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Comparative arrhythmia patterns among patients on tyrosine kinase inhibitors

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Journal of Interventional Cardiac Electrophysiology Aims and scope Submit manuscript

Abstract

Background

Tyrosine kinase inhibitors (TKIs) are widely used in the treatment of hematologic malignancies. Limited studies have shown an association between treatment-limiting arrhythmias and TKI, particularly ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. We sought to comprehensively assess the arrhythmia burden in patients receiving ibrutinib vs non-BTK TKI vs non-TKI therapies.

Methods

We performed a retrospective analysis of consecutive patients who received long-term cardiac event monitors while on ibrutinib, non-BTK TKIs, or non-TKI therapy for a hematologic malignancy between 2014 and 2022.

Results

One hundred ninety-three patients with hematologic malignancies were included (ibrutinib = 72, non-BTK TKI = 46, non-TKI therapy = 75). The average duration of TKI therapy was 32 months in the ibrutinib group vs 64 months in the non-BTK TKI group (p = 0.003). The ibrutinib group had a higher prevalence of atrial fibrillation (n = 32 [44%]) compared to the non-BTK TKI (n = 7 [15%], p = 0.001) and non-TKI (n = 15 [20%], p = 0.002) groups. Similarly, the prevalence of non-sustained ventricular tachycardia was higher in the ibrutinib group (n = 31, 43%) than the non-BTK TKI (n = 8 [17%], p = 0.004) and non-TKI groups (n = 20 [27%], p = 0.04). TKI therapy was held in 25% (n = 18) of patients on ibrutinib vs 4% (n = 2) on non-BTK TKIs (p = 0.005) secondary to arrhythmias.

Conclusions

In this large retrospective analysis of patients with hematologic malignancies, patients receiving ibrutinib had a higher prevalence of atrial and ventricular arrhythmias compared to those receiving other TKI, with a higher rate of treatment interruption due to arrhythmias.

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Data Availability

Data available upon request.

References

  1. Ferguson FM, Gray NS. Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018;17:353–77.

    Article  CAS  PubMed  Google Scholar 

  2. Lee C-S, Rattu MA, Kim SS. A review of a novel, Bruton’s tyrosine kinase inhibitor, ibrutinib. J Oncol Pharm Pract. 2016;1:92–104. https://doi.org/10.1177/1078155214561281.

    Article  CAS  Google Scholar 

  3. Ganatra S, Sharma A, Shah S, Chaudhry GM, Martin DT, Neilan TG, et al. Ibrutinib-associated atrial fibrillation JACC Clin Electrophysiol. 2018;12:1491–500. https://doi.org/10.1016/j.jacep.2018.06.004.

    Article  Google Scholar 

  4. Wiczer TE, Levine LB, Brumbaugh J, Coggins J, Zhao Q, Ruppert AS, et al. Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving ibrutinib. Blood Adv. 2017;1:1739–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lampson B, Yu L, Barrientos J, Jacobsen E, Banerji V, Jones J, et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Clin Lymphoma Myeloma Leuk. 2016;129(18):2581–4. https://doi.org/10.1016/j.clml.2016.07.075.

    Article  Google Scholar 

  6. Salem J-E, Manouchehri A, Bretagne M, Lebrun-Vignes B, Groarke JD, Johnson DB, et al. Cardiovascular toxicities associated with ibrutinib. J Am Coll Cardiol. 2019;74:1667–78.

    Article  CAS  PubMed  Google Scholar 

  7. Guha A, Derbala MH, Zhao Q, Wiczer TE, Woyach JA, Byrd JC, et al. Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies. J Am Coll Cardiol. 2018;72:697–8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Fazal M, Wei C, Chuy KL, Hussain K, Gomez SE, Ba SS, et al. Tyrosine kinase inhibitor-associated ventricular arrhythmias: a case series and review of literature. J Interv Card Electrophysiol. 2022. https://doi.org/10.1007/s10840-022-01400-z.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Baptiste F, Cautela J, Ancedy Y, Resseguier N, Aurran T, Farnault L, et al. High incidence of atrial fibrillation in patients treated with ibrutinib. Open Heart. 2019;6:e001049.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17:200–11.

    Article  CAS  PubMed  Google Scholar 

  11. Fradley MG, Gliksman M, Emole J, Viganego F, Rhea I, Welter-Frost A, et al. Rates and risk of atrial arrhythmias in patients treated with ibrutinib compared with cytotoxic chemotherapy. Am J Card. 2019;124(4):539–44. https://doi.org/10.1016/j.amjcard.2019.05.029.

    Article  PubMed  Google Scholar 

  12. Munir T, Brown JR, O’Brien S, Barrientos JC, Barr PM, Reddy NM, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94:1353–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–23.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dong R, Yan Y, Zeng X, Lin N, Tan B. Ibrutinib-associated cardiotoxicity: from the pharmaceutical to the clinical. Drug Des Devel Ther. 2022;16:3225–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80–7.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mato AR, Nabhan C, Barr PM, Ujjani CS, Hill BT, Lamanna N, et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood. 2016;128:2199–205.

    Article  CAS  PubMed  Google Scholar 

  19. Prashar A, Ilsar R, Roncolato F, Hopkins A. Recurrent ventricular fibrillation with different tyrosine kinase inhibitors for chronic myeloid leukemia. HeartRhythm Case Rep. 2020;6:770–3.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cheng M, Yang F, Liu J, Yang D, Zhang S, Yu Y, et al. Tyrosine kinase inhibitors-induced arrhythmias: from molecular mechanisms, pharmacokinetics to therapeutic strategies. Front Cardiovasc Med. 2021;8:758010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Marine JE. Nonsustained ventricular tachycardia in the normal heart: risk stratification and management. Card Electrophysiol Clin. 2016;8:525–43.

    Article  PubMed  Google Scholar 

  22. Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388:319–32.

    Article  CAS  PubMed  Google Scholar 

  23. Essa H, Lodhi T, Dobson R, Wright D, Lip GY. How to manage atrial fibrillation secondary to ibrutinib. JACC Cardio Oncol. 2021;3:140–4.

    Article  Google Scholar 

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Funding

This work is supported by National Institutes of Health grants K08 HL148540 (J.W.R), K08 HL153798 (P.C.), R01 HL83359, R01 HL149134, R01 HL162260 (S.M.N.), K23 HL145017 (T.B.), K23 HL166977, and American Heart Association Career Development Awards (A.J.R, J.W.R., and P.C.).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Stanford University, Stanford, CA, USA

    Chen Wei & Sofia Elena Gomez

  2. Department of Cardiovascular Medicine, Stanford University, 453 Quarry Road, Room 334C, Stanford, CA, 94304, USA

    Muhammad Fazal, Ridhima Kapoor, Albert J. Rogers, Sanjiv M. Narayan, Paul J. Wang, Ronald M. Witteles, Alexander C. Perino, Paul Cheng & Tina Baykaner

  3. Department of Internal Medicine, Kaiser Permanente Santa Clara Homestead Medical Center, Santa Clara, CA, USA

    Alexander Loh

  4. Stanford University School of Medicine, Stanford University, Stanford, CA, USA

    Shayena Shah

  5. Division of Cardiology, Department of Medicine, City of Hope Comprehensive Medical Center, Duarte, CA, USA

    June-Wha Rhee

Authors
  1. Chen Wei
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  2. Muhammad Fazal
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Contributions

T.B. and J.W.R. conceived and designed the study. C.W., M.F., and A.L. collected patient data. C.W., M.F., and A.L. analyzed the data. R.K., S.E.G., S.S., A.J.R., S.M.N., P.W., R.M.W., A.C.P., and P.C. contributed to design the study and provided critical input on the manuscript. C.W., M.F., A.L., T.B., and J.W.R. wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to June-Wha Rhee or Tina Baykaner.

Ethics declarations

Ethical approval

The retrospective study protocol was approved by the Institutional Review Board of Stanford University. Approval number IRB-59813.

Informed consent

Not applicable.

Conflict of interest

The authors declare no competing interests. Chen Wei, MD: None. Muhammad Fazal, MD: None. Alexander Loh: None. Ridhima Kapoor, MD: None. Sofia Gomez, MD: None. Shayena Shah, BA: None. Albert J. Rogers: National Institutes of Health grant K23 HL166977 and American Heart Association.Sanjiv M. Narayan, MD, PhD: Consulting fees from Abbott, TDK Incorporated and Beyond Limits.ai. Paul J. Wang, MD: None. Ronald Witteles, MD: Consulting fees from Pfizer, Alnylam, Eidos, Ionis, NovoNordisk, Intelia, and Janssen unrelated to this work. Alexander C. Perino: Research support from the American Heart Association, Pfizer Inc and Bristol Myers Squibb. Consultant for Abbott, Pfizer Inc and Bristol Myers Squibb.Paul Cheng, MD: National Institutes of Health grant K08 HL153798. T. Baykaner: Speaker and consultant fees from Biotronik, Medtronic and PaceMate unrelated to this work. June-Wha Rhee, MD: Sponsored research grant from Pfizer unrelated to this work.

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Chen Wei and Muhammad Fazal are co-first authors.

June-Wha Rhee and Tina Baykaner are co-correspondents.

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Wei, C., Fazal, M., Loh, A. et al. Comparative arrhythmia patterns among patients on tyrosine kinase inhibitors. J Interv Card Electrophysiol 67, 111–118 (2024). https://doi.org/10.1007/s10840-023-01575-z

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  • DOI: https://doi.org/10.1007/s10840-023-01575-z

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