|Year : 2017 | Volume
| Issue : 4 | Page : 140-144
Assessment of chronic myeloid leukemia patients' adherence with “tyrosine kinase inhibitors” in King Abdulaziz Medical City
Saad Saleh Aldughaythir1, Yousef Alolah2, Mohsen Alzahrani3, Fahad Abdulaziz Alsayed1, Bader Muaykil Alqahtani1, Omar Abdulrahman Alhathlol1
1 Department of Medicine, College of Medicine, King Saud bin Abdulaziz University, Riyadh, KSA
2 Department of Pharmacy Practice, College of Pharmacy, King Saud bin Abdulaziz University, Riyadh, KSA
3 Department of Oncology, King Abdulaziz Medical City, Riyadh, KSA
|Date of Web Publication||12-Jan-2018|
Dr. Saad Saleh Aldughaythir
College of Medicine, King Saud bin Abdulaziz University, Riyadh
Source of Support: None, Conflict of Interest: None
CONTEXT: Worldwide, chronic myeloid leukemia (CML) accounts for 15% of all leukemia types. CML treatment and outcome has improved dramatically from the average survival of 3–5 years in the past to almost normal life expectancy with the new targeted therapy with tyrosine kinase inhibitors (TKI). Compliance of CML patients with oral TKIs is a medically challenging issue preventing achieving a favorable outcome.
AIMS: The aim of this study is to assess CML patients' adherence to treatment in King Abdulaziz Medical City (KAMC).
SUBJECTS AND METHODS: This is a prospective, observational study that includes all patients diagnosed with CML in KAMC-Riyadh (KAMC-R) where patients were interviewed before receiving TKI prescription and during a subsequent visit. Consent, demographics, and medication data were obtained in the first encounter. Compliance and reasons for noncompliance were assessed using pill count methods during the second visit.
STATISTICAL ANALYSIS USED: Statistical analysis was performed using SPSS.
RESULTS: A total of 63 CML patients are followed and treated in KAMC-R at the time of conducting this study. Sixteen patients were excluded from the study due to either loss of follow-up or using a non-TKI treatment option. The study was conducted on 47 patients; male:female ratio was 20 (40%):28 (60%). The mean age was 51 years (range 23–76 years). Twenty-four patients (51%) were fully compliant to the TKIs while 23 patients (49%) were not compliant. The study reported three main reasons for noncompliance, drug toxicity in 7 patients (30%), forgetfulness in 7 patients (30%), and ignorance in 2 patients (9%).
CONCLUSIONS: To the best of our knowledge, this is the first study assessing compliance of CML patients with TKIs among Saudi population. Noncompliance with TKIs is a major health-care problem affecting the outcome of treatment. Stressing on patient education before and during TKIs treatment might improve the compliance.
Keywords: Chronic myeloid leukemia, compliance, tyrosine kinase inhibitors
|How to cite this article:|
Aldughaythir SS, Alolah Y, Alzahrani M, Alsayed FA, Alqahtani BM, Alhathlol OA. Assessment of chronic myeloid leukemia patients' adherence with “tyrosine kinase inhibitors” in King Abdulaziz Medical City. J Appl Hematol 2017;8:140-4
|How to cite this URL:|
Aldughaythir SS, Alolah Y, Alzahrani M, Alsayed FA, Alqahtani BM, Alhathlol OA. Assessment of chronic myeloid leukemia patients' adherence with “tyrosine kinase inhibitors” in King Abdulaziz Medical City. J Appl Hematol [serial online] 2017 [cited 2018 Jan 16];8:140-4. Available from: http://www.jahjournal.org/text.asp?2017/8/4/140/223177
| Introduction|| |
Chronic myeloid leukemia (CML) is a malignant hematologic disorder characterized by a clonal disorder of hematopoietic stem cells that occurs as a result of a translocation between chromosomes 9 and 22, known as Philadelphia chromosome. It accounts for 15% of all leukemia cases worldwide. CML has recent advances in targeted therapeutic options with tyrosine kinase inhibitors (TKI) leading to both improvements in survival and reduction in morbidity and mortality.
There are many treatment options indicated for CML patients to control the progression of the disease and help patients to reach their therapeutic target which is complete hematological, cytogenetic, and molecular response. Historically, chemotherapy, mainly hydroxyurea, busulfan, cytarabine, and interferon-alpha were commonly used to treat CML patients, with an average survival of around 3–5 years. Allogeneic stem cell transplant was the only curative option for CML patients. In the past two decades, a huge transformation in the treatment of CML occurred due to the approval of imatinib, a “TKI,” which made CML a chronic disease rather than a fatal disease. Nowadays, 88% of CML patients are expected to have a 5-year survival.
TKIs work by inhibiting the tyrosine kinase domain, which is responsible for the unregulated cell division in CML, by binding to a segment of the kinase domain that fixes the enzyme in a closed or nonfunctional state. In a study conducted on CML patients receiving imatinib in Ataturk University Medical Faculty Training Hospital between 2006 and 2009, they all showed a complete hematological response and 71% of them showed a complete cytogenetic response. In 2010, the USFDA approved dasatinib and nilotinib, the second generation of TKIs, characterized by fewer side effects and better outcome. The use of allogeneic stem cell transplant in the treatment of CML in the current TKI era has been reduced significantly and most of the patients enjoy long-term survival with oral medications and lower toxicity profile.
Some CML patients fail to achieve optimal response to TKIs due to multiple reasons including resistance to TKIs, intolerance to TKIs side effects, or due to nonadherence with their TKIs. A global data show that one-third of CML patients are not fully adherent to TKIs.,, One of the studies that were carried out in the UK assessed 87 patients' adherence to TKI and showed that 98% of them are not fully adherent. However, there is no known published data in the Middle East assessing adherence of CML patients to their TKIs and the effect of drug compliance on the disease outcome. It is believed that such study will help health-care providers to improve management guidelines and patient care. Therefore, this study was conducted to assess the compliance of CML patients to the use of TKI medications in King Abdulaziz Medical City in Riyadh (KAMC-R) and the effect of drug compliance on disease response.
| Subjects and Methods|| |
This study was designed as a case series, prospective, observational study with two points of assessment during 2 consecutive different visits, 3 months apart.
The primary objective is to study the adherence of CML patients to oral TKIs.
The secondary objectives are to study the effect of the adherence on outcome and reasons for nonadherence in the study population.
Study site and sample size
The study was conducted over a period of 12 months, from July 2015 to July 2016. The study was conducted in the Outpatient Hematology Clinic in KAMC-R, Kingdom of Saudi Arabia (1300-bed referral teaching hospital). All patients with the diagnosis of CML on TKI therapies are included in this study. Patients who lose the follow-up during the period of the study and patients who are treated by non-TKI options were excluded from the study.
In this study, the adherence of enrolled and eligible CML patients to oral TKIs (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) was assessed over a period of 90 days. The method that was used to evaluate patients' compliance was tablet counts. Patients were interviewed twice, first to obtain verbal consent and collect patients' demographic, medical, and treatment data before starting the regimen and second after finishing the regimen to assess the adherence and reasons of nonadherence. Hematological response by CBC count and molecular response by quantitative measurement of the fusion protein (BCR-ABL) at the first visit and the follow-up visit after 3 months were obtained and recorded from the hospital clinical information system.
Approval by the ethical board at King Abdullah International Medical Research Center for our study proposal was obtained before starting the study; IRB approval number is 486/15. The data collected and patients interviewed by three study members who were trained in the method of pill counting. Standardized data collection sheet was generated to collect these data. The response assessment from blood investigations was obtained from the hospital electronic health records.
Statistical analysis was performed using SPSS software version 22 (IBM, Armonk, NY: IBM Corp.). Continuous and categorical variables are given as the mean and as the number and percentage, respectively. Chi-square test was used to compare between categorical variables. P < 0.05 was considered to be statistically significant.
| Results|| |
A total of 63 CML patients were included in this study from KAMC-R; 13 patients were excluded due to loss of follow-up, 2 patietns were excluded after they were instructed by the treating physician to stop taking medications during the period of the study when they achieved deep molecular response, and 1 patient was excluded after he was shifted to other non TKIs treatment. The study was conducted on 47 patients and showed a higher prevalence of the disease among female population in our institute; male:female ratio was 20 (42.5%):27 (57.5%). The mean age of patients was 51 years old (range 23–76). More than half of our patients are over 50 years old, n = 28 (60%). The education level of subjected patients was variable.
By measuring the compliance using the pill counting method, the study showed that 24 patients (51%) were fully compliant to the TKIs while 23 patients (49%) were not compliant. Among noncompliant patients and during 90 days, 4 patients (17%) took at least one extra dose, 6 patients (26%) missed up to 5 doses, 4 patients (17%) missed 6–10 doses, 2 (8.6%) patients missed 11–15 doses, and 7 patients (30%) missed >15 doses. The study showed that more than half of the noncompliant patients were females, n = 14 (60.8%), while noncompliant patients were males, n = 9 (39.2%) [Table 1].
The study reported three main reasons for noncompliance; side effects were reported as a reason for noncompliance in 7 patients (30.4%), forgetfulness in 7 patients (30.4%), and laziness in 2 patients (9%). Seven patients (30.4%) claimed that they are fully compliant although our counting method suggests the opposite. Moreover, 11 patients reported difficulties in being compliant to the medication, 8 of whom (73%) have shown to be noncompliant.
We found that the following factors affect compliance to oral TKIs: patient age, level of education, type of TKI medication, and duration of disease. Our study showed that the noncompliance rate decreases with increasing patient's age; 8 out of 13 patients (61.5%) whose age range from 20 to 39 have shown to be noncompliant, 11 out of 21 (52.4%) patients whose age range from 40 to 59 have been reported as noncompliant, and 4 out of 13 (30.7%) patients whose age are >60 years old have shown to be noncompliant. There is no significant difference in the level of compliance between different age groups, P = 0.297 [Table 1].
Noncompliance rates have shown to be higher in illiterate patients and patients with bachelor degree or more, 9 out of 14 (64.2%) and 8 out 13 (61.5%) patients were reported as noncompliant, respectively. The majority of patients, n = 14 (70%), with primary or high school level have shown to be compliant. There is no significant difference in the level of compliance between different educational levels, P = 0. 181 [Table 1].
In relation to the TKIs used by the patients, patients who are using dasatinib showed a higher rate of noncompliance with n = 9 (75%) and nilotinib showed a lower rate of noncompliance with n = 4 (44%). Fifteen patients (56.5%) who were using imatinib were reported as fully compliant. There is no significant difference in the level of compliance between different TKIs, P = 0. 158 [Table 2].
The study showed that the noncompliance rate was higher in newly diagnosed patients (<1 year since starting the TKIs therapy), n = 2 (100%), and patients who has been taking the TKIs for >5 years, n = 11 (52.3%), while those who have been taking the TKIs for 1–2 years, n = 2 (66.7%), and 3–5 years, n = 12 (57.1%), showed higher rate of compliance. There is no significant differences in the level of compliance between various durations since starting TKIs, P = 0.476. This study also showed that the frequency of TKIs administration per day and polypharmacy has no impact on compliance [Table 2].
We have reported a decrease in the molecular response with at least one log increase in BCR-ABL percentage in four noncompliant patients while none of the compliant patients have shown a decrease in the molecular response, which implies an effect of compliance on the outcome.
| Discussion|| |
In this study, we report the pattern and the outcome of compliance to TKI drugs in 47 patients. Although there is no available data regarding the prevalence of the disease in Saudi Arabia, Albakr's study reviewed the incidence of the disease in Saudi Arabia in 2009 and reported 100 cases which are around half of our participants in this study. The review also reported a higher incidence of the disease among the male population, which is consistent with the global data. However, female population represents the majority of CML cases in our institute.
Noncompliant to the treatment of chronic diseases, for example, diabetes mellitus, hypertension, and dyslipidemia has already been investigated and assessed.,,, However, noncompliance to relatively newly introduced oncology medications has been rarely assessed worldwide, and almost never assessed locally although it carries a huge medical and economic burden.
The literature showed a variation in the rate of patients' compliance to TKIs, and this might be due to the differences in the assessment tools that had been used. ADAGIO study has used subjective method, for example, Basal Assessment of Adherence Scale and objective method, for example, pill counts and showed a higher rate of compliance in the subjective measure. This is consistent with our finding where 30% of noncompliant patients responded negatively when they were asked about their compliance behavior. This implies that some patients have false self-perception about their compliance, and objective measures should be employed to obtain an accurate result.
Some variables were associated with noncompliance such as age, number of years since diagnosis, and educational background. Younger patients reported a lower rate of compliance, and this was consistent with the study that was conducted by Hammersmith Hospital. Moreover, newly diagnosed patients and patients who spent >5 years using TKIs have shown a lower rate of compliance; ADAGIO study has reported similar result and interprets it as patients become laxer on their medication over the years. Noncompliance among newly diagnosed patient could be attributed to lack of enough education about the disease and treatment. In our cohort, patients with low education levels and those with bachelor degree or more have shown a lower compliance rate; this was expected for patients with lower education level as some studies suggested so., However, it was an unexpected finding regarding those with bachelor degree or more to be noncomplaint.
Surprisingly, the frequency of TKI administration per day and polypharmacy did not influence compliance in this study, and interestingly, an increased number of comorbidities improve compliance with TKIs. However, this result cannot be extrapolated due to small sample size.
Most studies evaluated imatinib while a limited number of studies evaluated the second generation TKIs, for example, nilotinib and dasatinib. This study showed that patients on dasatinib have a higher rate of noncompliance, unlike imatinib and nilotinib which showed the opposite; although patients on nilotinib were expected to show a higher rate of noncompliance due to its multiple daily doses and complex guidelines for administration, a study conducted in Italy reported similar results. Patient who was taking bosutinib has shown to be compliant although it is associated with multiple side effects. We think patients valued bosutinib since it is second line; however, more patients on bosutinib are needed to reach a solid conclusion.
In general, compliance reduces the risk of poor treatment outcome by 25%. However, patients should be observed for a longer period to look for the impact of noncompliance on the molecular response. Yet, observing patients in longer period has no significance over observing patients for short period and might be enough to show the effects on molecular response, especially patients in major molecular response as some studies suggested.,
Various methods were found in the literature to evaluate compliance. For example, microelectronic monitoring system, which is the gold standard, was used in the study that was conducted in Hammersmith Hospital. Other studies used Basel Assessment of Adherence Scale and Morisky Medication Adherence Questionnaire. Pill counts and medication possession ratio were also used in others.,,
This study cannot be generalized to the whole CML population due to the following limitations; small sample size, short follow-up period to review the compliance, and the fact that it was conducted in one center. Therefore, we recommend including multicenter for future research to obtain a larger group of patients with longer follow-up period. In addition, during our study, we assess adherence using pill count method which is not very reliable, and for future studies, we advise to use a more reliable method such as electronic medication dispensers.
| Conclusion|| |
To the best of our knowledge, this is the first study assessing compliance of CML patients with TKIs among Saudi population. Noncompliance with TKIs is a major health-care problem that affects the outcome of treatment and might lead to wastage of resources and premature switching to more expensive options. Applying intensive patient education before and during TKIs treatment might improve compliance, therapeutic outcomes and reduce the total cost of care of CML patients.
We would like to thank the research unit members at King Saud bin Abdulaziz University for their unlimited support.
Financial support and sponsorship
This study was financially supported by King Abdullah International Medical Research Center, Riyadh, KSA.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hoffbrand A, Moss P. Essential Hematology. 6th
ed., Ch. 14. London: Wiley-Blackwell; 2001. p. 192-3.
Semin H. Chronic myeloid leukemia: A historical perspective. Semin Hematol 2010;47:302-11.
Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, et al.
Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009;23:1054-61.
Richard H, Denise F. Lippincott's Illustrates Reviews Pharmacology. 5th
ed., Ch. 39. North America: Lippincott Williams & Wilkins; 2012. p. 509-10.
Yousef B, Flat E. Hematologic, cytogenetic, and molecular responses to imatinib therapy for chronic myeloid leukemia: A single-center experience in Turkey. Turk J Med Sci 2012;42:31-8.
Cortes J, Quintás-Cardama A, Kantarjian HM. Monitoring molecular response in chronic myeloid leukemia. Cancer 2011;117:1113-22.
Hiwase DK, Yeung DT, White DL. Optimizing the selection of kinase inhibitors for chronic myeloid leukemia patients. Expert Rev Hematol 2011;4:285-99.
Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, et al.
Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 2010;28:2381-8.
Noens L, van Lierde MA, De Bock R, Verhoef G, Zachée P, Berneman Z, et al.
Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: The ADAGIO study. Blood 2009;113:5401-11.
Darkow T, Henk HJ, Thomas SK, Feng W, Baladi JF, Goldberg GA, et al.
Treatment interruptions and non-adherence with imatinib and associated healthcare costs: A retrospective analysis among managed care patients with chronic myelogenous leukaemia. Pharmacoeconomics 2007;25:481-96.
Rashed A, Osamah K. Incidence trend of leukemia reported cases in the Kingdom of Saudi Arabia, an observational descriptive statistic from Saudi cancer registry. Int J Biomed Res 2014;5:522-9.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
Sabate E. Adherence to Long-Term Therapies: Evidence for Action. Ch. 1. Geneva: World Health the Organization; 2003. p. 4.
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487-97.
Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to medications: Insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Annu Rev Pharmacol Toxicol 2012;52:275-301.
Partridge AH, Avorn J, Wang PS, Winer EP. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst 2002;94:652-61.
Al-Rasheedi AA. The role of educational level in glycemic control among patients with type II diabetes mellitus. Int J Health Sci (Qassim) 2014;8:177-87.
Santoleri F, Sorice P, Lasala R, Rizzo RC, Costantini A. Patient adherence and persistence with imatinib, nilotinib, dasatinib in clinical practice. PLoS One 2013;8:e56813.
DiMatteo MR. Variations in patients' adherence to medical recommendations: A quantitative review of 50 years of research. Med Care 2004;42:200-9.
de Almeida MH, Pagnano KB, Vigorito AC, Lorand-Metze I, de Souza CA. Adherence to tyrosine kinase inhibitor therapy for chronic myeloid leukemia: A Brazilian single-center cohort. Acta Haematol 2013;130:16-22.
Le Cesne A, Ray-Coquard I, Bui BN, Adenis A, Rios M, Bertucci F, et al.
Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: An open-label multicentre randomised phase 3 trial. Lancet Oncol 2010;11:942-9.
Jönsson S, Olsson B, Söderberg J, Wadenvik H. Good adherence to imatinib therapy among patients with chronic myeloid leukemia – A single-center observational study. Ann Hematol 2012;91:679-85.
[Table 1], [Table 2]