Introduction: Bruton tyrosine kinase inhibitors (BTKi) are highly efficacious oral agents FDA-approved for treatment of specific B-cell malignancies. BTKi are generally administered until disease progression, intolerable toxicity, or death. The emergence of cardiovascular adverse events (CVAE) including hypertension (HTN), arrhythmias, heart failure, and sudden death have limited the use of ibrutinib (Ibr), the first-in-class BTKi FDA-approved in 2013. Hypertension (HTN) is a frequent and cumulative toxicity of Ibr that is associated with increased risk of major adverse cardiac events. Alternate covalent BTKi (acalabrutinib, zanubrutinib) and non-covalent BTKi (pirtobrutinib) have lower rates of CVAE in clinical trials compared with Ibr. The objective of this study was to analyze the real-world incidence of HTN and CVAE in patients (pts) on Ibr and the outcome of pts with new or worsening HTN on Ibr who were then transitioned to an alternate BTKi.

Methods: We conducted a retrospective electronic medical record review of pts with hematologic malignancies treated with Ibr from January 2013 to July 2024 at the University of Pennsylvania. Blood pressure (BP), cardiovascular medications, comorbidities, and CVAE were analyzed prior to Ibr (baseline), while on Ibr, and while on subsequent BTKi (acalabrutinib, zanubrutinib, or pirtobrutinib). Eligible pts had at least 3 BP measurements available during each of the following periods: 1) within 12 months of Ibr initiation; 2) while on Ibr; and 3) while on subsequent BTKi. All available BP values were used to calculate medians and means for each therapy period. HTN was defined as elevated systolic BP (SBP) ≥130 and/or diastolic BP (DBP) ≥80 on more than one occasion with physician confirmation of the diagnosis. Worsening HTN was defined as pts with antecedent HTN with an increase in the number or doses of prescribed antihypertensives. Graphpad/R 4.4.0 were used for statistical analysis.

Results: A total of 114 pts received Ibr for 408.7 patient-years and 77 (68%) of pts had CLL. The median age was 67 (range 27-86) and 81 (71%) pts were men. On Ibr, 109 (96%) pts had systolic HTN and 100 (88%) had diastolic HTN. Across all BTKi, 74 (65%) pts had a CVAE. CVAE led to Ibr discontinuation in 58 (51.5%) pts, including HTN (n = 20, 18%), atrial fibrillation (n = 25, 22%), other arrhythmia (n = 1, 0.9%), palpitations (n = 2, 1.8%) and hemorrhage (n = 10, 8.8%). Among all pts on Ibr, 67 (59%) had either new onset HTN (n = 49, 43%) or developed worsening HTN with an increase in anti-HTN medications (n = 18, 16%). The median time on Ibr to first elevated SBP and maximum SBP were 32 (95% CI: 24 – 49) and 342 (95% CI: 229 – 604) days, respectively. The median time on Ibr to first elevated DBP and maximum DBP were 114 (95% CI: 83 –199) and 335 (95% CI: 250 – 465) days, respectively. Among the 109 pts with HTN on Ibr, transition to acalabrutinib (n = 67, 61%) or zanubrutinib (n = 33, 20%) resulted in a mean reduction in SBP of -9 mm/Hg (95%CI: -13 to -5.1) and -6 mm/Hg (95%CI: -11 to -0.8), respectively, without a change in number of antihypertensive medications. There were no observed differences in SBP, DBP, or the number of anti-HTN medications among pts with HTN on Ibr who transitioned to pirtobrutinib (n = 9, 8%). Among pts with HTN on Ibr, 45 (41.3%) had resolution of HTN with a median time to resolution (mTTR) of 2,277 days (95% CI: 1,996 – 2,463), although this time estimate is biased by infrequent follow-up. Among 55 pts with documented HTN on Ibr who transitioned to acalabrutinib, 20 (36.4%) had resolution of HTN with mTTR of 1,463 days (95% CI: 976 – NE). Among pts with documented HTN on Ibr who transitioned to zanubrutinib (n = 26) and pirtobrutinib (n = 8), HTN resolved in 8 (30.8%) and 2 (25%) with mTTRs of 683 (95%CI: 606 – NE) and NR (95%CI: 158 – NE) days, respectively.

Conclusion: BTKi are associated with increased risk of CVAE; 43% of pts on Ibr developed new onset HTN and 52% of pts discontinued Ibr due to a CVAE. Among pts with HTN on Ibr, transition to alternate covalent BTKi was associated with a reduction in mean SBP as well as resolution of HTN, in some patients, without an increase in number or dose of antihypertensive medications. Despite the development of HTN on Ibr, BP can improve after replacing Ibr with an alternate BTKi.

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2025
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