Tumor Lysis, Adverse Events, and Dose Adjustments in 297 Venetoclax-Treated CLL Patients in Routine Clinical Practice

Abstract

Purpose: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.Experimental Design: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.Results: The group was 69% male, 96% had relapsed/ refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.Conclusions: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

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

“…Recent large retrospective, multicentre series (Mato et al, ; Eyre et al, ) have demonstrated reassuringly similar efficacy and survival to trial outcomes. A toxicity analysis [including rates of tumour lysis syndrome (TLS), dose interruptions and discontinuations] has been assessed in a recent all‐age cohort (Roeker et al, ) but the specific question of efficacy and tolerability in elderly non‐trial patients has not been specifically addressed.…”

“…Recent large retrospective, multicentre series (Mato et al, 2018b;Eyre et al, 2019) interruptions and discontinuations] has been assessed in a recent all-age cohort (Roeker et al, 2019) but the specific question of efficacy and tolerability in elderly non-trial patients has not been specifically addressed.…”

B cell signalling pathways—New targets for precision medicine in chronic lymphocytic leukaemia

“…The potency of the targeted agents is supported by retrospective studies on CLL patients that have been treated with reduced doses of ibrutinib or venetoclax in order to limit toxicities. [100][101][102][103][104][105] These studies show that the effect of the treatment is not compromised by lowering the dose, indicating that further dose adjustment studies are warranted.…”

“…Based on analyses of phospho flow data, it was shown that synergy between the two drugs can be achieved at doses that are much lower than the recommended daily dose of both ibrutinib and venetoclax. The potency of the targeted agents is supported by retrospective studies on CLL patients that have been treated with reduced doses of ibrutinib or venetoclax in order to limit toxicities 100‐105 . These studies show that the effect of the treatment is not compromised by lowering the dose, indicating that further dose adjustment studies are warranted.…”

Making clinical trials work for older patients with chronic lymphocytic leukemia

“…There has been an explosion of targeted therapies in the last 10 years across all diseases, however, just because a drug is targeted does not mean it is well tolerated. In CLL, real-world analyses have been helpful to explore the differences in tolerability of drugs between clinical trials and clinical practice [13,14], However, identifying these discrepancies is not enough, and research needs to also focus on why real-world scenarios are different from trials and what we can do to eliminate these disparities.…”