Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western World, with an incidence of 5.7 cases per 100,000 inhabitants every year1. Median age at diagnosis is 72 years1. Since the disease affects mainly elderly individuals, it is often accompanied by at least one severe comorbidity2.

The condition can manifest itself in several ways, some patients experiencing an indolent and stable course and others demonstrating a more aggressive form, with cytogenetic alterations that sometimes result in poorer prognosis3,4. 80–85% of patients remain asymptomatic, and only patients with an active form of the disease (15—20%) requiring treatmen.5.

New treatment options for CLL have been introduced in recent years, which have resulted in changes to the clinical guidelines. Such therapies, which have been classified into first-line and post-relapse treatments, include oral antineoplastics, Bruton's tyrosine kinase inhibitors (ibrutinib and acalabrutinib), phosphatidylnositol kinase 3 inhibitors (idelalisib) and inhibitors of the anti-apoptotic protein B-cell lymphoma (venetoclax).

Adherence to these drugs may not always be optimal as their use typically involves daily administration at the patients' home, longer treatment times and the risk of adverse events. This is a particularly serious concern as poor adherence may negatively impact the patients' response and survival and lead to an increase in healthcare costs as more consultations and hospital admissions are usually necessary. For those reasons, the World Health Organization has identified poor adherence as a public health problem6.

On the other hand, the symptoms associated with the disease, the adverse events resulting from existing treatments, and the knowledge that CLL is an incurable condition, may take a significant toll on the patients' quality of life. Quality-of-life measurements could provide an in-depth understanding of the impact that the disease and its treatment have on the patients' perception of their wellbeing.

Some published studies have evaluated adherence to oral antineoplastics in patients with other hematologic neoplasms such as chronic myeloid leukemia (CML)7,8 and multiple mieloma9,10. Other authors have looked into the quality of life of patients with CLL receiving either no treatment or conventional treatment11,12. However, few studies have evaluated adherence to the new oral antineoplastic drugs and the quality of life of patients who take them13.

The purpose of this study was to determine the adherence to oral antineoplastic treatment and the quality of life of patients with CLL. The secondary goals included a comparison of adherence and quality of life according to the drug received and the line of treatment applied.

This was a descriptive retrospective study carried out between June and November 2021 in a third-level hospital. Subjects comprised all the patients with CLL in at the oncology unit of the hospital's pharmacy department treated with oral antineoplastics (ibrutinib, acalabrutinib, idelalisib or venetoclax) since at least 6 months prior to inclusion. Patients treated with clinical research samples in the context of a clinical trial were excluded. The study was approved by the regional Ethics Committee for Research with Medicinal Products.

Adherence was measured using both the standardized 8-item Morisky Medication Adherence Scale (MMAS-8)14 and the leftover pill counting method15. In the latter case, the adherence rate was calculated using the following formula:

Patients whose adherence was ≥90% were considered adherent. The 90% threshold was selected based on the published literature, more specifically, on the study by Marin etal8.

Quality of life was measured on the basis of three questionnaires: the QLQ-C30 questionnaire, developed by the European Organization for Research and Treatment of Cancer (EORTC)16,17; the EQ-5D-3L questionnaire, created by the EuroQol Group18; and the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) scale19.

Two telephone interviews were scheduled: the first one at the time of inclusion and the second one at three months from inclusion. The first interview was dedicated to administering the questionnaires, obtaining demographic data and asking patients about leftover medication. At the second interview, questions were asked again about leftover medication and the adherence rate was calculated.

The patient's electronic medical records were reviewed and the following data was recorded: sociodemographic variables (sex, age), clinical variables (including comorbidities, according to the Cumulative Illness Rating Scale (CIRS-G)20, cognitive status (according to Pfeiffer's test21, current and previous treatment, time from initiation of current treatment, adverse events [according to the Common Terminology Criteria for Adverse Events22 (CTCAE) v5.0 scale] and concomitant medication.

A descriptive analysis was carried out of the variables collected during the study. Quantitative variables are expressed as absolute values and percentages. Quantitative variables are presented as mean ± standard deviation (variables with parametric distribution) and median and interquartile range (variables with nonparametric distribution). The Kolmogorov–Smirnov test was used to evaluate the distribution of data.

The comparison of variables between the groups was carried out by means of Student's t test for parametric variables and using Mann–Whitney's U test for nonparametric variables. To analyze correlations between two qualitative variables, use was made of Pearson's correlation coefficient (r) for parametric data and Spearman's correlation coefficient (rho) for nonparametric data. Statistical significance was set at a p value <0.05.

The statistical analysis was carried out using version 25.0 of the SPSS software package (IBM) for PCs.

Twenty-eight patients were identified as candidates for participation in the study. Two patients died before giving informed consent and three had their treatment modified. The final sample comprised 23 patients: 15 males and 8 females, with a mean age of 69.7 (± 8.02) years. Mean score on the CIRS-G scale was 6.13 (± 4.14), with 18 patients showing no cognitive impairment and 5 showing moderate–mild impairment on Pfeiffer's test. The median number of concomitant treatments was 5 (range: 1–12) and the median number of previous treatments for CLL was 1 (range: 0–5). Eighteen patients were on treatment with ibrutinib (8 of them were taking the drug as first-line treatment) and 5 were taking venetoclax (none as first-line treatment). No patients were on acalabrutinib or idelalisib. Mean time on those oral antineoplastics up to inclusion in the study was 1.57 (± 0.98) years.

Fourteen patients did not demonstrate any adverse reaction to the treatment during the performance of the study. The other patients did present adverse events (AEs), all of them grade 1 or 2. AEs included hypertension (3 patients), hematuria (2 patients), myelotoxicity (1 patient), constipation (1 patient), and epistaxis and musculoskeletal disorders (1 patient).

Twenty patients (86.9%) demonstrated high adherence and three (13.1%) moderate adherence according to the MMAS-8 test. Table 1 shows non-adherence as measured by the answers of patients to the different questions in the questionnaire. The questions eliciting higher levels of non-adherence were questions 1 (Do you sometimes forget to take your medication?), 4 (Do you sometimes forget to take your medicines when you go on a trip or when you leave home?), and 8 Do you often find it difficult to remember that you must take all your medicines?).

Mean adherence according to the leftover pill counting method was 98.07% (± 2.21). All patients considered themselves to be adherent to treatment (overall adherence was >90%). A detailed analysis of adherence percentages shows that 20 patients presented with an adherence rate > 95% and 3 patients were seen to have an adherence rate between 90 and 95%. These 3 patients were the same ones who demonstrated moderate adherence on the MMAS-8 test.

The results of the EQ-5D-3L questionnaire (Table 2) showed that all patients were autonomous for self-care and 91.3% (21 patients) were autonomous for their activities of daily living (ADLs), 69.6% (16 patients) experienced no mobility problems, 78.3% (18 patients) did not report anxiety or depression, and 56.5% (13 patients) presented with some degree of pain. No patient claimed to have “many problems” on any of the dimensions evaluated.

The results of the EORTC QLQ-C30 questionnaire (Table 3) showed high scores on all functional scales, which means that the patients' functional level was high/healthy. Patients obtained top median scores (100 points) on three of the functional scales. Specifically, they could carry out their ADLs with no impediments (median: 100 points; range: 100–100); they could lead a normal social/family life without interference from their treatment (median: 100 points; range: 100–100), and their degree of anxiety, concern and irritability, and the intensity of their symptoms as assessed on this scale were very low (median: 100 points; range: 83–100). According to the EORTC QLQ-C30 scale, the score for overall health status/quality of life was 66.5 points (range: 58–83) out of 100, which denotes good health and a satisfactory quality of life. As regards symptoms-related items, patients had a low level of symptoms (fatigue: 11.11 (0–22.22), pain 16.66 (0–49.99) and nausea/vomiting 16.66 (0–33). Symptoms such as dyspnea (0; 0–0), insomnia (0; 0–6.38), anorexia (0; 0–0) and diarrhea (0; 0–0) were not reported.

The mean score on the FACIT-T scale was 46 (± 4.77), which indicates an absence of fatigue (Table 4).

The treatment subgroup analysis (ibrutinib vs venetoclax) did not demonstrate statistically significant adherence-related differences between the results of the MMAS-8 questionnaire (ibrutinib: 15 highly adherent patients and 3 moderately adherent ones; venetoclax: 5 highly adherent patients; p = 0.083) and those obtained following application of the leftover pill counting method (97.96 ± 1.46 vs 98.1 ± 2.41; p = 0.908). As far as quality of life was concerned, no significant differences were observed between the EORTC questionnaire (Table 3) and the FACIT-F scale (45.78 ± 5.31 vs 46.8 ± 2.05; p = 0.518). When the same data was analyzed according to lines of treatment (first line vs. other lines) no significant differences were observed between the results of the MMAS-8 questionnaire (1st line: 8 highly adherent patients; other lines: 12 highly adherent patients and 3 moderately adherent patients; p = 0.082) and those obtained when applying the leftover medication method (97.52 ± 2.42 vs 99.09 ± 1.33; p = 0.106). Differences were also absent with respect to quality of life, according to the EORTC QLQ-C30 questionnaire (Table 3), and fatigue (45 ± 5.3 vs 47.88 ± 2.99; p = 0.178).

The present study evaluated adherence and quality of life in patients diagnosed with CLL treated with the new oral antineoplastic agents for at least 6 months. The results obtained showed that patients treated with ibrutinib or venetoclax demonstrated high adherence rates, according to the MMAS-8 questionnaire and the leftover pill counting method. According to the EQ-5D-3L and EORTC QLQ-C30 questionnaires all of them had a good quality of life. Application of the FACIT-F questionnaire revealed an absence of fatigue.

Incorporation of oral antineoplastics to the treatment of CLL has resulted in an improvement in terms of efficacy as these agents are capable of controlling the disease even in patients with adverse genetic and/or molecular factors. The severity associated with neoplastic disease may make one presume optimal adherence. However, there tends to be wide variability, with adherence rates in hemato-oncologic patients ranging between 14% and 100%23.

In the context of CLL, Garner etal.13 analyzed the impact of adherence on the real-world health outcomes of CLL patients treated with ibrutinib for at least 6 months. They calculated the adherence rate on the basis of dispensing records and set the adherence threshold at 95%. However, the mean adherence rate of their patients stood at 91.7%. The authors concluded that, even if their data was based on a limited patient sample, their lower-than-expected adherence rate warranted the establishment of oral chemotherapy management programs that provided information on adverse event management, reviewed drug–drug interactions and encouraged collaboration with other specialists in order to overcome the barriers to adherence. The authors also recognized that pharmacists were ideally placed to spearhead such programs. The good tolerance to treatment exhibited by the patients and the fact that they received pharmaceutical care at every appointment with the pharmacy department may have contributed to the good adherence outcomes eventually obtained in the study.

On the other hand, quality of life data is becoming increasingly important in connection with hemato-oncologic patients as it allows an assessment not only of the impact of disease but also of the impact of any intervention on the patients' ADLs, making it therefore possible to analyze potential differences between treatments,

Youron et al24 was the first study to evaluate quality of life in patients with CLL treated with the new oral antineoplastics (ibrutinib). These authors evaluated quality of life in patients with CLL by means of the EORTC QLQ-C30 and QLQ-CLL17 questionnaires25, and compared their results with those of a control group made up of healthy individuals. All the subjects had to fill out the questionnaire once during the course of the study, except for those on chemotherapy, who filled it out at the beginning and at the end of treatment. The study concluded that patients treated with ibrutinib scored higher on social functioning and demonstrated less fatigue and appetite loss than those on chemotherapy. Moreover, those patients obtained lower scores on the items related to “future health and functioning concerns” than patients treated with chemotherapy on the QLQ-CLL17 questionnaire.

Patients included in this study obtained higher scores than those in Youron etal. on all functional scales, except cognitive function. It should be mentioned that the median age in the samples was different, with patients in Youron etal. being younger (median: 59 years; range: 44–70) than those in the present study (mean age: 69.7 years ± 8.02). Age could explain the differences observed in cognitive status but cannot justify the higher functional scores obtained in our sample. As far as symptoms are concerned, patients in this study obtained better results, scoring 0 points on some of the symptoms. The only item where our patients obtained lower scores than Youron etal. was overall health status. This may be due to the fact that those authors excluded patients with severe comorbidities whereas our study admitted all the patients who met the inclusion criteria.

The strengths of this study are related to the fact that, as recommended by the literature, a combination of two different methods was used to measure adherence15. This made it possible to obtain reliable complementary information and minimize the limitations of each one of the methods. Moreover, although an adherence rate ≥ 80% is considered acceptable for chronic cases (Dashputre etal.)26, even for cancer patients, a threshold adherence rate ≥ 90% was selected for this study on the basis of the findings in Marin etal.8, a seminal hemato-oncologic study that establishes a relationship between adherence and therapeutic outcome in patients diagnosed with CML with complete cytogenetic response treated with imatinib. The quality-of-life questionnaires used in the study (EORTC QLQ-C30, EQ-5D-3L and the FACIT-F scale) were selected based on the published literature and because they were commonly used in CLL clinical trials27. Finally, it must be highlighted that this study, which provides the first data available on the subject based on a Spanish sample, was carried out in conjunction with the hospital's Hematology Department as a stepping stone to carrying out a larger-scale multicenter study that may provide a better understanding not only of the patients' adherence rate and quality of life, but also of the factors capable of driving them. The study was also meant to pave the day to an analysis with greater statistical power.

One possible limitation of this study is that the leftover pill counting method for measuring adherence was applied on the telephone instead of face-to-face in the pharmacy department. The reason why pill counting was done remotely was that most patients were on the hospital's telepharmacy program, which comprised remote pharmaceutical care (telephone interviews), administered by an oncological pharmacist prior to dispatching medicines to the patient's home. All questionnaires and medication counts were done remotely through a telephone interview, following the same protocol for every patient.

Another limitation of this study was that the quality-of-life questionnaire was only administered once, which made it impossible to understand the effect of the progression of the disease or the improvement of the symptoms on the patients' wellbeing, or to gage the effect of the treatment on the patients' quality of life over a long period of time. It should be said that the CLL-specific QLQ-CLL17 questionnaire25 (complementary to the QLQ-C30 questionnaire) was not included in our study because the questionnaire was being validated by the EORTC group at the time the study was conducted.

The reduced size of the sample and the high number of adherent patients may explain why no statistically significant differences were observed when the data was analyzed per treatment subgroup and per line of treatment. At the same time, those factors prevented a determination of the factors that could predict low adherence to treatment or impact the patients' quality of life.

In a nutshell, it can be concluded that patients with CLL treated with oral antineoplastics demonstrated a high rate of adherence and claimed to have a good quality of life, with high scores on functional scales, a low intensity of symptoms and no fatigue. The factors contributing to these good results include the patients' high tolerance to the treatment and the effective pharmaceutical care provided at the different consultations.

This is the first study in Spain to contribute real world data on the adherence and quality of life of patients with chronic lymphocytic leukemia treated with the new oral antineoplastics. The results obtained in this pilot study will pave the way for the design of a larger-scale multicenter study on the subject that provides an understanding not only of adherence rates and quality of life but also of the factors that could be used as predictors of poor adherence and/or poor quality of life.

No funding.

This research project was authorized by the Ethics Committee for Research with Medical Products of Cantabria (internal code 2021/169 (decision 9/2021 of 14 May 2021).