Treatment adherence and adverse event management in chronic lymphocytic leukemia: challenges and strategies for the future

Figures & data

Table 1. Interventions needed to support OAA adherence throughout the course of treatment.

WHO Adherence Domain	Cause of Nonadherence	Patients to receive intervention	Action Needed by care team for Initiative	References
Pre-Treatment Initiation
Social/Economic Factors	Lack of Education about Treatment	All patients	Educate patients: self management of treatment side effects treatment effect on disease how to take medication as prescribed (timing, food) importance of adherence≥90%	[11,12]
Post- Treatment Initiation
Health System/Health Care Team Factors	Lack of communication with care team	All	Schedule check-ins with patients at set intervals that contain: CMR Social needs assessment Collect PROM	[11,13]
Therapy-Related Factors	Side Effects/Treatment Toxicities	All	Schedule check ins to collect PROM Optimize regimen based on PROM	[11,13]
Patient- Related Factors	Forgetfulness	Patients with < 90% adherence	Educate patients to: use pill dosage boxes build medication adherence into the daily routine, store medication in a visual and commonly used area, use clear and monitored treatment schedules to prompt medication taking behavior	[11,14]
	Medication Hesitancy/Fear	Patients with < 90% adherence that have obtained medication Patients who have verbalized hesitancy to HCP	Educate patients about: side effect self-treatment regimen treatment effect on disease	[15]
Both Pre- and Post-Treatment Initiation
Health System/Health Care Team Factors	Lack of coordination of Care	All	Provide standard of care prophylaxis for treatment toxicities Provide Specialty Pharmacy Referral Order labs that accompany treatment Maintain patient REMS eligibility (if applicable) Schedule check ins with patient and care team at predetermined intervals	[11,13,16]
	Unmanaged Drug–drug and drug–disease interactions (DDIs)	All	(1) Conduct CMR (2) Address DDIs (adjust medication regimen)	[13]
	Lack of Access to Social Services	Patients with < 90% adherence Patients with a low score on social needs assessment during Patients identified by HCP as having socioeconomic barriers	Complete social needs assessment at check in Refer to Social Services as needed	[13]
Social/Economic Factors	Financial Toxicity of OAA	All	Complete Prior Authorization if indicated Refer to Patient Assistance Program as needed Evaluate insurance changes and coverage at each scheduled check in Refer to social services	[11,17]
	Socioeconomic Disparity	Patients with < 90% adherence Patients with HCP-identified social needs Patients with needs identified on social needs assessment	Complete social needs assessment at check in Refer to Social Services as needed	[17]
	Low health Literacy	Patients identified by HCP as having low health literacy (health literacy assessment)	(1) Conduct assessment of health literacy (2) Provide additional education throughout the course of treatment	[14]

Outlined in this table are the interventions suggested to support adherence to overcome barriers faced during treatment. The treatment barriers are broken WHO adherence domains, the phase in treatment when they are usually experienced, and matched with the action needed by the care team to overcome the barrier (PROM = Patient Reported Outcome Measure, CMR = Comprehensive Medication Review, HCP = Healthcare Provider).

Table 2. Reasons for oral anticancer agent (OAA) nonadherence.

	Pre-Treatment Initiation Phase	Post-Treatment Initiation Phase	References
Health System/Health Care Team Factors	Lack of coordination of Care Unmanaged Drug-drug and drug-disease interactions (DDIs) Lack of Access to Social Services	Lack of coordination of Care Lack of communication with care team Unmanaged Drug-drug and drug-disease interactions (DDIs) Lack of Access to Social Services	[11,13,16,17]
Therapy-Related Factors	None	Side Effects/Treatment Toxicities	[11,13]
Social/Economic Factors	Lack of Education about Treatment Financial Toxicity of OAA Socioeconomic Disparity Low health Literacy	Financial Toxicity of OAA Socioeconomic Disparity Low health Literacy	[11,12,14,17]
Patient-Related Factors	None	Forgetfulness Medication Hesitancy/Fear	[11,14,15]
Condition-Related Factors	Disease-Related Symptoms		[11,18]

Reasons for nonadherence are broken into two treatment phases; pre- and post-treatment initiation as well as different domains to reveal their origin.

Table 3. Adverse events associated with targeted anticancer therapies.

	BTKi	Anti-CD20antibodies	BCL-2 inhibitors	Anti-CD52antibodies	PI3K inhibitors
Thrombocytopenia	x	x	x	x	x
Infection	x	x	x	x	x
Neutropenia	x	x	x	x	x
Major Adverse Cardiovascular Events (MACE) *	x
Atrial Fibrillation or Arrhythmia	x
Bleeding	x
Tumor Lysis Syndrome		x	x
Infusion Reactions		x		x
Hypersensitivity		x			x
Mucocutaneous reactions		x (rituximab)			x
Hepatotoxicity					x
Pneumonitis					x
Colitis/Intestinal Perforation					x
Hypertension	x

Each of the major adverse events associated with each class of therapies used to treat CLL are elucidated (MACE = nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death).

Table 4. Oral anticancer agent dosing considerations.

Oral Dosage form Administration Considerations
Medication	Daily Dose/Frequency	Food Considerations	Hepatic Dosing	Renal Dosing	CYP interactions		DDI dose adjustments	References
BTKi
Ibrutinib	420 mg Once Daily	None	Reduce to 140 mg	NA	3A	Strong CYP3A inhibitor: Reduce dose to 140 mg (mild CYP3A inhibitor CYP3A inducer: avoid		[6]
Zanubrutinib	160 mg Twice Daily OR 320 mg Once Daily	None	Reduce to 80 mg BID	NA	3A	Strong CYP3A inhibitor: Reduce dose to 80 mg once daily Moderate CYP3A inhibitor: Reduce dose to 80 mg BID CYP 3A inducer: avoid		[23]
Acalabrutinib	100 mg Every 12 Hours	None	None	NA	3A	Avoid gastric reducing agent Strong CYP3A inhibitor: avoid Moderate CYP3A inhibitor: reduce to 100 mg daily CYP3A inducer: avoid		[24]
Pirtobrutinib	200 mg Once Daily	None	None	Severe: Reduce Dose 100 mg if dose was 200 mg, otherwise give 50 mg	3A, 2C8, 2C19	Strong CYP3A inhibitor: reduce by 50 mg CYP3A inducer: increase dose to 300 mg if it is 200 mg otherwise increase by 50 mg		[7]
BCL-2 Inhibitors
Venetoclax	Ramp up over 5 weeks (20 mg-400 mg) Once Daily, then 400 mg Once Daily	With meals	Reduce by 50%	NA	3A	Strong CYP3A inhibitor: contraindicated in CLL Moderate CYP3A or P-gp inhibitor: reduce by 50% CYP3A inducer: contraindicated		[8]
PI3K inhibitors
Idelalisib	150 mg Twice Daily	None	None	NA	3A	Strong CYP3A inhibitor: avoid Strong CYP3A inducer: avoid		[10]
Duvelisib	25 mg Twice Daily	None	None	NA	3A	Strong CYP3A inhibitor: reduce dose to 15 mg twice daily Strong CYP3A inducer: avoid		[25]

Dosing reductions or medication discontinuations due to drug–drug interactions and organ dysfunction are listed. Medication dosing schedule and instructions (with/without food) are included as well.

Figure 1. A possible structure for a multidisciplinary intervention to support patients with CLL with oral anticancer agent (OAA) adherence. In the pRE-TREATMENT INitiation phase (writing of the prescription until patient receives medication), support begins with referrals to social services as needed, detailed medication education, management of OAA financial toxicity, and ensuring care coordination (ordering of labs, referral to specialty care pharmacy, ordering prophylactic medications, REMS compliance when needed, and scheduling follow ups). In the post- treatment initiation phase (patient receipt of medication until discontinuance of medication), support begins with a check-in 2 weeks after the first dose of medication taken: PROs, CMR and social needs assessment conducted. Patients found nonadherent due to forgetfulness or hesitancy will be provided education. Toxicities will be managed, potential DDIs will be addressed, and medication regimen will be simplified as needed. Patients found to have SDoH barriers will be referred to social services and financial toxicities will be managed. Following the initial check in 2 weeks after initiating therapy, follow ups will be scheduled every 2–4 weeks until patient is stable on treatment. Patients stable on treatment will have follow ups every 3–6 months until discontinuation of treatment.

Burkhart PV, Sabaté E. Adherence to long-term therapies: evidence for action. J Nurs Scholarsh. 2003;35(3):207.

 PubMed Web of Science ®Google Scholar

Muluneh B, Schneider M, Faso A, et al. Improved adherence rates and clinical outcomes of an integrated, closed-loop pharmacist-led oral chemotherapy management program. J Oncol Pract. 2018;14(6):e324–e334. doi: 10.1200/JOP.17.00039

 PubMed Web of Science ®Google Scholar

Farris KB, Cadwallader T, Farley J, et al. Implementation of a model integrating primary and oncology pharmacists’ care for patients taking oral anticancer agents (OAA). Explor Res Clin Soc Pharm. 2022;7:100163. doi:10.1016/j.rcsop.2022.100163

 PubMedGoogle Scholar

Hall AE, Paul C, Bryant J, et al. To adhere or not to adhere: rates and reasons of medication adherence in hematological cancer patients. Crit Rev Oncol Hematol. 2016;97:247–262. doi: 10.1016/j.critrevonc.2015.08.025

 PubMed Web of Science ®Google Scholar

Iacorossi L, Gambalunga F, Fabi A, et al. Adherence to oral administration of endocrine treatment in patients with breast cancer: a qualitative study. Cancer Nurs. 2018;41(1):E57–E63. doi: 10.1097/NCC.0000000000000452

 PubMed Web of Science ®Google Scholar

Oncology Pharmacy Education Network. Care coordination: the role of pharmacy to help manage patients with cancer on oral oncolytics. Association Of Community Cancer Centers (ACCC). 2021;36(5):70–74.

 Google Scholar

Almodóvar AS, Ross E, Nahata MC, et al. Social needs of dual-enrolled medicare-medicaid patients with medication nonadherence in a telehealth medication therapy management program. J Manag Care Spec Pharm. 2023;29(2):210–215. doi:10.18553/jmcp.2023.29.2.210

 PubMed Web of Science ®Google Scholar

Hallek M, Cheson BD, Catovsky D, et al. CLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745–2760. doi: 10.1182/blood-2017-09-806398

 PubMed Web of Science ®Google Scholar

Imbruvica (ibrutinib). Package insert. Sunnyvale, CA: Janssen Biotech, Inc and Pharmacyclics; 2015.

 Google Scholar

Brukinsa (zanubrutinib). Package insert. BeiGene USA: Inc.; 2019.

 Google Scholar

Calquence (acalabrutinib). Package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2022.

 Google Scholar

Jaypirca (pirtobrutinib). Package insert. Indianapolis, IN: Eli Lilly; 2023.

 Google Scholar

Venclexta (venetoclax). Package insert. South San Francisco, CA: Genentech; 2016.

 Google Scholar

Zydelig (idelalisib). Package insert. Foster City, CA: Gilead; 2014.

 Google Scholar

Copiktra (duvelisib). Package insert. Las Vegas, NV: Secura Bio; 2018.

 Google Scholar