Minimal residual disease-guided venetoclax plus rituximab for patients with previously untreated chronic lymphocytic leukemia (VERITA PALG-CLL5): primary endpoint analysis of the prospective, multicenter, Phase 2 trial

Abstract Background: Fixed-duration regimens combining the selective BCL-2 antagonist venetoclax with an anti-CD20 antibody are currently the standard of care for chronic lymphocytic leukemia (CLL). The aim of this study was to determine whether adjusting the duration of such therapy based on minimal residual disease (MRD) status could improve treatment outcomes. Methods: VERITA PALG-CLL5 is a prospective, multicenter, phase 2 study aimed to assess the efficacy and safety of MRD-guided venetoclax plus rituximab (VR) in untreated CLL. Following the standard venetoclax ramp-up phase, patients received venetoclax 400 mg PO daily combined with rituximab 375 mg/m² during the first infusion, then 500 mg/m² IV every 4 weeks during Cycles 1-6, and then every 8 weeks thereafter. The duration of VR treatment was 12, 18, or a maximum of 24 cycles, depending on MRD response. In patients who achieved a complete remission (CR) with bone marrow (BM) MRD<10-4 (undetectable MRD, uMRD) by 8-colour flow cytometry at Cycle 12 or Cycle 18 assessments, VR was discontinued. The study's primary objective was to demonstrate that this strategy leads to a 35% CR BM uMRD rate at therapy completion. This pre-specified primary endpoint analysis was performed after all study participants had completed treatment. Results: Between February 2022 and May 2023, 103 patients were recruited in 10 Polish Adult Leukemia Group centers. The patients' median age was 66 years (range 38-85), and 56 (54%) were male. Del17p or TP53 mutation was present in 14 (13%) patients, and 55 (56%) patients had unmutated IGHV status. Besides TP53 mutations, the most prevalent recurrent gene mutations were SF3B1 (22; 21.6%), NOTCH1 (15; 14.7%), XPO1 (11; 10.8%), BIRC3 (11; 10.8%), ATM (7; 6.9%), DDX3X (7; 6.9%), and BRAF (6; 5.9%). Tumor lysis syndrome (TLS) risk was high in 40 (38%) and medium in 52 (50%) of patients. At the data cutoff on July 31, 2025, the median follow-up for patients alive and not lost to follow-up was 29 months (IQR, 26–31.4). Treatment response was assessed in 101 patients, as 2 were withdrawn early (in the ramp-up phase and cycle 1) due to complications (prolonged COVID-19 and AIHA) and were followed only for survival. The study met its primary endpoint, achieving CR with uMRD in 62 (61.4%) study participants. At cycle 12 assessment, the overall response rate (ORR) was 100%, including 44 (44%) patients with CR uMRD who subsequently discontinued therapy per study protocol. An additional 10/52 (19%) and 8/40 (20%) patients who continued treatment to cycles 18 and 24, respectively, achieved CR uMRD. In addition to the 62 patients with CR uMRD, the following responses were observed at post-treatment assessment: 2 (2%) CR with detectable MRD, 25 (24.8%) partial remission (PR) with uMRD, 7 (6.9%) PR with detectable MRD, 3 (3%) PR with MRD status not assessed and 2 (2%) disease progressions. BM uMRD was confirmed in 88 (90.7%) patients at any time during therapy. Of the 179 MRD tests performed simultaneously in peripheral blood (PB) and BM, uMRD status was obtained in 147 BM tests out of 164 PB tests with uMRD (89.6%). During the follow-up period, three patients experienced disease progression. Four deaths were recorded, all in patients maintaining CR uMRD response (stroke, other primary malignancy, suicide, and unknown). Estimated progression-free survival (PFS) probability at 30 months was 92.7% (95% CI 87.0–98.9%), and overall survival (OS) probability at 30 months was 96.1% (95% CI 91.6–100.0%). Unmutated IGHV status and TP53 aberrations had no impact on patients' PFS (HR: 0.79, 95% CI: 0.2-2.9, and HR: 0.97, 95% CI: 0.1-8.0, respectively) and OS (HR: 0.13, 95% CI: 0.1-1.4, and HR: 0.99, 95% CI: 0-inf, respectively). None of the analyzed recurrent CLL mutations had an impact on PFS or OS. Treatment was generally well tolerated. No cases of clinical TLS were observed. Hematological toxicity was the most frequent, with neutropenia of any grade observed in 69.9% of patients, followed by thrombocytopenia (10.7%) and anemia (8.7%). A total of 11 grade 3+ infections were recorded in 9 (8.7%) patients. AIHA and immune thrombocytopenia were noted in 3 and 1 patients, respectively. Conclusions: VERITA-PALG-CLL5 study showed high efficacy and a favorable safety profile of MRD-guided venetoclax plus rituximab in patients with untreated CLL, including high-risk patients. These results support further development of MRD-guided treatment strategies for CLL.