DP043 | AN MRD-GUIDED FRONTLINE TREATMENT FOR YOUNG PATIENTS WITH HIGH-RISK CLL INCLUDING VENETOCLAX AND OBINUTUZUMAB FOLLOWED BY VENETOCLAX AND ZANUBRUTINIB IN PATIENTS WITH DETECTABLE MINIMAL RESIDUAL DISEASE: PRELIMINARY RESULTS FROM GIMEMA CLL222

A significant proportion of patients with chronic lymphocytic leukemia (CLL) who undergo a fixed-duration treatment with the venetoclax and obinutuzumab (VenO) combination achieved undetectable minimal residual disease (uMRD) with more prolonged progression-free survival than those with detectable MRD (dMRD). Therefore, a treatment strategy aimed at reducing residual disease may enhance outcomes for this latter group of patients. The GIMEMA CLL2222 (VIS) study is a multicenter, phase 2 trial investigating a front-line MRD-guided treatment approach for young (≤65 years) patients with high-risk CLL, defined by the presence of unmutated IGHV and/or TP53 disruption (TP53 mutation and/or deletion). Here, we provide preliminary data from this study. The study design includes an initial phase with six VenO courses. At the end of the VenO combination therapy (EOCT, month 9), MRD is evaluated by ASO-PCR, both in the peripheral blood (PB) and bone marrow (BM). Patients with uMRD (<10-4) continue treatment with 6 additional courses of venetoclax. Those patients with dMRD receive the venetoclax and zanubrutinib combination (VenZan) until cycle 21. This study has two co-primary endpoints: 1. the rate of patients who achieved uMRD at the EOCT with VenO. 2. the rate of patients with dMRD at the EOCT who reach uMRD at the EOT with the VenZan combination. The planned enrollment for this study is 78 patients. As of March 2025, 49 patients started treatment. The median age was 59 years, 98% of patients were IGHV unmutated, and one IGHV mutated withTP53 disruption. Currently, the study's primary endpoint has been met, with 22 out of 26 (85%) evaluated patients showing uMRD in both PB and BM at the EOCT. The remaining 4 patients with dMRD at the EOCT started the VenZan combination. Adverse events were those usually described in patients receiving study drugs. Obinutuzumab was discontinued in one patient due to a severe infusion reaction. No disease progression or deaths have been reported. The preliminary data from this study show a high rate of deep responses with uMRD in patients carrying high-risk genetic features who received VenO. In the next phase of this study, the threshold for uMRD will be lowered to <10-6, extending treatment with VenZan to patients with residual leukemic cells between <10-4 and ≤10-6 to reduce further residual disease improving outcomes for patients with high-risk genetics, who tend to lose response rapidly.