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.
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.
Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN).
Creatinine clearance (CrCl) ≥ 60 mL/min (estimated by Cockcroft-Gault formula).
Total bilirubin (TBIL) ≤ 1.5 × ULN (unless due to Gilbert's syndrome or other non-hepatic causes).
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.
Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease.
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.
Single group
Zanubrutinib and sonrotoclax
DrugZanubrutinib: 160 mg BID, orally, administered until Cycle 15, 21, or 27, and thereafter until discontinuation criteria are met, disease progression, or unacceptable toxicity.(28d/cycle) Sonrotoclax: Starting from Day 1 of Cycle 3, a 4-week dose-escalation regimen is administered until the target dose of 320 mg QD is reached, then administered orally until Cycle 15, 21, or 27, and thereafter until discontinuation criteria are met, disease progression, or unacceptable toxicity. All patients must complete at least 12 cycles of combination therapy with zanubrutinib and sonrotoclax (C4-C15), with a maximum of 24 cycles of combination therapy (C4-C27). If uMRD6 is not achieved after 24 cycles of combination therapy, patients will receive zanubrutinib monotherapy as maintenance. For patients in whom assessment is feasible, treatment discontinuation may be considered upon achieving uMRD6 at any time point. Otherwise, treatment will be continued until disease progression.
uMRD6 rate at Cycle 15
defined as the proportion of patients achieving undetectable minimal residual disease (MRD negativity, \<10-⁶) in peripheral blood as assessed by next-generation sequencing (NGS)
complete response (CR) rate
Overall response rate is the proportion of patients who achieve a complete response to treatment defined by the iwCLL.
3-year Progression-free survival rate
PFS is defined as the time from the first dose of treatment to progression, or death due to any cause, whichever occurs first. For subjects without progression, relapse, or death at the time of analysis, EFS will be censored at the last assessment date.
3-year Overall survival tare
OS is defined as the time from the first dose of treatment to death due to any cause. Subjects who remain alive at the time of analysis will be censored at the last known alive date of the subject.
uMRD4 and uMRD6 rates of EOT
uMRD4 and uMRD6 rates assessed by flow cytometry and NGS after the actual end of combination therapy.
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