Monitoring and Improving Adherence to Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia: A Systematic Review

Figures & data

Table 1 Inclusion and Exclusion Criteria of Systematic Review

Concept	Inclusion Criteria	Exclusion Criteria
Population	Patients with chronic myeloid leukemia taking tyrosine kinase inhibitors	Mixed cancer population other than chronic myeloid leukemia, or patients with chronic myeloid leukemia but not taking tyrosine kinase inhibitors
Intervention	Education, counselling, cognitive behavioural therapy, adherence aids, mobile-based or any other interventions provided by healthcare providers to monitor and improve medication adherence	Medical, drug, surgical or transplantation-based intervention
Comparison	Usual care (not receiving additional support for adherence)	No comparison group
Outcome	Medication adherence (as measured using the Morisky Medication Adherence Scales, medication possession ratio, etc.); with or without clinical (morbidity or mortality), humanistic (quality-of-life or utility) or economic (cost-minimisation, cost-effectiveness, cost-saving, cost-benefit analysis) outcomes	No report on medication adherence
Study design	Randomized control trial, cohort study, comparison before and after study	Qualitative study, case report, case series, descriptive cross-sectional study, case-control study, systematic review
Type of publication	Original research	Abstract, conference proceeding, protocol, preprint or editorial article
Language of publication	English	Non-English

Figure 1 Flowchart of study selection.

Notes: PRISMA figure adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Available from: http://creativecommons.org/licenses/by/4.0/.¹⁸

Table 2 Characteristics of the Included Studies and Intervention Strategies

Authors	Region/ Setting (Sample Size)	Intervention Strategies					Intervention Delivery and Intensity (Healthcare Professionals)		Comparison	Intervention Duration	Adherence Measure (Data Sources)
		Education/Counselling	Print Material /Video	Support/Follow-Up	Pill Reminder	Diary	Face-to-Face/Phone Call/Email	Mobile Based (SMS/App/Web)
Randomised controlled trials
Tan et al (2020)^Citation27	Malaysia/2 hospitals (n = 129)	√	√	√	√	-	Face-to-face (pharmacist) 1–2 monthly	App daily	Usual care	6 months	MPR ≥ 90% (dispensing data)
Kekale et al (2016)^Citation28	Finland/8 hospitals (n = 86)	√	√	-	√	-	Face-to-face (nurse) at initiation	SMS daily	Usual care	9 months	Morisky-8 item ≥ 6 (participant interview)
Cohort studies
Dennison et al (2021)^Citation29	USA/1 medical centre (n = 40)	√	-	√	-	-	Face-to-face and phone call (pharmacist) If stable, 3 monthly. If unstable, 2–4 weekly.	-	Pre-treatment counselling, then as needed if referred (pharmacist)	4 years	Morisky 4-item score=0 (participant self-reporting)
Sawicki et al (2019)^Citation30	USA/Claim reimbursement database (n = 558)	√	-	√	-	-	-	Two-way SMS (pharmacist) 3 monthly and as needed	One-way SMS (pharmacist)	1 year	MPR ≥ 85% (claim database)
Lam et al (2015)^Citation35	USA/1 hospital (n = 44)	√	-	√	-	-	Face-to-face, phone call and email (pharmacist) As needed	-	Historical usual care at another hospital	5 years	MPR ≥ 90% (dispensing data)
Moon et al (2012)^Citation32	Korea/4 hospitals (n = 114)	√	-	√	√	-	Phone call (nurse) Every 2–8 weekly	SMS daily	Usual care	3 years	The dose taken/dose should be taken (source not specified)
Before-and-after comparison studies
Santoleri et al (2019)^Citation34	Italy/1 hospital (n = 44)	√	-	√	-	√	Face-to-face (pharmacist) As needed after review diary completed by patients	-	No diary	4 years	RDD/PDD (dispensing data)
Leader et al (2018)^Citation33	Israel/4 hospitals (n = 47)	√	-	√	-	-	Face-to-face (clinician, nurse, pharmacist, patient peer) At initiation	-	Usual care	3 months	Days with dosing taken as prescribed (MEMS)
Moulin et al (2017)^Citation36	Brazil/1 hospital (n = 23)	√	-	√	-	-	Face-to-face (pharmacist) monthly	-	Usual care	4 months	Morisky 4-item scale (participant interview)

Abbreviations: MPR, medication possession ratio; RDD/PDD, received daily dose/prescribed daily dose; MEMS, Medication-event-monitoring system; USA, United States of America; App, application; SMS, short message service; web, website.

Table 3 Methodological Quality of Included Randomized Controlled Trials

Study	Randomization Process	Deviation from Intended Intervention	Missing Outcome Data	Measurement of the Outcome	Selection of the Reported Result	Overall Risk
Tan et al (2020)	+	!	+	+	+	+
Kekale et al (2016)	!	!	!	–	+	!

Notes: +: low risk of bias; !: some concern; -: high risk of bias.

Table 4 Methodological Quality of Included Cohort Studies

Study	Selection				Comparability	Outcome			Total
	Representative of the Exposed Cohort	Selection of Non-Exposed Cohort	Ascertainment of Exposure	Demonstration that Outcome of Interest Not Present at the Start of the Study	Comparability of Cohorts (1) Main Factor (2) Additional Factor	Assessment of Outcome	Sufficient Follow-Up Time	Adequacy of Follow-Up
Dennison et al (2021)	1	1	1	1	2	0	1	0	7
Sawicki et al (2019)	1	1	1	1	2	1	1	1	9
Lam et al (2015)	1	0	1	1	2	1	1	1	8
Moon et al (2012)	1	1	1	1	1	0	1	0	6

Notes: 1: fulfilled; 0: not fulfilled.

Table 5 Quality Assessment of the Three Before-and-After Comparison Studies

Study	Introduction	Methods										Results					Discussion
	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q 10	Q 11	Q12	Q13	Q14	Q15	Q16	Q17	Q18	Q19	Q20
Leader et al (2018)	Y	N	N	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y
Santoleri et al (2018)	Y	N	N	Y	Y	Y	N	Y	Y	Y	N	Y	Y	N	Y	Y	N	N	N	Y
Moulin et al (2016)	N	N	N	Y	Y	Y	N	Y	Y	N	N	N	Y	N	?	Y	Y	Y	N	Y

Abbreviations: Y, Yes; N, No; ?, Do not know.

Figure 2 Relative ratio of the proportion of participants who adhered to tyrosine kinase inhibitors comparing the intervention versus no intervention groups.

Figure 3 Mean difference of tyrosine kinase inhibitors’ doses taken or received comparing intervention versus no intervention groups.

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