Real-world (RW) treatment (Tx) patterns, factors associated with discontinuation and toxicity across covalent BTK inhibitors (cBTKis) in first-line (1L) tx of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL)

Abstract INTRODUCTION cBTKis have become a standard 1L therapy for CLL/SLL. While second-generation (2G) cBTKis, acalabrutinib (Acala) and zanubrutinib (Zanu), have shown better tolerability than ibrutinib (Ibru) in clinical trials, especially with regard to cardiovascular (CV) safety, RW data on their usage, discontinuation, and toxicity remain limited. Understanding these patterns is critical for optimizing long-term CLL/SLL tx in routine practice. METHODS This retrospective observational cohort study included patients (pts) with CLL/SLL who initiated 1) tx with a cBTKi (Ibru, Acala, or Zanu) between 11/21/2019 and 07/31/2023, in the US community setting. Data were sourced from the iKnowMed electronic health record through 08/15/2024. Outcomes included the probability of pts discontinuing tx (TTD), receiving next tx or dying (NT+D), which were estimated using Kaplan-Meier (KM) methods, along with reasons for discontinuation. Cox models identified factors associated with discontinuation. The occurrence of toxicities, including cardiovascular (CV; atrial fibrillation [AF], hypertension [HTN]) and non-CV (bleeding requiring tx, infection requiring antimicrobial therapy, headache, neutropenia), was reported as proportions and incidence rates per 1000 patient-months (pt-mo). RESULTS In total, 584 pts met eligibility criteria and were included in the analysis: 65.8% received Ibru (n=384), 25.7% Acala (n=150), and 8.6% Zanu (n=50). The median follow-up durations were 35.6 mo for Ibru, 42.3 mo for Acala, and 16.1 mo for Zanu. The mean age of the study population was 73 years (standard deviation [sd]: 11), 37.8% were female, 76.5% White, 81.7% non-Hispanic or Latino, 38.5% with a CCI score ≥ 1, and 52.9% with an ECOG score of 0 or 1. Overall, 65.9% of pts (n=385) discontinued 1L tx (median TTD 23.0 mo; 95% confidence interval [CI] 19.7-26.2), including 38.4% (148/385) due to toxicities and 9.9% (n=38/385) for progression or death. At 24 mo, the KM-estimated discontinuation probabilities were 56.6% (Ibru), 39.0% (Acala), and 49.2% (Zanu); NT+D probabilities were 35.6% (Ibru), 28.5% (Acala), and 18.9% (Zanu). Several factors were associated with a shorter TTD in the multivariate analysis, including: ECOG performance status of 1 vs 0 (hazard ratio [HR] = 1.38; 95% CI: 1.04-1.84; p = 0.026), Charlson comorbidity index of ≥3 vs 0-2 (HR = 1.74; 95% CI: 1.18-2.58; p = 0.006); deletion 17p (HR = 1.43; 95% CI: 1.04-1.98; p = 0.029); the occurrence of infections (HR = 1.44; 95% CI: 1.03-2.01; p = 0.036) or bleeding events (HR = 2.03; 95% CI: 1.31-3.14; p = 0.002). Acala was associated with a significantly longer TTD compared to Ibru (HR = 0.61; 95% CI: 0.47-0.79; p < 0.001), while Zanu did not differ significantly from Ibru (HR = 0.81; 95% CI: 0.51-1.29; p = 0.374). With regards to CV events, AF occurred in 10.4% of pts on Ibru (4.16/1000 pt-mo), 8.0% on Acala (2.78/1000 pt-mo), and 8.0% on Zanu (4.69/1000 pt-mo). HTN was reported in 9.4% (Ibru, 3.68/1000 pt-mo), 8.7% (Acala, 3.00/1000 pt-mo), and 4.0% (Zanu, 2.34/1000 pt-mo). Regarding non-CV events, infections occurred in 14.8% (Ibru, 6.09/1000 pt-mo), 20.0% (Acala, 7.47/1000 pt-mo), and 12.0% (Zanu, 7.53/1000 pt-mo). Bleeding events were reported in 7.8% (Ibru, 3.05/1000 pt-mo), 8.0% (Acala, 2.71/1000 pt-mo), and 8.0% (Zanu, 4.78/1000 pt-mo). Headaches occurred in 6.5% (Ibru, 2.57/1000 pt-mo), 36.7% (Acala, 19.5/1000 pt-mo), and 12% (Zanu, 12.0%; 7.89/1000 pt-mo). Neutropenia was observed in 4.7% (Ibru, 1.79/1000 pt-mo), 2.7% (Acala, 0.88/1000 pt-mo), and 12.0% (Zanu, 7.27/1000 pt-mo). CONCLUSIONS In this RW 1L cBTKi-treated CLL/SLL cohort, discontinuation was higher than observed in clinical trials across cBTKis and was largely driven by toxicities. Likewise, worsened performance status, higher comorbidity burden, and cytogenetic abnormalities (deletion 17p) were also associated with earlier discontinuation. Adverse events were aligned with clinical trial findings: Ibru was associated with higher rates of AF and HTN; Acala with increased headache incidence; and Zanu with more frequent bleeding and neutropenia event rates. Extended follow-up is needed to evaluate long-term outcomes with 2G cBTKis, including TTD and its associated factors. These results highlight the unmet need for tx strategies that improve tolerability and prolong time on therapy for patients with CLL/SLL in the RW community oncology setting.