Resolution of Ibrutinib-Associated Hypertension with Transition to Alternate Covalent Bruton's Tyrosine Kinase Inhibitor
Authors: Tomasulo Emily B. , Therwhanger Dylan , Chong Emeline R. , Hughes Mitchell E. , Fradley Michael G. , Schuster Stephen J. 
Published: December 2024

Background: Bruton's tyrosine kinase inhibitors (BTKi) are FDA-approved for the treatment of B-cell malignancies until disease progression or unacceptable toxicity. Ibrutinib (Ibr), the first-in-class covalent BTKi, is associated with cardiac adverse events (AEs) including hypertension (HTN), arrhythmias, heart failure, and sudden death. The real-world incidence of HTN on Ibr (34.8%, 33.2% &gt; grade 3) (Roeker et al. JAMA 2019) is significantly higher than that reported in clinical trials (19%, 8% &gt; grade 3) (Byrd et al. Blood 2019). The frequency of HTN with later generation covalent BTKis varies: acalabrutinib (Acala; 9.4%, 4.1% grade &gt;3) (Byrd et al. JCO 2021) and zanubrutinib (Zanu; 21.9%, 14.8% &gt; grade 3) (Brown et al. NEJM 2023). There are limited data on the outcomes of Ibr-associated emergent or exacerbated HTN following transition to an alternate covalent BTKi.
Methods: An electronic medical record search was performed of patients (pts) treated with Ibr at the University of Pennsylvania between January 1, 2013 and May 1, 2024 who had documented systolic blood pressure (SBP) &gt;120 mmHg and/or diastolic blood pressure (DBP) &gt;80 mmHg. Pts with a diagnosis of large B-cell lymphoma were excluded. BPs were extracted and median SBP and DBP were calculated for each pt at three time points: 1) pre-Ibr 2) on Ibr and 3) on subsequent covalent BTKi. Medical comorbidities and antihypertensive (aHTN) medications with doses were tabulated. HTN was defined as SBP ≥ 130 mmHg and/or DBP ≥ 80mmHg. The Wilcoxon signed rank test was used to analyze BP changes for each pt across BTKis.
Results: At data cutoff, 26/239 (10.9%) pts discontinued Ibr due to HTN (with or without additional cardiac AEs). Twenty-four patients had chronic lymphocytic leukemia and two had Waldenström's macroglobulinemia; median age was 64 (range, 38 - 77) and median number of prior treatments was 1 (range, 0 - 3). Prior to Ibr, 12/26 (46%) pts had preexisting HTN; among these patients, 11/12 (92%) were on aHTN medications (median aHTNs 1; range, 1 - 3). Of the 26 pts who discontinued Ibr, 9 (34.6%) developed atrial fibrillation and 13 (50%) developed any grade HTN; among pts who discontinued Ibr solely due to HTN, 6/13 (46.2%) had treatment-emergent HTN and 7/13 (53.9%) had treatment-exacerbated HTN. Regardless of antecedent hypertension or aHTN therapy, Ibr was preferentially associated with SBP elevation. Pts who discontinued Ibr and started Acala (n=15) had a reduction of median SBP from 137 (IQR 131 - 147) on Ibr to 125 (IQR 118 - 131) on Acala (p= 0.016). Resolution of systolic HTN after transition from Ibr to Acala coincided with a reduction in number of aHTN agents from a median of 1.5 (0-4) to 1 (0-3), respectively, and a 34% mean aHTN dose reduction. Among the 15 pts on Acala as second BTKi, 2 developed AEs and were transitioned to Zanu; 7 pts transitioned directly from Ibr to Zanu. Treatment with Zanu (n=9) resulted in a reduction of median SBP from 140 (130 - 145) on Ibr to 124 (122 - 132) on Zanu (p=0.0391). While transition to Acala was associated with a reduction in both number and dose of aHTNs, pts transitioned to Zanu had comparable number of aHTNs, albeit a mean dose reduction of 20.3%.
Conclusion: Irrespective of baseline HTN and aHTN medications, Ibr is associated with a preferential increase in SBP; perhaps related to off-target kinase effects. Transition from Ibr to either Acala or Zanu was associated with resolution of systolic HTN with concomitant reduction in aHTN agents (Acala only) and doses (Acala and Zanu). Further research is needed to elucidate the mechanism(s) of systolic HTN on BTKis and to define optimal pharmacologic therapy.