Background and Significance:

For patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), fixed-duration treatment with a covalent Bruton tyrosine kinase inhibitor (cBTKi) and a B-cell lymphoma 2 inhibitor (BCL-2i) is now a first-line (1L) treatment option. CLL is a persistent disease with no definitive cure. Despite advancements in novel targeted combination therapies, a substantial proportion of patients experience disease progression following fixed-duration 1L treatment and require subsequent lines of therapy or retreatment. Furthermore, as seen in prior studies of cBTKi + BCL-2i, patients with unmutated IGHV were more likely to achieve undetectable minimal residual disease (uMRD) compared with patients with mutated IGHV yet were also more likely to relapse sooner. It remains unclear whether longer treatment duration for patients with CLL and higher genetic risk may lead to longer remissions. More prospective clinical trial data are needed to understand whether patients can be effectively retreated with finite-duration (total 14 cycles or 24 cycles) cBTKi + BCL-2i at relapse; the only published data are derived from a small cohort of patients. Fixed-duration (total 14 cycles) combination therapy with the highly selective cBTKi acalabrutinib (A) + venetoclax (V) ± obinutuzumab (O) was found to improve progression-free survival (PFS) compared with chemoimmunotherapy in the phase 3 AMPLIFY trial in patients with treatment-naive CLL (Brown JR, et al. NEJM. 2025). The efficacy of AV-based retreatment in patients with CLL who experience relapse following 1L BTKi + BCL-2i therapy has not been previously evaluated. Results from this study will determine whether retreatment with finite-duration cBTKi + BCL-2i can provide therapeutic benefit to patients with CLL/SLL after relapse.

Study Design and Methods

This phase 2, open-label, multicenter, single-arm, global study (MAVRiC: Mutation-guided finite-duration AV for Relapse in CLL/SLL; NCT07024706) aims to assess the efficacy and safety of IGHV- and TP53-mutation risk‒guided, finite-duration AV after prior fixed-duration BTKi + BCL-2i therapy.Eligible patients are aged ≥18 years with a diagnosis of CLL/SLL who require treatment per International Workshop on CLL (iwCLL) 2018 criteria, had prior finite cBTKi + BCL-2i ± O 1L treatment, and had a partial response or better maintained for ≥2 years after treatment completion with subsequent relapse. Key exclusion criteria were clinically significant cardiovascular disease within 6 months of enrollment, active central nervous system involvement, Richter transformation, active significant infection, and creatinine clearance of <30 mL/min (per Cockroft-Gault equation) or serum creatinine >2 times the upper limit of normal. Patients will receive AV (A 100 mg oral twice daily [BID] and V 400 mg oral once daily [QD]) in 28-day cycles; lead-in A 100 mg BID will be given in cycles 1–2, and V dosing will begin in cycle 3 with the label-prescribed 5-week ramp-up dosing up to 400 mg QD. Subsequently, IGHV and TP53 mutational status will guide AV duration. Cohort 1 will include patients with lower-risk CLL/SLL (those with mutated IGHV and no TP53 aberrations) treated with AV in cycles 3–14; cohort 2 will include patients with higher-risk CLL/SLL (those with unmutated IGHV and/or TP53 aberrations) treated with AV in cycles 3–24. The primary endpoint is overall response rate per iwCLL 2018 criteria as assessed by the investigator after 12 cycles of combination AV. Key secondary endpoints include PFS, duration of response, event-free survival, time to next treatment, overall survival, safety/tolerability (including tumor lysis syndrome), and rate of uMRD (<10−5) in peripheral blood at 3 months after end of treatment using clonoSEQ. Patients will be followed for 5 years from cycle 1 day 1 until death, withdrawal of consent, or end of study. Global enrollment, planned for 80 patients, is expected to begin in 2025.

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2025
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