Management of Bruton Tyrosine Kinase Inhibitor–Associated Toxicities
Atrial fibrillation, bleeding, infection, and other adverse events may occur with this therapy.
Inhibition of bruton tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with B-cell malignancies. By targeting BTK, a critical kinase in proximal B-cell receptor (BCR) signaling, this class of small molecule inhibitors impairs BCR signaling and activation of NF-kB and inhibits cell proliferation and migration.1
Ibrutinib (Imbruvica; Pharmacyclics and Janssen) was the first effective and selective BTK inhibitor approved by the FDA as a breakthrough therapy in 2013 for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Its approval introduced the option of chemotherapy-free treatment for this patient population. Since then, ibrutinib has gained approval in other B-cell malignancies, including mantle cell lymphoma (MCL), Waldenstr m macroglobulinemia, and marginal zone lymphoma.2
Second-generation BTK inhibitor acalabrutinib (Calquence; AstraZeneca), with reduced off-target effects, was approved in 2017 and 2019 for the treatment of MCL and CLL/SLL, respectively.3 Zanubrutinib (Brukinsa; BeiGene), another second-generation BTK inhibitor, was approved in 2019 for the management of relapsed/refractory MCL.4
All 3 approved BTK inhibitors act via irreversible covalent binding to C481, found in the adenosine triphosphate–binding pocket of BTK. Mutations in the C481 binding site are known to cause clinical resistance to irreversible BTK inhibition. Third-generation BTK inhibitors currently in clinical studies exhibit reversible noncovalent binding to BTK. These BTK inhibitors act independently of covalent binding to C481 and can achieve target inhibition of both wild-type and C481S-mutated BTK. Therefore, they may overcome resistance mediated by this mutation.5,6
Toxicities and management of adverse events (AEs) arise throughout therapy with BTK inhibitors. The following toxicities and AEs focus on the 2 approved agents in CLL/SLL.
Development of atrial fibrillation (AF) has been the most common cause leading to discontinuation of ibrutinib. Male gender, aged 65 years and older, history of valvular heart disease, and hypertension at the time of diagnosis have been identified as independent risk factors for de novo AF. AF occurs initially in about 6% of patients on ibrutinib, increasing to 10% to 15% over 2 years.7,8 In comparison, the risk of AF in patients on acalabrutinib is slightly lower, ranging from 3.6% to 6%.9,10
For patients with a long history of poorly controlled AF, alternative treatment such as a BCL2 inhibitor may be preferred. For patients with limited risk factors (CHA2DS2-VASc score of 0-1), BTK inhibitors may be reinitiated at the prior dose once symptoms have resolved to baseline. For patients with 2 or more risk factors, management is clinician dependent. Discontinuation of a BTK inhibitor and anticoagulation vs resuming therapy at previous or reduced dose have both been done in practice.11
A β-blocker is preferred over a nondihydropyridine calcium channel blocker (eg, verapamil and diltiazem) for the management of AF due to lack of drug interaction with BTK inhibitors. Anticoagulation with either a direct oral anticoagulant or enoxaparin is preferred for patients with higher CHA2DS2-VASc scores. Combination of a BTK inhibitor and a vitamin K antagonist is discouraged because of fatal subdural hematoma reported in clinical study.11
Minor bleeding such as low-grade ecchymoses and petechiae occurred in up to two-thirds of patients on ibrutinib. Major bleeding occurred less frequently, in 2% to 9% of patients on ibrutinib.7,8 In contrast, major bleeding was seen in only 2% of patients on acalabrutinib monotherapy, with minor bleeding observed in 37% of patients. 9,10 Bruising, commonly seen with BTK inhibitors, does not confer an increased risk of major hemorrhage, and therapy can safely continue without interruption.
BTK inhibitors should be held for either 3 days for a minor procedure or 7 days for a major procedure, both before and after, because of the increased periprocedural bleeding risk. For minor bleeding, holding ibrutinib results in the resolution of bleeding tendency in 2 to 3 days. For severe bleeding, platelet transfusions can be given when appropriate regardless of platelet count. The risk of bleeding increases when patients are on concurrent anticoagulation and antiplatelet therapy. Acalabrutinib may be preferred over ibrutinib for people on dual antiplatelet agents or needing both anticoagulant and antiplatelet therapy.12
Infection of any grade occurred in more than 50% of patients on BTK inhibitors, particularly during the initial treatment period. Pneumonia was the most common infectious complication, occurring in up to 12% of patients. Recent reviews have also highlighted the prevalence of opportunistic infections, including pneumocystis jirovecii (PJP) and aspergillus infection in patients on BTK inhibitors.13 Patients with relapsed/refractory disease, heavily pretreated, and with a known history of infection are at a higher risk for developing infectious complications. CLL guidelines do not specifically address the role of PJP prophylaxis, and practices vary across institutions. However, patients who are at higher risk should consider PJP prophylaxis. Varicella-zoster virus (VZV) reactivation has also been identified while a patient is on BTK inhibitors, and VZV prophylaxis may be appropriate in patients with prior infections.11
Other AEs may occur with BTK inhibitors (see TABLE11,12).
Given the impressive efficacy and activity of BTK inhibitors in the treatment of newly diagnosed and relapsed/refractory CLL, it is vital that the care team become familiar with the management of BTK inhibitor–emergent toxicities.
Shan Li O'Connor, PharmD, BCOP, until recently was a hematology/oncology clinical pharmacist for Seattle Cancer Care Alliance at Overlake in Bellevue, Washington.
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2. Imbruvica. Prescribing information. Pharmacyclics and Janssen; 2019. Accessed May 2021.
3. Calquence. Prescribing information. AstraZeneca; 2019.
4. Brukinsa. Prescribing information. BeiGene; 2019. https://www.brukinsa.com/prescribing-information.pdf
5. Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443. doi:10.1200/JCO.2016.70.2282
6. Wen T, Wang J, Shi Y, et al. Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances. Leukemia 2021;35(2):312–332. doi:10.1038/s41375-020-01072-6
7. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. doi:10.1056/NEJMoa1400376
8. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388
9. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2
10. Ghia P, Pluta A, Wach M, et al. Acalabrutinib (Acala) versus idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): ASCEND final results. J Clin Oncol. 2020;38(suppl 15):8015-8015. doi:0.1200/JCO.2020.38.15_suppl.8015
11. Brown J. How I treat CLL patients with ibrutinib. Blood. 2018;131(4):379-386. doi:10.1182/blood-2017-08-764712
12. Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020(1):336-345. doi: 10.1182/hematology.2020000118
13. Rogers KA, Mousa L, Zhao Q, et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies. Leukemia. 2019;33(10):2527-2530. doi:10.1038/s41375-019-0481-1