Introduction

Acalabrutinib is a novel selective, second-generation Bruton’s tyrosine kinase (BTK) inhibitor with dramatic efficacy against B cell malignancies [1,2,3,4,5]. Compared to ibrutinib, a first in-class BTK inhibitor, acalabrutinib has lower alternative kinase inhibition and off-target activity [6,7,8]. Due to a high burden of cardiotoxicity, namely the development of new or worsened hypertension or arrhythmias in follow-up, indefinite ibrutinib use has been limited to those without intolerable effects or disease progression [9,10,11,12,13,14,24, 25]. Within this, only those with patients aged 20 to 69 years without a diagnosis of diabetes were included, akin to the originally validated prediction model.24 The observed rates of hypertension were calculated using the cumulative incidence of blood pressure ≥ 140/90 mmHg at 3-month intervals across the initial year of treatment. The Framingham-predicted rate of new hypertension within 1 year was estimated by averaging the individual patient probabilities obtained after applying individual patient-level risk factors. All analyses were performed with R version 3.6.2 and SAS Software version 9.4, and the statistical tests were two-sided with statistical significance evaluated at the α = 0.05 significance level.

Results

Overall, 280 patients treated with acalabrutinib were identified (Additional file 1: Figure S1). The mean age was 63.7 ± 10.1 years (range 20–89 years), and 28.9% of patients were female. Most (89.0%) had chronic lymphocytic leukemia (CLL), and 279 had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Seventy-two patients were previously treated with ibrutinib; 165 (58.9%) had baseline hypertension at the time of acalabrutinib initiation, of which 57% were on at least 1 antihypertensive medication. Additional baseline characteristics are described in Table 1.

Incident hypertension

Over a median follow-up of 41 months (IQR 20–62 months; range 0–76 months), 59.2% developed new or worsened hypertension, utilizing a SBP cutoff of 130 mmHg (Fig. 1; Additional file 1: Table S1), of which 84.3% had at least probable association with acalabrutinib [23]. The mean increase in SBP was + 7.2 (19.7) mmHg, with a median time to maximum SBP increase of 6 months. A ≥ 10 mmHg increase in SBP from baseline was observed in 35% of patients, and a ≥ 20 mmHg increase was observed in 13.5% of patients (Additional file 1: Table S2). Among those without baseline hypertension, 62 patients (53.9%) developed new hypertension after acalabrutinib initiation, wherein the mean increase in SBP (SD) was 16.7 mmHg (24.2), with a median time to maximum SBP increase of 15 months. Within 1 year of follow-up, the mean maximum increase in SBP was 14.4 mmHg, with a median time to maximum increase in SBP of 6 months, in those with new hypertension. This included 82.3% (n = 51) who reached hypertension thresholds within 6 months of acalabrutinib initiation. In those with baseline hypertension, worsened hypertension was noted among 45.5% (n = 75), including 50.7% (n = 38) with an increase in CTCAE hypertension grade. Moreover, among those treated without intervening monoclonal antibody therapy (obinutuzumab, a known blood pressure depressant), the mean increase in SBP (SD) was 6.45 mmHg (20.0) and the mean peak increase in SBP was 10.1 mmHg, with a median time to maximum SBP increase of 6 months (Additional file 1: Table S3). In total, 9 (3.5%, excluding 20 with baseline high-grade hypertension) developed new high-grade (≥ 3) hypertension while on acalabrutinib, including 1.7% of those without baseline hypertension. No patients required dose reduction due to hypertension. One patient required hospitalization for worsened hypertension (and diastolic heart failure).

Fig. 1
figure 1

A. Change in mean blood pressure during acalabrutinib treatment over the 60-month study period; standard deviation represented by error bars. B. Cumulative incidence of new hypertension (HTN) across time following acalabrutinib initiation. C. Cumulative incidence of worsened HTN across time following acalabrutinib initiation

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In univariate analysis, BMI > 25, prior arrhythmia, and history of heart failure were associated with new or worsened hypertension (Additional file 1: Table S4). There was no relationship between acalabrutinib dose and new or worsened hypertension development. However, in multivariable modeling, Black ancestry [hazard ratio (HR) 4.35, 95% confidence interval (CI) 1.21–15.63; P = 0.024], prior AF (HR 1.63, 95% CI 1.06–2.49; P = 0.025), and BMI (HR 1.05, 95% CI 1.02–1.09; P = 0.005) remained associated with new or worsened hypertension (Table 2). These effects were consistent even after removing patients previously on ibrutinib to account for possible confounding of prior AF (Additional file 1: Table S5A). Among patients without baseline hypertension, Black ancestry and prior arrhythmias were significantly associated with development of new hypertension (Additional file 1: Table S5B); additionally, there was a trend of association between baseline SBP and new hypertension development (HR 1.75 across baseline SBP strata vs SBP ≥ 120 mmHg; P = 0.126). Among those with baseline hypertension, only age and BMI were associated with worsened hypertension development (Additional file 1: Table S5C).

Table 1 Baseline characteristics. The median duration of acalabrutinib use was 41.2 months
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Table 2 Multivariable predictors for the development of new or worsened hypertension (HTN) (n = 280)
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Effect of standard antihypertensive therapies

The initiation of antihypertensive therapy was required for 43 patients, including 10 without baseline hypertension. Over time, 17 required combination therapy for the management of hypertension after acalabrutinib initiation. The most common treatment was diuretics, followed by calcium channel blockers and beta-blockers. There was no difference in effect of any specific class on blood pressure control (Additional file 1: Table S6A-C). Yet, the initiation of combination therapy was associated with a –3.32 mmHg reduction in SBP over time (Additional file 1: Table S6D).

Relationship of new or worsened hypertension to major cardiovascular events

MACE were observed among 41 patients (14.6%), including 18.2% with new or worsened hypertension. This was compared to 11.2% with MACE among those without new or worsened hypertension after acalabrutinib initiation (Additional file 1: Table S7). Most events, including 62.1% of arrhythmias, were of probable or definite association with acalabrutinib [23]. AF was the most common cardiovascular complication during acalabrutinib use (8.2%), followed by ventricular arrhythmia (2.9%), SVT (2.5%), and heart failure (2.1%); 1 patient had sudden death. In those with MACE, 66.7% had at least two cardiac risk factors. There was no clear difference in MACE by new or worsened hypertension status in a multivariable model containing known predictors of MACE (HR 1.12, P = 0.751; Table 3; Additional file 1: Table S8A-B). However, the magnitude of early SBP increases within 1 year of acalabrutinib initiation related to the risk of subsequent AF (P < 0.001; Additional file 1: Figure S2), as well as MACE (P < 0.001; Fig. 2). For every 5 mmHg SBP increase, there was a 27% (0.27) increase in MACE risk (P < 0.001), and a 42% (0.42) increase in the risk for AF development (P < 0.001). Among those with new or worsened hypertension, there was no difference in MACE risk by antihypertensive initiation status. Further, in landmark analysis restricted to those free of disease progression with continued acalabrutinib use beyond 3 months, there was no difference in progression-free survival or mortality by new or worsened hypertension status (Additional file 1: Figure S3).

Table 3 Multivariable predictors of major adverse cardiovascular events (MACE) during acalabrutinib use.*
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Fig. 2
figure 2

A Cumulative incidence of major cardiovascular events (MACE) across time following acalabrutinib initiation. B. Risk of develo** MACE defined by hazard ratio (HR) stratified by peak systolic blood pressure (SBP) increase within 1 year of acalabrutinib initiation. Dotted line represents hazard ratio = 1. *Asterisks denote statistical tests that did not converge or strata with ≤ 3 patients

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Comparative incidence of hypertension with acalabrutinib

Moreover, in those without baseline hypertension, 24.4% developed new hypertension using older JNC-8 cutoffs for hypertension classification. Among those patients aged 20 to 69 years without a diagnosis of diabetes (n = 83), the cumulative incidence of at hypertension at 1 year was 20.5%. This translated into an observed new hypertension cumulative incidence of 205 per 1,000 person-years. Compared to the Framingham risk predicted rate of 24 per 1,000 person-years, this translated into an observed-to-expected ratio of 8.5 (P < 0.001; Fig. 3). Yet, when compared to the previously reported Framingham-adjusted new hypertension rate at 1 year of 312 per 1,000 person-years [11] (12.9 observed-to-expected ratio), this translated into a relative risk reduction of 34.1% for acalabrutinib vs. ibrutinib for incident hypertension (RR 0.66, P < 0.001; Additional file 1: Table S9).

Fig. 3
figure 3

A. Observed versus predicted cumulative incidence of new hypertension (HTN) rates at 1 year, including population and Framingham risk-adjusted rate for ibrutinib [11, 24]. Reflects the JNC-8 HTN cutoff of 140/90 mmHg, in comparison with established HTN prediction models.24 Subjects without known discussion of parenteal history of HTN were assigned a value of 1 (i.e., one of two parents with HTN) in the Framingham model B. Observed versus predicted cumulative incidence of new HTN, including incidence of grade 3 or higher HTN, at 0, 3, 6, 9, and 12 months

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Discussion

In this evaluation of the incidence, risk factors, and ramifications of hypertension after acalabrutinib initiation, nearly 50% of patients developed new or worsened hypertension within 1 year of treatment initiation. Outside of Black ancestry and BMI, there are no other factors associated with the development of incident acalabrutinib-related hypertension. Although the rate of hypertension was markedly lower than observed with ibrutinib, the adjusted incidence was still over eightfold higher than predicted at 1 year. This relationship remained even after accounting for age and the burden of traditional cardiovascular risks. In those with early SBP elevation, the rate of other MACE was elevated. Further, blood pressure elevation control frequently required combinational therapy. Nevertheless, no antihypertensive class clearly prevented worsening hypertension. Given the growing use of second-generation BTK inhibitors, and the lack of real-world data to inform their use, these data may have important ramifications on the interpretation and management of cardiovascular risk in patients treated with these emerging therapies.

The observation of increased hypertension with acalabrutinib adds to a growing body of evidence linking BTK inhibition with blood pressure modulation. In an evaluation of ibrutinib-treated patients, initiation of ibrutinib is associated with a 71% incidence of new hypertension after treatment initiation [11]. Similarly, in a separate multicenter evaluation, ibrutinib associated with a median increase of > 13 mmHg in SBP measures within months of treatment initiation [26]. In acalabrutinib-focused studies, secondary analyses suggest that up to 40% of patients may experience increase in hypertension grade or see new hypertension [4]. Although landmark trials, including the ACE-CL-001 and ELEVATE-RR trials, have attempted to evaluate the incidence of hypertension as a secondary outcome, due to the only more recent emergence of the relevance of hypertension with BTK inhibitor therapy, without untreated controls, the measures, timing, and implementation of contemporary blood pressure definitions were not well established [1, 11, 18, 27, 28]. Furthermore, due to potential confounding nature of comorbid risk factors, understanding the true effects of therapy has remained challenging [27]. Within this study, we observed that acalabrutinib treatment results in increased rate of incident hypertension, even after accounting for confounding traditional risk factors. The establishment of these effects provides a key basis for the assessment of the vascular effects of next-generation BTK inhibition among B cell patients treated with these emerging therapies.

Blood pressure elevation is often underappreciated clinically in patients presenting for ongoing anticancer therapies [28, 29]. Due to the confounding nature of blood pressure elevation in cancer populations, particularly at times of increased stress, potential fear of negative news, and necessary focus on potentially fatal disease control, blood pressure elevations may be less well recognized in clinical care settings. However, increasingly accelerated hypertension has been noted to contribute to the unanticipated higher burden of cardiovascular events among patients treated with BTK inhibitors and other anticancer therapies [11, 28]. Blood pressure increases appeared broader and more pronounced with acalabrutinib treatment in the ASCEND trial than the standard therapy arm [30]. This was also clearly observed in the ACE-CL-001 and ACE-CL-003 phase 1b/2 studies [1, 4]. Outside of the current evaluation, post-marketing evaluations of the effects of acalabrutinib or other next-generation BTK inhibitor therapies are largely unavailable. Given the potential for differential observations after clinical dissemination in more focused investigation, and the unintended but serious consequences of cardiotoxicity, enhanced surveillance may prove beneficial.

Although reasons for these observations are not clear, acalabrutinib has reduced inhibition of alternative kinases inclusive of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), and interleukin 2-inducible T cell kinase (ITK) in preclinical models compared to ibrutinib [1, 6,7,8]. Furthermore, in a recent preclinical AF model, acalabrutinib did not share activity with the C-terminal Src kinase (CSK), a pathway linked with AF in mice receiving ibrutinib therapy [15]. Conversely, as with ibrutinib, acalabrutinib may share indirect nitric oxide inhibition [31]. Despite differences in the degree of activation, downstream remodeling inclusive of vasoconstriction and replacement fibrosis have been postulated [11, 27]. These alterations have been recognized to drive disproportionate manifestations of cardiovascular disease in other populations [32,33,34]. However, with BTK inhibitors, elucidation of these pathways may require additional mechanistic and prospective studies.

Limitations

Several limitations should be acknowledged. Due to the retrospective nature of this study, and prevalent BTKi use, no cancer-specific control was available. Follow-up was non-uniform. Similarly, the approach and timing of blood pressure acquisition were non-uniform. While antihypertensives were frequently employed in those with higher elevation, the timing and decision to initiate antihypertensive therapy was at the discretion of treating clinicians. We could not fully determine the effect of antihypertensive therapies on MACE risk or blood pressure control due to variability in treatment regimens. Similarly, the selected class and dose of therapy was not predetermined. However, the low incidence of acalabrutinib discontinuation suggests at least some efficacy of combinational standard antihypertensive care. Although we adjusted for multiple factors, it is possible that the presence of cancer increases hypertension risk [27]. Moreover, some out-of-hospital cardiac events may have gone uncaptured, despite extensive search.

Conclusions

Patients treated with BTK inhibitors face an increased risk of cardiovascular sequelae. Treatment with acalabrutinib associates with significantly elevated risk of early onset hypertension, even after accounting for traditional risk factors. However, the degree of this hypertension is reduced compared to ibrutinib. Given the anticipated increase in acalabrutinib use, further studies evaluating the mechanisms and optimal management strategies for hypertension are needed.