A Real-World Comparative Analysis of Hypertension and Time to Treatment Failure with Acalabrutinib Vs Ibrutinib in Treatment-Naïve Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Authors: Ermann Daniel A. , Dranitsaris George , Blau Sibel , Peevyhouse Aaron , Neuhalfen Heather , Yong Alan SM , Wahlstrom Tina K. , Thompson Samantha L. , Teschemaker Anna , Shetty Vikram , Narkhede Mayur S. 
Published: December 2024

Introduction:
A major advance in the care of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the development of Bruton tyrosine kinase inhibitors (BTKis). Ibrutinib was the first BTKi to be approved and has demonstrated sustained progression-free survival over 8 years of follow-up in treatment-naïve patients with CLL/SLL (Barr et al. 2022). However, there is concern about the tolerability of ibrutinib, which is characterized by hypertension (HTN) and major adverse cardiovascular events (MACE). Acalabrutinib is a second generation BTKi that has also demonstrated durable disease response but with a potentially improved safety profile versus ibrutinib. Acalabrutinib has not been compared with ibrutinib in treatment-naïve patients with CLL/SLL in a randomized trial. This real-world analysis compared the risk of HTN and time to treatment failure (TTF) with acalabrutinib versus ibrutinib monotherapy in treatment-naïve patients with CLL/SLL.
Methods:
This retrospective, observational study used electronic medical record data from ONCare Alliance, a network of 29 community oncology/hematology practices across the United States. The study included patients with treatment-naïve CLL/SLL initiating either acalabrutinib or ibrutinib monotherapy on or between January 1, 2017 and December 31, 2023. The primary endpoint was time to the development of new HTN/worsening of pre-existing HTN. New/worsening HTN was defined as the addition of an anti-HTN medication, an increase in the dose of a current anti-HTN medication, a dose modification or discontinuation of the BTKi due to elevated blood pressure, or a provider statement reporting new/worsening HTN. The secondary endpoint was TTF, defined as time from treatment initiation to discontinuation due to disease progression, drug intolerability, patient/provider choice, or death. Data collection included patient and disease characteristics, comorbidities, history of prior HTN and MACE, and Eastern Cooperative Oncology Group performance status (ECOG PS). The primary and secondary endpoints were evaluated using multivariate Cox proportional hazard regression analysis. To control for selection bias, propensity scores were used to weight the comparative multivariate analyses. Sensitivity analyses evaluated primary and secondary endpoints in scenarios without propensity score weighting, using different applications of the propensity scores, excluding non-responders and excluding patients without a history of HTN.
Results:
The analysis included 454 patients (227 per treatment group). Baseline characteristics of patients in the acalabrutinib and ibrutinib groups were well balanced with respect to median age (72 vs 73 years), ECOG PS, median Charlson comorbidity score (3 vs 3), median systolic (130 vs 127 mmHg) and diastolic (72 vs 71 mmHg) blood pressure (BP), and history of HTN (67.8% vs 66.5%). After a median follow-up of 18 months, drug discontinuations due to intolerability were more common with ibrutinib versus acalabrutinib (47.1% vs 20.3%; p &lt; 0.001). Median time to new/worsening HTN was not reached (NR) with acalabrutinib or ibrutinib, and median TTF was NR with acalabrutinib and 16.1 months with ibrutinib. After a propensity score weighted Cox proportional hazard analysis versus ibrutinib, acalabrutinib was associated with a significantly lower risk of new/worsening HTN (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.10-0.43; p &lt; 0.001) and a longer TTF (HR: 0.42, 95% CI: 0.31-0.56; p &lt; 0.001). Sensitivity analyses were consistent with the primary analyses.
High baseline systolic BP (HR: 1.03; p &lt; 0.001), presence of B symptoms (HR: 2.23, p = 0.007), and a history of valvular heart disease (HR: 3.11, p = 0.039) increased the risk of new/worsening HTN. Older age (HR: 1.03, p &lt; 0.001), high comorbidity burden based on the Charlson comorbidity score (HR: 1.09, p = 0.039), history of atrial fibrillation (HR: 1.51, p = 0.023), and ECOG PS ≥ 2 (HR: 1.48, p = 0.05) increased the risk of treatment failure.
Conclusions:
In treatment-naïve patients with CLL/SLL, acalabrutinib monotherapy was associated with a lower rate of new/worsening HTN, fewer discontinuations due to intolerability, and a prolonged TTF versus ibrutinib, even after statistical adjustments to reduce potential selection bias.