Drivers and Barriers to Medication Adherence in Patients with Chronic Myeloid Leukaemia: A Qualitative Study

Chronic myeloid leukaemia(CML) constitutes approximately 15% of adult leukaemia cases. It affects slightly more men than women and has an average onset at 64-68 years. Most patients (60-85%) are diagnosed in the initial chronic phase (CP-CML) based on symptoms such as night sweats, abdominal pain, infections, fatigue, weight loss, or bruising ^{1, 2, 3}. 15-40% are asymptomatic and often identified by routine blood tests. If untreated, CP-CML will progress to an accelerated phase (AP-CML) and a fatal blast phase (BP-CML) in three to five years ^{1, 4, 5}.

With the introduction of the tyrosine kinase inhibitor (TKI) imatinib in 2001, CML patients have obtained revolutionary survival rates close to normal ⁶. 2^nd generation TKIs dasatinib, nilotinib, and bosutinib have since been approved ⁷, followed by 3^rd generation ponatinib ^{4, 8, 9}. Some patients are initially treated with hydroxyurea ⁴. Prior to TKIs, patients could be treated with interferon-alpha (IFNa), and allogeneic stem-cell transplantation (SCT) remains an option with elevated mortality rates. As CML is a low-grade symptom disease, treatment often represents patients’ main disease impact ^{3, 10}. Side effects are mostly considered mild to moderate but may include edema, diarrhoea, pleural effusions, nausea, muscosceletal or abdominal pain, rashes, fatigue, or headache ^{1, 2, 3, 4, 7, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21}.

“Three levels of TKI treatment response may be obtained: complete hematologic, cytogenetic, and molecular responses (CHR, CCyR, and CMR) reflecting successive decrease in leukemic cells ⁴. Efficacy is highest in CP-CML and certain milestone responses should occur within 3, 6, and 12 months after initiating treatment ^{4, 22}. Treatment should be re-evaluated if milestones are not reached ^{23, 24}. Response rates are deeper and faster with 2^nd generation TKIs compared to imatinib, and patients with rapid response have better long-term outcomes than those with slower or no response to therapy ^{11, 13, 17, 20, 22}. Yet imatinib is still the most widely used TKI due to cost-effectiveness and acceptable side effects. CML patients with long-lasting sustained CMR, amounting to 10-15% of patients, may be eligible for discontinuation ^{9, 12, 16, 18, 25}.

Medication adherence, i.e. ‘the extent of conformity to the recommendations about day to day treatment by the provider with respect to timing, dosage and frequency’ ³ is crucial to achieve optimal treatment response ^{6, 7, 8, 11, 12, 17, 26, 27, 28, 29, 30, 31, 32}. Yet the fact that CML has become a manageable chronic disease with much improved quality of life (QoL) may challenge adherence ^{4, 8, 26}. Non-adherence in up to 25-30% of CML patients have been suggested ^{4, 7, 19, 26, 27, 28, 30, 33}. Side effects are the most frequent reason for intentional non-adherence and has been associated with a negative impact on activities such as travels, other illness, psycho-social well-being and QoL ^{3, 4, 6, 7, 9, 10, 11, 13, 14, 15, 17, 26, 29, 31, 33, 34}. Unintentional non-adherence is mostly due to careless slips. Non-adherence has also been linked to lacking knowledge about CML and treatment, co-payment, poor communication from health care providers and complacency due to sustained disease control ^{2, 3, 4, 6, 7, 10, 11, 12, 14, 17, 19, 26, 27, 28, 29, 30, 31, 32}. Results diverge about adherence and type of TKI and may relate to the drug as well as patients’ experiences with earlier treatments ^{7, 8, 19}.

The aim with the present study was to explore in depth the drivers and barriers to CML patients’ adherence in a Danish health care setting.

We used qualitative methods in order to examine patient perspectives on factors that may affect adherence behaviour in Danish CML patients. An initial literature search was carried out in PubMed, Embase and PsycInfo using the search terms ‘chronic myelogenous/myeloid/myelocytic leukemia/CML’ or ‘chronic granulocytic leukemia/CGL’ in combination with ‘patient’ and ‘perspectives/experiences/ preferences’ or ‘quality of life’ or ‘adherence/compliance/nonadherence’. From a total of 341 identified abstracts of journal articles published within the past ten years, 67 described QoL and treatment adherence in patients with CML and were thus selected for full-text analysis – five used qualitative methods ^{19, 29, 35, 37, 38}.

The literature study informed the research design using focus groups to elicit discussions about a broad variety of patient perceptions of disease and treatment. The participants were encouraged to discuss convergent and divergent views and experiences on each topic. Four focus groups and three individual interviews with a total of 20 self-selected CML patients, 12 women and eight men, were carried out. Participants were invited via The Danish Patient Organisation for Lymphoma, Leukaemia and MDS (LyLe) that posted invitations in the LyLe and CML specific Facebook groups. Interested CML patients contacted the researchers directly for further information and screening. Due to the focus on subjective patient perspectives, no medical records were collected, and as participation was anonymous, ethical committee approval was not required. Written consent was obtained from all participants. The focus groups were set in conference rooms in four cities across Denmark to elicit potential regional differences. Each included 4-6 participants to create confidential settings for open discussions among peers about their perceptions of CML and experiences with treatment. Individual telephone interviews were carried out with two patients who were unable to attend a focus group and one focus group participant who wished to share additional information.

The focus groups lasted two hours and were moderated by G. Lee Mortensen using a semi-structured interview guide ^{40, 41}. When introducing the focus group discussions, the participants were told of the aim to explore all possible perspectives and encouraged to voice converging as well as diverging views, provide examples and elaborate on their own and others’ experiences. The interviews began with descriptions of the participants’ CML diagnosis and then moved on to its subsequent impact on their QoL, i.e. their physical and psychosocial well-being and functioning. The patients then described their treatment experiences and perceptions of drivers and barriers to TKI treatment adherence (Table 2).

The interviews were transcribed verbatim and analysed using Nvivo 8 software (QSR International) and inductive content analysis ⁴². This involved an analysis of the participants’ statements in a manner to generate clusters of meaning about their perceptions of CML and treatment. First, the transcripts were read through numerous times (by two researchers independently) to get familiar with the data. Secondly, the data was coded into topics (categories) that were raised during the focus groups – mostly reflecting the topics in the question guide – and discussed among the researchers until agreement was reached. Some categories were collapsed; others were spilt up into separate categories. Thirdly, the main themes (sub-categories) within each topic were identified, and finally, recurrent connections between topics and themes were analysed. This generated a pattern of the relative significance that the topics and themes had for the participants, i.e. their perceptions of CML and drivers and barriers to treatment adherence.

The 20 participants were aged between 36-75 years (mean 60.9) and had been diagnosed for 1-19 years (mean 6.23). 18 had a partner, all had children (four living at home) and 13 were grandparents. At the time of the interviews, they attended haematological clinics at seven hospitals across Denmark, 12 were retired, four worked reduced hours and five still had full-time work. Previously, six had worked reduced hours and six had taken early retirement due to the diagnosis (Table 1).

Table 2. Participant characteristics

Five main topics were discussed during the focus groups, namely the perceived QoL impact of getting CML, disease perceptions of CML, treatment experiences, adherence issues, and finally, the prospect of treatment discontinuation.

This study is the first to qualitatively explore adherence in CML patients in a Danish health care setting. In-depth understanding of patient perspectives is crucial to provide locally relevant and individually tailored care and support throughout the disease course. Our participants’ disease perceptions had changed from fear of death at diagnosis to gradually adjusting to CML as a chronic condition. A large cross-cultural study has described this as a common five stage disease course in CML involving periods of crisis, hope, adaptation, new normal, and uncertainty. This basically linear process contains a cyclical component as patients experiencing uncertainty, due to treatment resistance or intolerance for instance, may return to earlier stages to then establish a new normal ³⁵. This concurs with our finding that the participants were mostly able to live fairly normal lives with a tolerable disease burden but had reactivated worries when treatment stopped working, or side-effects or fear of infections reduced their QoL and functioning. Hence our description of the disease perception of CML as being in a state of fragile peace.

In CML, adherence has been measured using various methods, e.g. as percentage rates, using adherence measure scores, or categorising adherence into low, medium or high levels ³¹. Previous studies have been carried out in very different health care settings and sub-populations, e.g. CML patients receiving only one or three types of TKI. This variety hampers comparability as well as understanding of how CML patients may weigh the various factors and influence medication or simply unburdened by it. The participants’ attitudes to discontinuation were closely related that of influencing their medication adherence. In addition, discrepancies have been shown between patients´ self-reported adherence and physicians who may overestimate adherence if deducting this from clinical outcomes only ^{29, 37}.

Most of our participants expressed very high adherence to TKI treatment in the sense that they only rarely forgot to take it – not intentionally or without agreement with the haematologist. When explaining their reasons to adhere, they recurrently mentioned ‘owing it’ to the fortune of having a manageable form of cancer and the privilege of receiving free specialised health care. Most were very satisfied with their care: the continuity with the same haematologist, easy accessibility, personal communication and treatment planning throughout the disease journey. All felt knowledgeable about CML and the importance of adherence, notably including the patient who discontinued treatment. Knowledge may thus be a precondition to adherence but not enough in itself. These factors are all known drivers to adherence along with longer disease duration, fear of the consequences of not adhering, using concurrent medication, having social support and using systems of reminders. Our results also confirm previous study results that relate higher levels of adherence to higher perceived functional status and QOL, including ability to work, and low burden of symptoms and side effects (between 3 and 36). Our participants described their role functioning as crucial to uphold a positive self-image and normality, which they felt was vital to a meaningful life. Symptoms thus became especially burdensome when negative affecting identity and social relations.

Only one participant had intentionally non-adhered to TKI treatment and few had considered it. Our study confirms that side effects were a main reason for this, exacerbated by comorbidity and poor social support. Side effects thus acted as a barrier to adherence due to its reduction in his psychosocial well-being and role functioning ^{3, 6, 9, 14, 33, 38}. Several participants suggested that comprehensive patient care should include psychosocial support including information about peer support from patient networks. Though very rare, careless slips were the most common reason for unintentional non-adherence in our participants. Unlike other studies, our sample did not allow us to associate this with younger age, living alone and male gender, however (Between 2-39). While others have suggested that non-adherence may be caused by complacency and sustained disease control ^{4, 6, 29, 30, 31, 38}, this was not the case in our participants although some speculated this might be the case in settings without public health care. Paradoxically then, higher QoL – stemming from successful treatment – may thus act as a barrier as well as a driver to adherence.

Only few studies have assessed patient perspectives on planned medication discontinuation due to sustained treatment response. Sanford and colleagues showed that side effects and daily adherence were reasons for some patients to want and feel safe discontinuing, while fear of relapse and disappointing others were reasons to reject discontinuation ¹⁶. In another study, half the patients dared not discontinue even if their treatment response was optimal, but 16% were interested to avoid side effects, and 20% were indifferent ¹². In our explorative study, the participation of four patients in treatment-free remission allowed for unforeseen and for important novel insights into their experiences andthe other participants’ reflections on this topic. Most were diagnosed before the results from stop-trials were known and had only later heard of this option. Based some participants’ descriptions of positive feelings of freedom from medication, normality and wellness – and others’ hopes for this – we hypothesise that if informed about the prospect of treatment-free remission already at diagnosis, this may act an important driver to adherence in patients at risk of non-adherence and perhaps improve acceptance of side effects throughout the disease course. Medication adherence is not only influenced by the presence of side effects but as much by patients’ coping with them ⁶. Also, patients’ disease perceptions are influenced by the temporal perspective of disease and treatment, notably whether it is chronic, cyclical or transient ⁴³. We therefore suggest that the prospect of treatment discontinuation and its perceived impact on health-related QoL and adherence should be further explored as results from clinical stop trials are gained. This finding may be significant in Denmark as well as other health care settings.

As described in the health belief model (HBM), patients’ medication taking behaviour is contingent on their evaluation of the gains and losses of taking it ⁷⁴⁴. A variety of factors may act as drivers and barriers to adherence in patients with CML. Individual factors, such as self-assessed QoL and burden of disease and side-effects are interrelated elements in an environment influenced both by the patient’s personal context (health status, work, familial and social roles and support) and the context of the specific health care system. In other words, the impact of side effects, for instance, may differ in a context with/without co-payment or with/without the prospect of planned discontinuation.

We used qualitative methods to explore patient perspectives on drivers and barriers to adherence. While previous quantitative studies have described various factors affecting adherence and their prevalence, our approach allowed for an in-depth understanding of ways in which these may be interrelated. For instance, how side effects or dietary restrictions may reduce patients’ QoL due to activity impairment in core role function domains such as parenting and work potentially leading to non-adherence. As such, our results have explanatory strength and are analytically valid but not statistically generalizable due to the small sample size. While we have shown that successful role functioning is closely related to one’s professional and family situation – factors that are related to age – a quantitative analysis of the impact on adherence of demographic factors such as work status and age was not possible. Likewise, our data did not allow relating adherence to exact age or number of years since diagnosis but rather to explain the importance of patients’ age to their overall life situation and the significance of treatment options at diagnosis to their hope and motivation.

Our study likely involves some inclusion bias as most participants were high-functioning and well-treated with good social support and relatively low current symptom burden. They participated in patient networks that may include fewer men and non-adherent patients less inclined to participate in study interviews. Due to the selection method of inclusion, men were underrepresented compared to the general CML patient population. The study indicates that women may sometimes need more detailed information than men, but this too should be confirmed by larger studies. Also, as our study did not include participants without children or who were diagnosed before the birth of their children, we were unable to gain knowledge about the potential impact of the CML diagnosis on the decision to have children or continue treatment during pregnancy. Finally, non-adherence may be associated with stigma potentially leading to social desirability bias with overstatements of adherence.

Overall, the health care of Danish CML patients supported these participants’ adherence to TKI treatment. Health care providers play a key role in addressing drivers and barriers to CML patients’ adherence throughout their disease journey. Continuous communication is required about their health-related QoL to allow for sustained symptom management and modification of treatment, if necessary. QoL and role functioning are closely related to adherence which is critical to ensure optimal treatment outcomes. Our study indicate that CML patients may benefit from being informed about the possibility of treatment discontinuation if they achieve stable complete molecular response and the impact of this prospect on adherence should be further explored.

GLM has conceived of the study, managed and carried out the literature study, designed the qualitative interview study, carried out the data collection and analysis and acted as main author of the manuscript. JM has provided medical expert advice to GLM, authored the medical parts of the manuscript and reviewed the entire manuscript. GLM has received an unrestricted research grant for the study from Pfizer, Denmark, which was not involved in the study, analysis or manuscript. JM has no conflicts of interest.

The authors wish to thank the study participants for their time and openness about their disease experiences. We are also indebted to the Danish patient organisation for Lymphoma and Leukemia (LyLe), and particularly its chair Rita O. Christensen, for her dedication to the project, her help including study participants and valuable counsel along the way. Finally, GLM is indebted to Ivan Bredbjerg Madsen for his invaluable assistance with the literature study and focus groups.

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