BTK inhibitors approved in Canada for CLL: Strategies for adverse event management

Nicole Dunse, Irene Hibbert, Sarah Doucette, Anna Christofides

Abstract


Bruton tyrosine kinase (BTK) inhibitors are an effective therapy for the treatment of chronic lymphocytic leukemia (CLL), particularly in patients who present with high-risk features. The first-in-class BTK inhibitor, ibrutinib, is generally tolerable. However, unique adverse events (AEs) of concern, including cardiovascular toxicity and bleeding have been observed, prompting the development of next-generation inhibitors, such as acalabrutinib, with an improved safety profile. Nevertheless, as BTK inhibitors are given as a continuous therapy, and therapy interruptions have been associated with decreased efficacy, appropriate management of AEs related to any agent within this class is critical for optimizing outcomes. This paper will serve as a learning resource for Canadian oncology nurses on the BTK inhibitors currently approved in Canada for the treatment of CLL. It includes a description of the unique safety profiles of the BTK inhibitors and suggests strategies for monitoring and managing related AEs.


Full Text:

PDF

References


Abramson, J. (2019). How I manage adverse events associated with BTK Inhibitors. Clinical Care Options Oncology. https://www.clinicaloptions.com/oncology/programs/btk-inhibitor-ae-management/clinicalthought/ct1/page-1

Advani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., … Fowler, N. H. (2013). Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-Cell malignancies. Journal of Clinical Oncology, 31(1), 88-94. https://doi.org/10.1200/jco.2012.42.7906

Ahn, I. E., Farooqui, M. Z. H., Tian, X., Valdez, J., Sun, C., Soto, S., … Wiestner, A. (2018). Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood, 131(21), 2357-2366. https://doi.org/10.1182/blood-2017-12-820910

American Heart Association. (2016a). What are the symptoms of atrial fibrillation (Afib or AF)? https://www.heart.org/en/health-topics/atrial-fibrillation/what-are-the-symptoms-of-atrial-fibrillation-afib-or-af

American Heart Association. (2016b). What is high blood pressure? https://www.heart.org/en/health-topics/high-blood-pressure/the-facts-about-high-blood-pressure/what-is-high-blood-pressure

AstraZeneca Canada Inc. (2019). Product monograph including patient medication information: PrCALQUENCE®. https://www.astrazeneca.ca/content/dam/az-ca/downloads/productinformation/calquence-product-monograph-en.pdf

Awan, F. T., Schuh, A., Brown, J. R., Furman, R. R., Pagel, J. M., Hillmen, P., … Byrd, J. C. (2019). Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Advances, 3(9), 1553-1562. https://doi.org/10.1182/bloodadvances.2018030007

Badillo, M., Nava, D., Rosa, M., Chen, W., Guerrero, M., & Wang, M. (2020). Acalabrutinib: Managing adverse events and improving adherence in patients with mantle cell lymphoma. Clin J Oncol Nurs, 24(4), 392-398. https://doi.org/10.1188/20.Cjon.392-398

Banerji, V., Aw, A., Robinson, S., Doucette, S., Christofides, A., & Sehn, L. H. (2020). Bruton Tyrosine Kinase Inhibitors for the frontline treatment of chronic lymphocytic leukemia. Current Oncology, 27(6), 645-655. https://doi.org/10.3747/co.27.6795

Barr, P. M., Brown, J. R., Hillmen, P., O’Brien, S., Barrientos, J. C., Reddy, N. M., … Byrd, J. C. (2017). Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood, 129(19), 2612-2615. https://doi.org/10.1182/blood-2016-12-737346

Barr, P. M., Robak, T., Owen, C., Tedeschi, A., Bairey, O., Bartlett, N. L., … Ghia, P. (2018). Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: Extended phase 3 results from RESONATE-2. Haematologica, 103(9), 1502-1510. https://doi.org/10.3324/haematol.2018.192328

Bitar, C., Farooqui, M. Z. H., Valdez, J., Saba, N. S., Soto, S., Bray, A., … Cowen, E. W. (2016). Hair and nail changes during long-term therapy with ibrutinib for chronic lymphocytic leukemia. Jama Dermatology, 152(6), 698-701. https://doi.org/10.1001/jamadermatol.2016.0225

Bond, D. A., & Woyach, J. A. (2019). Targeting BTK in CLL: Beyond ibrutinib. Current Hematologic Malignancy Reports, 14(3), 197-205. https://doi.org/10.1007/s11899-019-00512-0

Burger, J. A., Barr, P. M., Robak, T., Owen, C., Ghia, P., Tedeschi, A., … Kipps, T. J. (2019). Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. https://doi.org/10.1038/s41375-019-0602-x

Byrd, J. C., Harrington, B., O’Brien, S., Jones, J. A., Schuh, A., Devereux, S., … Furman, R. R. (2016). Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. New England Journal of Medicine, 374(4), 323-332. https://doi.org/10.1056/nejmoa1509981

Byrd, J. C., Hillmen, P., Ghia, P., Kater, A. P., Chanan-Khan, A. A. A., Furman, R. R., … Jurczak, W. (2021). First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. Journal of Clinical Oncology, 39(Suppl 15), abstr 7500. https://doi.org/10.1200/JCO.2021.39.15_suppl.7500

Byrd, J. C., Hillmen, P., O’Brien, S. M., Barrientos, J. C., Reddy, N. M., Coutre, S., … Brown, J. R. (2017). Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study. Journal of Clinical Oncology, 35(Suppl 15), 7510-7510. https://doi.org/10.1200/JCO.2017.35.15_suppl.7510

Canadian Cancer Society. (n.d.-a). Diarrhea. https://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/managing-side-effects/diarrhea/?region=on

Canadian Cancer Society. (n.d.-b). Managing side effects: Fatigue. https://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/managing-side-effects/fatigue/?region=on

Chanan-Khan, A., Cramer, P., Demirkan, F., Fraser, G., Silva, R. S., Grosicki, S., … Investigators, H. (2016). 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 Oncology, 17(2), 200-211. https://doi.org/10.1016/s1470-2045(15)00465-9

Cheung, M. C., & Amitai, I. (2020). Real-world outcomes of patients treated with single-agent ibrutinib for chronic lymphocytic leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A systematic review and meta-analysis. Blood, 136(Suppl 1), 14-14. https://doi.org/10.1182/blood-2020-140577

Coutre, S. E., Byrd, J. C., Hillmen, P., Barrientos, J. C., Barr, P. M., Devereux, S., … O’Brien, S. M. (2019). Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Advances, 3(12), 1799-1807. https://doi.org/10.1182/bloodadvances.2018028761

De Weerdt, I., Koopmans, S. M., Kater, A. P., & Van Gelder, M. (2017). Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica, 102(10), 1629-1639. https://doi.org/10.3324/haematol.2017.164103

Dickerson, T., Wiczer, T., Waller, A., Philippon, J., Porter, K., Haddad, D., … Addison, D. (2019). Hypertension and incident cardiovascular events following ibrutinib initiation. Blood, 134(22), 1919-1928. https://doi.org/10.1182/blood.2019000840

Ellison, L. F. (2016). Increasing survival from leukemia among adolescents and adults in Canada: A closer look. Health Rep, 27(7), 19-26.

Estupiñán, H. Y., Berglöf, A., Zain, R., & Smith, C. I. E. (2021). Comparative analysis of BTK Inhibitors and mechanisms underlying adverse effects. Frontiers in Cell and Developmental Biology, 9. https://doi.org/10.3389/fcell.2021.630942

Ghia, P., Pluta, A., Wach, M., Lysak, D., Kozak, T., Simkovic, M., … Jurczak, W. (2020). ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. Journal of Clinical Oncology, 38(25), 2849-2861. https://doi.org/10.1200/jco.19.03355

Hallek, M. (2017). Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. American Journal of Hematology, 92(9), 946-965. https://doi.org/https://doi.org/10.1002/ajh.24826

Hallek, M., Cheson, B. D., Catovsky, D., Caligaris-Cappio, F., Dighiero, G., Döhner, H., … Kipps, T. J. (2018). iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood, 131(25), 2745-2760. https://doi.org/https://doi.org/10.1182/blood-2017-09-806398

Heart and Stroke Foundation of Canada. (n.d.). Atrial fibrillation. https://www.heartandstroke.ca/heart-disease/conditions/atrial-fibrillation#:~:text=Atrial%20fibrillation%20

Iberri, D. J., Kwong, B. Y., Stevens, L. A., Coutre, S. E., Kim, J., Sabile, J. M., & Advani, R. H. (2018). Ibrutinib-associated rash: A single-centre experience of clinicopathological features and management. Br J Haematol, 180(1), 164-166. https://doi.org/10.1111/bjh.14302

Janssen Inc. (2021). Product monograph including patient medication information:PrIMBRUVICA®. https://www.janssen.com/canada/sites/www_janssen_com_canada/files/prod_files/live/imbruvica_cpm.pdf

Johnson, A., & Burns, B. (2020). Hemorrhage. in StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK542273/

Kaptein, A., de Bruin, G., Emmelot-van Hoek, M., van de Kar, B., de Jong, A., Gulrajani, M., … Barf, T. (2018). Potency and selectivity of BTK Inhibitors in clinical development for B-Cell malignancies. Blood, 132(Suppl 1), 1871-1871. https://doi.org/10.1182/blood-2018-99-109973

Lampson, B. L., Yu, L., Glynn, R. J., Barrientos, J. C., Jacobsen, E. D., Banerji, V., … Brown, J. R. (2017). Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood, 129(18), 2581-2584. https://doi.org/10.1182/blood-2016-10-742437

Lipsky, A. H., Farooqui, M. Z. H., Tian, X., Martyr, S., Cullinane, A. M., Nghiem, K., … Wiestner, A. (2015). Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib [Article]. Haematologica, 100(12), 1571-1578. https://doi.org/10.3324/haematol.2015.126672

Lipsky, A. H., & Lamanna, N. (2020). Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology, 2020(1), 336-345. https://doi.org/10.1182/hematology.2020000118

Mato, A. R., Nabhan, C., Thompson, M. C., Lamanna, N., Brander, D. M., Hill, B., … Ujjani, C. S. (2018). Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: A real-world analysis. Haematologica, 103(5), 874-879. https://doi.org/10.3324/haematol.2017.182907

Milne, K., Sturrock, B., & Chevassut, T. (2020). Chronic lymphocytic leukaemia in 2020: The future has arrived. Current Oncology Reports, 22(4). https://doi.org/10.1007/s11912-020-0893-0

Mock, J., Kunk, P. R., Palkimas, S., Sen, J. M., Devitt, M., Horton, B., … Maitland, H. (2018). Risk of major bleeding with Ibrutinib. Clinical Lymphoma Myeloma & Leukemia, 18(11), 755-761. https://doi.org/10.1016/j.clml.2018.07.287

Moreno, C., Greil, R., Demirkan, F., Tedeschi, A., Anz, B., Larratt, L., … Flinn, I. W. (2019). Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): A multicentre, randomised, open-label, phase 3 trial. The Lancet Oncology, 20(1), 43-56. https://doi.org/10.1016/s1470-2045(18)30788-5

National Cancer Institute. (2017). Common terminology criteria for adverse events (CTCAE) Version 5.0 https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf

National Cancer Institute. (2018). Bleeding and bruising (Thrombocytopenia) and cancer treatment. https://www.cancer.gov/about-cancer/treatment/side-effects/bleeding-bruising

National Cancer Institute. (2019). Skin and nail changes during cancer treatment. https://www.cancer.gov/about-cancer/treatment/side-effects/skin-nail-changes

Niiro, H., & Clark, E. A. (2002). Regulation of B-cell fate by antigen-receptor signals. Nature Reviews Immunology, 2(12), 945-956. https://doi.org/10.1038/nri955

Paydas, S. (2019). Management of adverse effects/toxicity of ibrutinib. Critical Reviews in Oncology/Hematology, 136, 56-63. https://doi.org/10.1016/j.critrevonc.2019.02.001

Rhodes, J. M., Lore, V. A., Mato, A. R., Chong, E. A., Barrientos, J. C., Gerson, J. N., … Schuster, S. J. (2020). Ibrutinib-associated arthralgias/myalgias in patients with chronic lymphocytic leukemia: Incidence and impact on clinical outcomes. Clinical Lymphoma Myeloma and Leukemia, 20(7), 438-444.e431. https://doi.org/10.1016/j.clml.2020.02.001

Rozovski, U., Harris, D. M., Li, P., Liu, Z. M., Jain, P., Ferrajoli, A., … Estrov, Z. (2018). Ibrutinib inhibits free fatty acid metabolism in chronic lymphocytic leukemia. Leukemia & Lymphoma, 59(11), 2686-2691. https://doi.org/10.1080/10428194.2018.1439167

Ruddy, K., Mayer, E., & Partridge, A. (2009). Patient adherence and persistence with oral anticancer treatment. CA: A Cancer Journal for Clinicians, 59(1), 56-66. https://doi.org/10.3322/caac.20004

Shanafelt, T. D., Wang, X. V., Kay, N. E., Hanson, C. A., O’Brien, S., Barrientos, J., … Tallman, M. (2019). Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. New England Journal of Medicine, 381(5), 432-443. https://doi.org/10.1056/nejmoa1817073

Sharman, J. P., Egyed, M., Jurczak, W., Skarbnik, A., Pagel, J. M., Flinn, I. W., … Byrd, J. C. (2020). Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): A randomised, controlled, phase 3 trial. The Lancet, 395(10232), 1278-1291. https://doi.org/10.1016/s0140-6736(20)30262-2

Sibaud, V., Beylot-Barry, M., Protin, C., Vigarios, E., Recher, C., & Ysebaert, L. (2020). Dermatological toxicities of Bruton’s Tyrosine Kinase Inhibitors. American Journal of Clinical Dermatology, 21(6), 799-812. https://doi.org/10.1007/s40257-020-00535-x

Statistics Canada. (2021). Number and rates of new cases of primary cancer, by cancer type, age group and sex [Table 13-10-0111-01] https://doi.org/https://doi.org/10.25318/1310011101-eng

Stephens, D. M., & Byrd, J. C. (2019). How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood, 133(12), 1298-1307. https://doi.org/10.1182/blood-2018-11-846808

Taghavi, S., & Askari, R. (2020). Hypovolemic shock. https://www.ncbi.nlm.nih.gov/books/NBK513297/. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK513297/

Woyach, J. A., Ruppert, A. S., Heerema, N. A., Zhao, W., Booth, A. M., Ding, W., … Byrd, J. C. (2018). Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. New England Journal of Medicine, 379(26), 2517-2528. https://doi.org/10.1056/nejmoa1812836


Refbacks

  • There are currently no refbacks.


Bookmark and Share