How I Treat

Chronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia among older adults in the Western world and accounts for about one-third of all leukemias.¹ In the United States alone more than 130,000 patients are affected by CLL, with an incidence of approximately 15,000 new cases diagnosed each year.² Formerly, prior to 2014, chemoimmunotherapy was viewed as the standard of care.² Since then, a shift in the treatment paradigm towards oral oncolytic agents has ensued. The most current CLL treatment arsenal includes therapies that target the B-cell receptor signaling pathways that promote the growth and/or survival of CLL cells.¹ Innovative drugs, such as ibrutinib (Imbruvica), may be classified as BCR signaling and BCL-2 pathway inhibitors. Ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase (BTK), inhibits overgrowth of B cells due to its ability to bind to the BTK molecule.³ Ibrutinib has been approved by the U.S. Food and Drug Administration (FDA) in the United States and Europe as a first-in-class, once-daily BTK inhibitor for the treatment of B-CLL/small lymphocytic leukemia (SLL) patients as initial therapy, as well as in patients with relapsed disease.¹The use of this relatively novel B-cell receptor signaling inhibitor results in high response rates and long progression-free survival (PFS) in patients with CLL and other indolent B-cell malignancies.⁴Chen and colleagues summarized that among treatment-related parameters, ibrutinib has shown an 18-month PFS and a 24-month overall survival (OS). Four percent of fit and unfit patients demonstrated a complete response (CR) and 82% had a partial response (PR). In addition, the researchers found that patients with del (17p) exhibited a 24-month PFS rate of 91% and a 24-month OS rate of 84%. Among this population, the del 17p group treated with ibrutinib had a 13% rate of CR and 85% PR rate after 24 months of treatment.² 

Mechanism of Action of Ibrutinib 

With the initiation of ibrutinib a rapid reduction of lymphadenopathy is associated with a concurrent lymphocytosis. The elevation in the absolute lymphocyte count is secondary to the migration of CLL cells from lymphoid tissue.¹ de Weerdt and colleagues concur that lymphocytosis inherently occurs as ibrutinib disrupts integrin-mediated adhesion and homing of malignant B cells to the lymphoid microenvironment.⁴ Generally, with continued ibrutinib therapy the lymphocytosis subsides as the overall tumor burden declines. Barr and colleagues demonstrated that BTK active-site occupancy in patients with CLL/small lymphocytic leukemia (SLL) treated with 420 mg once-daily dose was maintained at 24 hours. The researchers also noted the uncertainty of the impact of intermittent interruption of ibrutinib dosing on patient outcomes.⁵ 

Factors Influencing Adherence 
Ibrutinib offers convenience dosing with once-daily dosing of 420 mg that is thought to enhance dose adherence.⁶ Meanwhile, there are adverse effects (AEs) associated with ibrutinib that may deter patient adherence. For this reason it is imperative that patients are appropriately educated regarding the AEs related to ibrutinib and indications for reporting these events. According to the World Health Organization several factors exist that impede conformity to ibrutinib and other oncolytic therapy.⁷According to the research of Schneider and colleagues, issues with adherence can often be defined as being related to either the patient, the condition, the therapy, social and economic factors, or the health care team or system. Patient-related factors include cognitive awareness, comorbidities, polypharmacy, and psychosocial support systems, patient attitudes towards adherence. Condition-related factors include comorbidities, psychological obstacles, self-care capabilities, and gender. Therapy-related factors include adverse effects of therapy, treatment longevity, dosing requirements (daily vs multiple times/day), route of administration, dietary restrictions, and timely prescription refills. Social- and economic-related factors include issues such as the cost of treatment, socioeconomic status (with greater adherence seen in patients with a higher socioeconomic status), access to family support systems, and care center access. Health care team and system-related factors include provider-patient relationship, the occurrence of a detailed explanation of treatment, the assurance of on-going management, and education for patients and family members regarding each aspect of oral oncolytic therapy.⁷ 

Common AEs 
Ibrutinib has been associated with numerous AEs including fatigue, diarrhea (60%), thrombocytopenia, neutropenia, bleeding, bruising, petechiae, skin rash, arthralgia, myalgia, increased blood pressure, peripheral edema, weight gain, and atrial fibrillation.^1,8 While there are many potential adverse events, generally the majority of these events reported in CLL are classified as grades 1 and 2.⁹ There are, however, instances where hyperuricemia occurs, which is generally treated with allopurinol.¹ Vrontikis and colleagues infer that up to 11% of patients enrolled in clinical trials who received a 420 mg dose of ibrutinib experienced atrial fibrillation.¹⁰ An overview of important patient safety information is noted in Table 1.

Table 1. Safety Information, Warnings, Precautions¹¹

Event	Warnings and precautions
Hemorrhage	Grade 3 or higher bleeding events have occurred in up to 6% patients. Bruising and petechiae occurs in about 50% of patients. Monitor closely patients treated with anticoagulant therapies. Hold ibrutinib at least 3 to 7 days pre- and post-surgery.
Infections	Fatal and non-fatal infections have occurred with ibrutinib therapy, ie, bacterial, viral, and fungal. Grade 3 or higher infections were experienced in 14% to 29% of patients. Progressive multifocal leukoencephalopathy and Pneumocystis jirovecii pneumonia have occurred with ibrutinib therapy.
Cytopenias	Grade 3 or 4 cytopenias have occurred including: neutropenia (13%-29%), thrombocytopenia (5%-17%), and anemia (0%-13%) with single-agent ibrutinib
Cardiac Arrhythmias	The occurrence of grade 3 or higher ventricular tachyarrhythmias is noted as 0% to 1%. Atrial fibrillation and flutter occurred in 0% to 6% of patients on ibrutinib. Patients with prior cardiac risk factors should have a baseline ECG.
Hypertension	An incidence of 6% to 17% has occurred in patients treated with ibrutinib with median time to onset of 4.6 months.
Tumor Lysis Syndrome (TLS)	Infrequently reported, but should monitor patients with high tumor burden. Prophylaxis with allopurinol is recommended if indicated.

Patient-Reported AEs

The most common side effects reported in my practice include fatigue, diarrhea, elevated blood pressure, arthralgias, myalgias, bruising and petechiae, weight gain (particularly in females), and leg cramps. Although approximately 10% to 15% of our patients at some point in time experience documented atrial fibrillation, they are usually hesitant to notify their care team. In some cases, patients are aware when experiencing atrial fibrillation and in other cases they may be aware but avoid reporting for fear of discontinuing their ibrutinib.

The Role of the Nurse in Ibrutinib Treatment

As frontline providers, nurses are often responsible for patient education regarding oral oncolytics, understanding that patient education is of immense importance. Figure 1 provides a schematic summary of interventions for initiation of ibrutinib.¹² Oncology nurses, both registered nurses and advanced practice nurses, play a significant role in the education of patients with CLL/SLL regarding AEs associated with ibrutinib therapy. Kahl noted that oncology nurses are often the first point of contact for patients treated with ibrutinib.¹³

Additional nursing responsibility in some institutions include the the procurement of financial assistance for patients either initiating ibrutinib or those requiring on-going authorizations from insurance companies. This process can be labor-intensive and often leads to increased financial burden for patients.¹⁴ In general, health care providers are also adversely affected by repeated requirements for insurance prior authorizations and re-authorizations. Some institutions have financial consultants to manage patient insurance issues, yet many do not possess the medical knowledge to appropriately provide specific diagnostic information.  Consequently, this responsibility falls to nurses to complete this often tedious and extremely laborious process.

Figure 1. Steps to Initiating Ibrutinib¹²

Figure 1. A schematic summary of interventions for initiation of ibrutinib.

Patient Education

Treatment with oral oncolytic agents presents challenges in patient compliance, adherence, and management of adverse events. Betcher and colleagues indicate an upward trend in prescribing oral anticancer medications (OAMs) for patients with hematologic malignancies.¹⁴ The researchers also suggest that issues such as safety present challenges to adherence. Nonadherence can result in decreased overall patient response and may subsequently result in increased health care cost.^3,14Patient education is essential for successful initiation and adherence to ibrutinib dosing. Figure 2 illustrates an abbreviated algorithm for patient education.

Figure 2. Recommendations for Ibrutinib Patient Education

Figure 2. A snapshot guide for patient education prior to the initiation of ibrutinib. Adapted from: The MASCC Oral Agent Teaching Tool.¹²

Barr and colleagues noted that sustained adherence to ibrutinib is advised to achieve efficacy. Furthermore, the RESONATE study analyses demonstrated that optimal adherence to the recommended ibrutinib dose corresponded with superior patient outcomes.⁵

Personal Practice Strategies for Patients Receiving Ibrutinib

The following are strategies used in my leukemia practice for initiation of ibrutinib:

1.  Assess the patient’s knowledge of the drug and route of administration and provide written drug information sheets developed by the institution.

2.  Review the printed information with the patient in a step-by-step process (ie, purpose of the drug, dosage, dosing schedule, side effects, follow up requirements, and review of pertinent laboratory data and frequency of lab reviews).

3.  Allow patient to ask questions and provide a detailed response to all questions.

4.  Review and discuss each element of the informed consent prior to signing.

5.  Discuss a verbal and written patient agreement for adherence to drug dosing. In the case of patients who are enrolling on research protocols this process is completed by the research nurse or clinical research coordinator.

6.  Allow the patient to repeat their understanding of medication compliance and provide them with a diary or calendar for to record daily dosing.

7.  Reinforce the need to avoid missing or doubling doses.

8.  Provide explicit instructions regarding indications for holding ibrutinib dose (such as adverse effects or surgery). Instruct patients to contact provider as needed to ensure consistent dosing.

9.  Schedule return visit within 2 weeks of the initiation of ibrutinib and at least monthly thereafter unless indications exists for more frequent monitoring. In situations where patients rely on community physicians and/or advanced practice providers for on-going monitoring, explicit instructions should be provided in order to coordinate patient follow-up recommendations. The patient and community providers are requested to send (email or fax) all laboratory results obtained.

Barriers for Oral Oncolytic Agents

In an opinion piece published in 2016, Given describes several challenges to CLL patients treated with oral oncolytic medications such as ibrutinib.¹⁵ While oral agents are viewed by many as beneficial and offer convenient patient dosing, they are not without challenges. Traditionally, chemotherapy was the mainstay of treatment, which is often administered by nurses intravenously.¹⁵ A paradigm shift in cancer treatment strategies has led to the use of oral agents that are self-administered by patients. Subsequently this shift has led to more patient responsibility and accountability for adherence to oral therapies. While many barriers exist, in my clinical practice experience financial barriers seem to be more prevalent among patients with CLL (over 65 years), particularly those who are enrolled on Medicare. The older CLL population generally survive on fixed incomes and therefore are unable to afford excessive co-pay demands. Strategies to facilitate financial assistance include funding from non-profit foundations to supplement co-pay needs. Newer dosing formulations have created additional financial burden but have also shown to benefit patient adherence. Since the release of the new single-dose formulations of ibrutinib for CLL (ie, 140 mg, 280 mg, and 420 mg), patients are contacting providers with the desire to switch to one tablet rather than several capsules dosing. In my practice, patients have verbalized their approval of the single-tablet dose and are more apt to adhere to daily dosing with single-tablet dosing. In addition, several of the patients in my practice have experienced nausea, gastrointestinal discomfort, or acid reflux with the original 420 mg (3 capsules) compared with the now single-dose tablet, which seems to have improved the associated nausea and dyspepsia.

Management of Side Effects of Ibrutinib^11,16

·       Nausea: Ondansetron 8 mg or promethazine 25 mg every 6 to 8 hours as needed.

·       Infections: Prophylaxis for bacterial, viral, and fungal infections are prescribed for at-risk patients.

·       Cytopenias: Patients with neutropenia may be given pegfilgrastim (Neulasta) or filgrastim (Neupogen) if indicated, particularly if comorbid conditions exist. Patients should be instructed regarding monitoring for neutropenic fevers and to report to the emergency department for further evaluation of temperatures greater than or equal to 100.5 degrees Fahrenheit (parameters may vary by institution). Anemia and thrombocytopenia occur in some patients. Complete blood counts should be monitored monthly.

·       Cardiac arrhythmias: Patients should be well advised of the possibility of atrial fibrillation (most common arrhythmia) associated with ibrutinib treatment. Generally, a baseline ECG is obtained. If the patient reports any cardiac irregularities (beats), they are referred to cardiology for further evaluation and often have an internal heart monitor placed for on-going evaluation. In cases of documented atrial fibrillation, patients are typically started on a beta-blocker by cardiology.

·       Hypertension: Patients should be instructed to keep a daily log of blood pressure readings and encouraged to see an internist for appropriate management strategies to control blood pressure. If new onset, patients are initiated on antihypertensive medication.

·       Tumor lysis syndrome (TLS): Patients are typically started on allopurinol (Zyloprim, Aloprim) with initial dosing of ibrutinib. Labs are checked monthly to monitor the uric acid level. When normalized the allopurinol may be discontinued. Patients should be informed of the aspects of TLS and the need for interventions.

·       Arthralgias/myalgias: Providers should ensure awareness that these symptoms are often self-limiting, however, they may occasionally require medical management such acetaminophen (Tylenol) or tramadol (Ultram, ConZip). Other measures used may include heating pads and stretching exercises as tolerated.

·       Bruising/petechiae: Patients are instructed to avoid aspirin products unless indicated for cardiac etiology and closely monitored by cardiologist. Otherwise patients are informed that platelet function is inhibited by ibrutinib and therefore may increase risk for bleeding.

Nursing Implications

Nurses are on the forefront as health care providers in the care of CLL patients receiving oral oncolytic therapy. Often time nurses are the first and last point of contact during clinic visits. Moreover, in my institution, the majority of patient education is provided by the nurses or advanced practice providers. However, the degree of education provided by nurses may vary depending on the institution or clinical practice guidelines. The literature validates the essential role of nursing in patient education, adherence to oral therapy, and management of adverse events in collaboration with interprofessional team members (ie, physicians, pharmacists, advanced practice providers, social workers, and case managers). Ultimately, nurses positively affect drug adherence in patients with CLL receiving oral oncolytics.

References

1.     Kipps TJ, Stevenson FK, Wu CJ, et al. Chronic lymphocytic leukemia. Nat Rev Dis Primers.2017;3:16096. doi: 10.1038/nrdp.2016.96

2.     Chen Q, Jain N, Ayer T, et al. (2017). Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. J Clin Oncol. 2017;35(2):166-174.

3.     Smithson CR, Schneider SM. Ibrutinib: a new targeted therapy for hematologic cancers. Clin J Oncol Nurs. 2015;19(3):E47-51. doi: 10.1188/15.CJON.E47-E51

4.     de Weerdt I, Koopmans SM, Kater AP, van Gelder M. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica. 2017;102(10);1629-1639. doi: 10.3324/haematol.2017.164103

5.     Barr PM, Brown JR, Hillmen P, et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129(19):2612-2615. doi: 10.1182/blood-2016-12-737346

6.     Vioral A, Leslie M, Best R, Somerville D. Patient adherence with oral oncolytic therapies. Semin Oncol Nurs. 2014;30(3):190-199. doi: 10.1016/j.soncn.2014.05.007

7.     Schneider SM, Hess K, Gosselin T. Interventions to promote adherence with oral agents. Semin Oncol Nurs. 2011;27(2):133-141. doi: 10.1016/j.soncn.2011.02.005

8.     Aschenbrenner DS. New approved indication for ibrutinib. Am J Nurs. 2014;114(6):21. doi: 10.1097/01.NAJ.0000450426.74512.e2

9.     Goodman A. Journal of Hematology Oncology Pharmacy. Managing Patients Receiving Ibrutinib. http://jhoponline.com/ton-issue-archive/2014-issues/november-december-vol-7-no-6/16277-managing-patients-receiving-ibrutinib. Published November/December 2014. Accessed July 9, 2018.

10. Vrontikis A, Carey J, Gilreath JA, et al. Proposed Algorithm for Managing Ibrutinib-Related Atrial Fibrillation. Oncology (Williston Park). 2016: 15;30(11):970-4, 980-1, C3.

11. Imbruvica^® [package insert]. Sunnyvale, CA: Pharmacyclics, LLC; 2017.

12. Rittenberg CN. Meeting educational needs and enhancing adherence of patients receiving oral cancer agents through use of the MASCC Oral Agent Teaching Tool©. European Oncology & Haematology. 2012;8(2):97-100 doi: 10.17925/EOH.2012.08.02.97

13. Kahl KL. (2018). Nurses make a difference as the frontline in managing adverse from ibrutinib. Presented at: Oncology Nursing Society 43rdAnnual Congress; May 17-20, 2018; Washington, DC.

14. Betcher J, Dow E, Khera N. Oral chemotherapy in patients with hematological malignancies-care process, pharmacoeconomic and policy implications. Curr Hematol Malig Rep. 2016;11(4):288-94. doi: 10.1007/s11899-016-0325-2

15. Given BA. Oral oncolytic agents–A need for research to enhance patient centered? Cancer Nurs.2016;39(1):84-85. doi: 10.1097/NCC.0000000000000316

16. Green D. Ibrutinib impairs platelet function. NEJM Journal Watch. https://www.jwatch.org/na36628/2015/01/06/ibrutinib-impairs-platelet-function.  Published January 6, 2015. Accessed June 29, 2018.