Safety of Venetoclax Ramp-up before CD20 Antibody Administration in Chronic Lymphocytic Leukemia
Authors: Rotbain Emelie Curovic , Werling Mikkel , Møller Frederiksen Casper , Poulsen Christian Bjørn , Hutchings Martin , Da Cunha-Bang Caspar , Niemann Carsten Utoft 
Published: December 2024

Introduction
Venetoclax and CD20 antibodies represent a synergistic combination used for the treatment of chronic lymphocytic leukemia (CLL). Clinical studies have demonstrated the efficacy of this combination, highlighting its ability to achieve deep and durable responses, even in high-risk CLL populations. Despite these advances, the optimal sequencing of venetoclax and CD20 antibody administration remains an active area of investigation. Most protocols initiate treatment with CD20 antibodies to reduce tumor burden and mitigate the risk of tumor lysis syndrome (TLS) associated with venetoclax. Other approaches commence with venetoclax to mitigate infusion-reactions upon CD20 antibodies and capitalize on the induction of apoptosis by venetoclax before introducing CD20 antibodies to enhance residual disease clearance. In Denmark, patients treated in routine care typically complete venetoclax ramp-up prior to the first CD20 antibody administration, while patients treated in clinical trials receive CD20 antibodies before initiating venetoclax. Here, we report data on the risk of TLS based on sequencing of venetoclax and CD20 antibody administration in a Danish nationwide population-based setting.
Methods
Using the Danish Lymphoid Cancer Research (DALY-CARE) data resource (https://doi.org/10.1101/2024.04.11.24305663), we identified CLL patients treated with venetoclax plus a CD20 antibody between 2015 and 2023. Patients were stratified based on whether they had received CD20 antibodies prior to or post venetoclax ramp-up. Safety was assessed using the Cairo-Bishop definition of laboratory TLS. The Cairo-Bishop definition was modified to only consider increases or decreases of ≥25% compared to the baseline if the value was above/below the normal range. Creatinine levels were used according to the Cairo-Bishop definition of clinical TLS. We identified the last value prior to treatment and the highest value (lowest for calcium) during the month after initiation of treatment by extracting data directly from the laboratory systems through DALY-CARE. For patients starting with venetoclax, the date of treatment was the date when the patient first received venetoclax, while for patients starting with CD20 antibodies, the date of treatment was the date when the patient first received CD20 antibodies (for patients starting with venetoclax, CD20 antibody treatment was thus not included in this period, whereas for patients starting with CD20, the first week of venetoclax ramp-up was included).
Results
A total of 226 patients treated with venetoclax plus a CD20 antibody were identified: 183 received venetoclax first (ven-first) and 43 received the CD20 antibody first (CD20-first). The median age at treatment was 72 years in the ven-first group and 69 years in the CD20-first group, with 72% and 70% of the patients being male, respectively. Complete laboratory data was available for 133 patients, while 196 patients had data for at least 4 out of 5 measurements.
Significant increase of potassium was observed in 9% and 26% (p-value = 0.008), uric acid in 39% and 40% (p-value = 1), phosphorus in 25% and 56% (p-value &lt; 0.001), and calcium in 2% and 3% (p-value = 1) in the ven-first and CD20-first group, respectively. According to the Cairo-Bishop definition of laboratory TLS, 28% of patients in the ven-first group fulfilled the criteria compared with 46% in the CD20-first group (p-value = 0.088). Significant increase of creatinine was seen in 9% of patients in the ven-first group and 14% in the CD20-first group (p-value = 0.452).
Conclusions
We demonstrate that venetoclax ramp-up prior to CD20 antibody treatment is not associated with an increased risk of clinical or laboratory TLS compared to CD20-first. Ven-first was associated with a lower risk of increased potassium and phosphorus levels while a trend for lower risk of laboratory TLS was identified.
Real-world data with automatized extraction of laboratory data thus indicate a higher rate of laboratory TLS compared to what has been reported in clinical trials, suggesting that TLS may be underreported in clinical trials.
Venetoclax ramp-up before CD20 antibody administration in a real-world setting is feasible and may be associated with a lower risk of TLS. External validation and prospective testing are recommended before changing the advised sequence of venetoclax and CD20 antibodies in CLL.