Real-world efficacy and safety of venetoclax-based therapy in israeli patients with CLL/SLL: Results from the reveal study

Abstract Introduction Venetoclax-based therapy has significantly altered the treatment landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), demonstrating substantial efficacy in pivotal clinical trials such as CLL14 and MURANO. Nevertheless, real-world data are crucial for assessing treatment effectiveness, tolerability, and outcomes across diverse patient populations. This report presents interim findings from the prospective, observational REVEAL study, which evaluates real-world outcomes of venetoclax-based therapies in treatment-naïve (TN) and relapsed/refractory (RR) CLL/SLL patients in Israel. Methods The REVEAL study enrolled adult CLL/SLL patients initiating venetoclax-based regimens across 13 Israeli centers since February 2019. This interim analysis includes data from 304 patients (TN=154, RR=150) up to September 2024. Study endpoints encompassed clinical overall response rate (ORR), complete response (CR), progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD) negativity measured in peripheral blood, and safety. Results Median ages at treatment initiation were 68 years (TN) and 70 years (RR). High-risk genetic features were more frequent in RR patients: del17p (TN 8.9%, RR 25%), TP53 mutations (TN 7.3%, RR 23%), unmutated IGHV (TN 64%, RR 80%). RR patients received a median of one prior therapy, with 44.7% previously treated with B-cell receptor inhibitors (BCRi). Most patients received venetoclax with anti-CD20 antibodies (TN: 95% obinutuzumab; RR: 73% rituximab, 10% obinutuzumab, 16% monotherapy). Median treatment durations were 12 months (TN) and 22 months (RR). In the TN cohort, the 12-month ORR was 98%, with a CR rate of 75%. After a median follow-up of 24 months, the median PFS was not reached, with a 3-year PFS of 83%. TN patients receiving a full dose of venetoclax (weighted average dose >80% of 400 mg) had a superior 2-year PFS compared to those on a reduced dose (93% vs. 71%, p=0.014). In TN patients, the 12-month MRD negativity at 10-4 was 90% and at 10-5 was 71%. The median OS was not reached for TN patients, with a 3-year OS of 86%. In the RR cohort, the 12-month ORR was 95%, with a CR rate of 64%. The median PFS for RR patients was 50.6 months, notably shorter with Del17p/TP53 mutations (24.7 months vs. median not reached, p=0.001). RR patients treated with venetoclax + rituximab or venetoclax monotherapy had a median PFS of 50.6 months and 13.2 months, respectively. For the RR patients treated with venetoclax + obinutuzumab (n=15), the median PFS was not reached. There was a significant difference between the 3 treatment regimens (p<0.001). Within the BCRi-exposed patients, those who progressed had a PFS of 20.5 months vs. 41.3 months for those intolerant to BCRi (p=0.049). In the RR cohort, full dose venetoclax showed better PFS with median PFS of 51.7 months vs. 41.3 months (p=0.045). In RR patients, 12-month MRD negativity (MRD5/MRD4 vs. MRD positive) was significantly correlated with better PFS (p=0.023). The median OS for RR patients was not reached, with a 3-year OS of 75%. Venetoclax monotherapy and prior BCRi exposure were significantly associated with an increased mortality risk compared to combination regimens (HR [95%CI] 3.7 [1.9, 7.6]) and BCRi-naïve patients (HR [95%CI] 2.22 [1.1, 4.5]). In a multivariable analysis with covariates Del(17p)/TP53, prior therapies, treatment regimen and BCRi exposure, the significant predictors of shorter PFS were: Del(17p)/TP53 (HR [95%CI]: 2.4 [1.3, 4.3]), number of prior therapies (1.6 [1.2, 2.0]) and venetoclax monotherapy vs. venetoclax + obinutuzumab (5.0, [1.1,22.1]), in RR patients. Serious adverse events (AEs) occurred in 45% of TN and 57% of RR patients, with neutropenia the most common Grade ≥3 event (TN: 23%, RR: 28%). Treatment was discontinued due to AEs in 9.7% of TN and 19% of RR cases, mainly due to neutropenia and infections. Infections were also the leading cause of death (TN:8/16, 50%, RR:10/34, 29%). Conclusions The REVEAL study confirms the real-world effectiveness and safety of venetoclax-based therapy in CLL, aligning with clinical trial data. In the relapsed/refractory (R/R) cohort, PFS was particularly favorable with venetoclax plus obinutuzumab. Our findings highlight the importance of regimen selection, treatment sequencing, and dose intensity to optimize outcomes in CLL/SLL.