Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Abstract

The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as chromosome 17p deletion [del(17p)] or progressive disease following B-cell receptor pathway inhibitors. We conducted a comprehensive analysis of the safety of 400 mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase I/II studies. Median age was 66 years and 60% had del(17p). Patients had received a median of three prior therapies (range: 0-15); 42% previously received ibrutinib or idelalisib. Median duration of exposure to venetoclax was 16 months (0-56). In the pooled analysis, the most common adverse events (AE) of any grade were diarrhea (41%), neutropenia (40%), nausea (39%), anemia (31%), fatigue (28%), and upper respiratory tract infection (25%). The most common grade 3/4 AEs were neutropenia (37%), anemia (17%), and thrombocytopenia (14%). With the current 5-week ramp-up dosing, the incidence of laboratory TLS was 1.4% (2/166), none had clinical sequelae, and all of these patients were able to ramp-up to a daily dose of 400 mg. Grade 3/4 neutropenia was manageable with growth factor support and dose adjustments; the incidence of serious infections in these patients was 15%. Ten percent of patients discontinued venetoclax due to AEs and 8% died while on study, with the majority of deaths in the setting of disease progression. Venetoclax as a long-term continuous therapy is generally well tolerated in patients with R/R CLL when initiated with the current treatment algorithm. .

Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post‐BCRinhibitor setting: aUKwide analysis

“…Our reported rate of clinical and biochemical TLS is that which resulted in unplanned admission and, as such, the rate may differ compared to series reporting all cases of biochemical TLS. Notwithstanding this caveat, the TLS rate of 1% is consistent with that reported in clinical trials (Stilgenbauer et al, 2016;Davids et al, 2018) following the modifications to the dosing schedule to mitigate against TLS risk. The rate of TLS in our series is lower than the US RWD set.…”

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

“…In the R/R and 1L populations, most AEs were low grade and, as expected based on the known modes of action and established tolerability profiles of both study drugs, 19,21,33 neutropenia was the most common grade 3-4 AE. Neutropenia was manageable with standard-of-care measures, and did not result in complications.…”

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia

“…The median age was 66 years (Roberts et al, ) across all patients with those ≥70 years achieving similar response depth, duration and minimal residual disease negativity compared to younger patients. AE rates, including grade (G) 3/4 AEs, serious AEs, and AEs leading to venetoclax dose reduction, interruption, or discontinuation did not differ according to age (<75 or ≥75 years) within a pooled analysis of 350 venetoclax‐treated trial patients (Davids et al, ).…”

“…This large international cohort suggests that venetoclax provides reassuringly similar efficacy and toxicity profiles in the ‘elderly’, defined in this cohort as ≥75 years of age at the time of starting venetoclax. We chose this age cut‐off to provide consistency with the recent analyses of toxicities in venetoclax‐treated clinical trial patients (Davids et al, ) which demonstrated no significant difference in toxicity profile or need for dose modifications in those <75 or ≥75 years. While rates of AEs and dose modifications were similar, older patients discontinued therapy more frequently due to toxicity.…”