteria.

Female subjects who are lactating or pregnant. Unwilling or unable to participate in all required study assessments and procedures.

Inability to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization for use of protected health information (in accordance with national and local privacy regulations).