MRD-Driven Venetoclax and Rituximab Combination in Previously Untreated Chronic Lymphocytic Leukemia: First Results of the Prospective, Multicenter, Phase II Trial of the Polish Adult Leukemia Group (VERITA PALG-CLL5)

Introduction: Fixed-duration regimens combining a selective BCL-2 antagonist venetoclax with an anti-CD20 antibody (rituximab or obinutuzumab) are the mainstay of current management of chronic lymphocytic leukemia (CLL). However, it is unknown whether the same duration of treatment is optimal for all patients. Clinical trials have shown that achieving undetectable measurable residual disease (MRD) with venetoclax-based regimens is associated with the best long-term outcomes in CLL. It can therefore be hypothesized that adjusting the duration of therapy to MRD status may provide an optimal balance between treatment activity and toxicity.

Methods: This prospective, multicenter, phase II study aimed to assess the efficacy and safety of MRD-driven combination of venetoclax and rituximab (VR) in treatment-naive 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. The duration of VR treatment was 12, 18, or a maximum of 24 cycles depending on the depth of response. For patients who achieved a complete response (CR) with bone marrow MRD<10^-4 (MRD-) by flow cytometry at the response assessments at Cycle 12 or Cycle 18, VR treatment was discontinued. The primary objective of the study was to demonstrate that this strategy leads to a 35% CR MRD- rate. Here, we present the results of a preplanned interim analysis performed after all study participants had responses assessed at Cycle 12.

Results: Between February 2022 and May 2023, all planned 103 patients were recruited in 10 Polish Adult Leukemia Group centers. The patients’ median age was 66 years (range 38-85), and 56 (54%) of them were male. Del17p or TP53 mutation was present in 13 (13%) patients. Fifty-three 53 (51%) patients had unmutated IGHV status, 41 (40%) had mutated IGHV status, while in 9 patients IGVH status was not determined. Tumor lysis syndrome (TLS) risk was high in 38% and medium in 51% of patients. The median study follow-up time was 17 months (range 1– 26). Response to treatment was assessed in 101 patients, as 2 were withdrawn early (ramp-up and Cycle 1) due to complications i.e. prolonged COVID-19 and AIHA with sepsis, and followed only for survival. The study met its primary endpoint with CR with bone marrow MRD- achieved by 50 (49%) study participants at the interim analysis, while 44 patients remained on therapy. At the assessment at Cycle 12, the overall response rate (ORR) was 98% including 45 (44%) CR MRD-, 4 (4%) CR MRD+, 39 (39%) partial remission (PR) MRD-, 11 (11%) PR MRD+, 1(1%) stable disease and 1(1%) progressive disease. Importantly, out of 25 patients who continued therapy and reached Cycle 18 assessment, 8 patients (32%) improved depth of response (3 pts. from PR MRD- to CR MRD-; 2 pts. from PR MRD+ to CR MRD-; 2 pts. from PR MRD+ to PR MRD- and 1 patient from SD to PR). Five patients completed 24 Cycles of VR treatment, all achieving PR MRD- at all Cycle 12, 18, and 24 assessments. Only 1 patient progressed during the study follow-up period. One death was recorded (suicide) in a patient with CR MRD-. Estimated progression-free survival (PFS) probability at 24 months reached 98.0% (95% CI 95.3-1.0), and overall survival (OS) probability at 24 months was 98.9% (95% CI 96.9-1.0). Treatment was overall well tolerated. Hematological toxicity was the most prominent with neutropenia of all grades (G) comprising 39% of adverse events (AEs). Grade 3/4 AEs were noted in 72 (69.9%) patients including G3/4 neutropenia observed in 54 (52.4%) study participants. However, G 3/4 infections were reported only in 5 (4.9%) patients. Of other AEs of interest, there were 5 cases of laboratory TLS, 3 AIHA, and 1 second primary malignancy.

Conclusions: The first results of the VERITA-PALG-CLL5 study indicate high efficacy of MRD-driven venetoclax plus rituximab combination in treatment-naïve CLL. Extending treatment beyond 12 cycles in patients who did not achieve CR MRD- was safe and led to improved depth of response in one third of patients.