Acessibilidade / Reportar erro

Adherence and/or discontinuation of imatinib mesylate in patients with chronic myeloid leukemia

ABSTRACT

Adherence to imatinib mesylate improves clinical outcomes and promotes a reduction in health expenditure. However, treatment duration and lack of efficacy decrease adherence to pharmacotherapy, resulting in increased mortality associated with Chronic Myeloid Leukemia. This study aimed to evaluate and compare adherence and/or discontinuation of imatinib mesylate in different studies from the literature. An integrative review of original articles published between the years of 2004 and 2014 was performed using the databases PubMed/MEDLINE, Scopus and SciELO. The descriptor "imatinib" was used in two combinations employing the connector AND between terms: "medication adherence'' AND ''imatinib" AND "leukemia'' and ''patient compliance'' AND "imatinib" AND "leukemia". We identified 476 studies, being 14 included in the study. The rates of adherence and discontinuation were diverse, ranging from 19.0 to 97.0% and from 1.8 and 41.0%, respectively, and a high number of longitudinal studies was observed (71.4%). Most studies used questionnaires as an indirect method to assess adherence and factors related to poor adherence were adverse drug reactions, dose changes and unavailability of the medication. Patient education associated with follow up by pharmacists and other health professionals can improve patient adherence and minimize the pharmacotherapy discontinuation.

Uniterms:
Chronic Myeloid Leukemia/treatment; Imatinib Mesylate/treatment adherence; Medication adherence; Pharmacotheraphy review.

INTRODUCTION

Chronic myeloid leukemia (CML) represents 7 to 20% of all hematologic neoplasias, with an incidence between one and two cases per 100,000 individuals per year (Mauro et al., 2015MAURO, M.J.; DAVIS, C.; ZYCZYNSKI, T.; KHOURY, H.J. The role of observational studies in optimizing the clinical management of chronic myeloid leukemia. Ther. Adv. Hematol. , v.6, n.1, p.3-14, 2015.). Its frequency is higher among adults aging between 55 to 60 years old and rare during childhood, accounting for only 3% of all the cases of CML (Tefferi et al., 2005TEFFERI, A.; DEWALD, G.W.; LITZOW, M.L.; CORTES, J.; MAURO, M.J.; TALPAZ, M. , KANTARJIAN, H.M. Chronic myeloid leukemia: current application of cytogenetics and molecular testing for diagnosis and treatment. Mayo Clin. Proc., v.80, n.3, p.390-402, 2005.; Suttorp, Millot, 2010SUTTORP, M.; MILLOT, F. Treatment of pediatric chronic myeloid leukemia in the year 2010: Use of tyrosine kinase inhibitors and stem-cell transplantation. Hematol. Am. Soc. Hematol. Educ. Progr., v.2010, n.1, p.368-76, 2010.). It affects both sexes, with a slight predominance in males in a ratio of 2.2 men for 1.4 women affected (Berger et al., 2005BERGER, U. ; MAYWALD, O. ; PFIRRMANN, M. ; LAHAYE, T.; HOCHHAUS, A.; REITER, A.; HASFORD, J. ; HEIMPEL, H. ; HOSSFELD, D.K. ; KOLB, H.J. ; LÖFFLER, H. ; PRALLE, H. ; QUEISSER, W. ; HEHLMANN, R. Gender aspects in chronic myeloid leukemia: long-term results from randomized studies. Leukemia, v.19, n.6, p.984-9, 2005.).

CML is characterized by a clonal myeloproliferative neoplasia of cells of the granulocyte lineage, which retains the abilities of maturation and differentiation (Perrotti et al., 2010PERROTTI, D.; JAMIESON, C.; GOLDMAN, J.; SKORSKI, T. Chronic myeloid leukemia: mechanisms of blastic transformation. J. Clin. Invest., v.120, n.7, p.2254-64, 2010.). It is associated with a specific cytogenetic mutation on chromosome "Philadelphia" (Ph) which is a cytogenetic marker of CML resulting from a reciprocal translocation between the long arms of chromosomes 9 and 22 containing the hybrid gene BCR/ABL. The coding of this gene is characterized by an enzyme with high tyrosine kinase activity responsible for the uncompensated cell proliferation, producing favorable conditions to the establishment of neoplastic process (Hehlmann, Hochhaus, Baccarani, 2007HEHLMANN, R.; HOCHHAUS, A.; BACCARANI, M. Chronic myeloid leukemia. Lancet, v.370, n.9584, p.342-50, 2007.; Marin et al., 2010MARIN, D.; BAZEOS, A.; MAHON, F.X.; ELIASSON, L.; MILOJKOVIC, D.; BUA, M.; APPERLEY, J.F.; SZYDLO, R.; DESAI, R.; KOZLOWSKI, K.; PALIOMPEIS, C.; LATHAM, V.; FORONI, L.; MOLIMARD, M.; REID, A.; REZVANI, K.; DE LAVALLADE, H.; GUALLAR, C.; GOLDMAN, J.; KHORASHAD, J.S. 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., v.28, n.14, p.2381-8, 2010.; Perrotti et al., 2010PERROTTI, D.; JAMIESON, C.; GOLDMAN, J.; SKORSKI, T. Chronic myeloid leukemia: mechanisms of blastic transformation. J. Clin. Invest., v.120, n.7, p.2254-64, 2010.). Clinically, the stages of the disease are differentiated according to their evolution, being divided into chronic, accelerated and blast crisis or acute phases. In the acute phase, survival rates decrease drastically (Cortes, Kantarjian, 2012CORTES, J.; KANTARJIAN, H. How I treat newly diagnosed chronic phase CML. Blood, v.120, n.7, p.1390-7, 2012.).

The therapeutic arsenal of CML comprises chemotherapeutic agents like busulfan and hydroxyurea, the immunobiological agent interferon α, hematopoietic stem cells transplantation which is the only curative treatment and tyrosine kinase inhibitors represented by first generation drugs such as imatinib mesylate and second generation drugs such as nilotinib and dasatinib. Used since 2001, imatinib has become the first-line therapy in clinical protocol of CML due to some advantages such as low toxicity, oral administration and significant improvements in survival rates of patients undergoing treatment (85%). Imatinib use during the chronic phase of the disease is able to provide complete hematologic response rates (CHR), complete cytogenetic remission (CCR) and complete molecular remission (CMR) higher than 90% (Cortes, Kantarjian, 2012CORTES, J.; KANTARJIAN, H. How I treat newly diagnosed chronic phase CML. Blood, v.120, n.7, p.1390-7, 2012.; Chen et al., 2014CHEN, T.C.; CHEN, L.C.; HUANG, Y.B.; CHANG, C.S. Imatinib adherence associated clinical outcomes of chronic myeloid leukaemia treatment in Taiwan. Int. J. Clin. Pharm., v.36, n.1, p.172-81, 2014.; Anderson et al., 2015ANDERSON, K.R.; CHAMBERS, C.R. ; LAM, N. ; YAU, P.S. ; CUSANO, F. ; SAVOIE, M.L.; SHEIKH, N. Medication adherence among adults prescribed imatinib, dasatinib, or nilotinib for the treatment of chronic myeloid leukemia. J. Oncol. Pharm. Pract., v.21, n.1, p.19-25, 2015.).

Adherence to treatment with tyrosine kinase inhibitors results in improved clinical outcomes and promotes reduction in health costs. However, some patients present poor adherence to tyrosine kinase inhibitors impairing the responses to the treatment (Noens et al., 2009NOENS, L.; VAN LIERDE, M.A.; DE BOCK, R.; VERHOEF, G.; ZACHÉE, P.; BERNEMAN, Z.; MARTIAT, P.; MINEUR, P.;, VAN EYGEN, K.; MACDONALD, K.; DE GEEST, S.; ALBRECHT, T.; ABRAHAM, I. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood , v.113, n.22, p.5401-11, 2009.; Hirji et al., 2013HIRJI, I.; GUPTA, S.; GOREN, A.; CHIROVSKY, D.R.; MOADEL, A.B.; OLAVARRIA, E.; VICTOR, T.W.; DAVIS, C.C. Chronic myeloid leukemia (CML): association of treatment satisfaction, negative medication experience and treatment restrictions with health outcomes, from the patient's perspective. Health Qual. Life Outcomes, v.11, p.167, 2013. DOI: 10.1186/1477-7525-11-167.). Adherence to pharmacotherapy is the adequate compliance with the treatment regimen proposed by the doctor or other health care provider and is related to demographic and social conditions of the patient and to characteristics of the disease and the treatment (WHO, 2003WORLD HEALTH ORGANIZATION. WHO. Adherence to long-term therapies. Evidence for action. Geneva: WHO, 2003. 194p.). Intentional factors (lack of knowledge of the disease, travel, lack of efficacy) and unintentional (duration of treatment, adverse effects, unavailability in health services, forgetfulness, financial difficulties) can sometimes have an impact on patient adherence to treatment with imatinib mesylate, resulting in an increase in the mortality rate associated with the progression of CML (Noens et al., 2009NOENS, L.; VAN LIERDE, M.A.; DE BOCK, R.; VERHOEF, G.; ZACHÉE, P.; BERNEMAN, Z.; MARTIAT, P.; MINEUR, P.;, VAN EYGEN, K.; MACDONALD, K.; DE GEEST, S.; ALBRECHT, T.; ABRAHAM, I. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood , v.113, n.22, p.5401-11, 2009.; Eliasson et al., 2011ELIASSON, L.; CLIFFORD, S.; BARBER, N.; MARIN, D. Exploring chronic myeloid leukemia patients' reasons for not adhering to the oral anticancer drug imatinib as prescribed. Leuk. Res. , v.35, n.5, p.626-30, 2011.).

One of the consequences related to non-adherence to imatinib is associated with resistance or intolerance to the drug. In this situation, many patients respond to tyrosine kinase inhibitors of second generation such as dasatinib and nilotinib, which are more potent drugs than imatinib and can improve the quality of life of patients with this clinical condition (Jabbour et al., 2012aJABBOUR, E.J.; KANTARJIAN, H.; ELIASSON, L.; CORNELISON, A.M.; MARIN, D. Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Am. J. Hematol. , v.87, n.7, p.687-91, 2012a.; Bhamidipati et al., 2013BHAMIDIPATI, P.K.; KANTARJIAN, H.; CORTES, J.; CORNELISON, A.M.; JABBOUR, E. Management of imatinib-resistant patients with chronic myeloid leukemia. Ther. Adv. Hematol., v.4, n.2, p.103-17, 2013.). However, the survival rate of patients with CML adherent to imatinib is 16.9% higher compared to non-adherent patients. Non-adherence and/or discontinuation to imatinib reduces the possibility of CCR in 18% of CML cases (Ganesan et al., 2011GANESAN, P. ; SAGAR, T.G.; DUBASHI, B.; RAJENDRANATH, R.; KANNAN, K. ; CYRIAC, S.; NANDENNAVAR, M. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am. J. Hematol., v.86, n.6, p. 471-4, 2011.). Thus, the adherence to imatinib can prevent complications or exacerbations of CML caused by treatment failures, which would result in hospitalizations and procedures related to increases in health care costs (Halpern et al., 2009HALPERN, R.; BARGHOUT, V.; ZAROTSKY, V.; WILLIAMS, D.E. Costs and utilization associated with imatinib adherence in patients with chronic myeloid leukemia or gastrointestinal stromal tumors. JCOM, v.16, n.5, p.215-23, 2009.; Cid et al., 2013CID, D.M; MAGALHÃES, S.M.; QUIXADÁ, A.T.; HONÓRIO, R.P.; COSTA, P.F.; REIS, S.R.; CARVALHO, S.M.; CID, D.A.; SUCUPIRA, R.M.; DE OLIVEIRA, M.F. Chronic myeloid leukemia: an overview of the determinants of effectiveness and therapeutic response in the first decade of treatment with imatinib mesylate in a Brazilian hospital. Rev.Bras. Hematol. Hemoter. v.35, n.6, p.389-94, 2013.).

Since adherence to imatinib is crucial for successful treatment of patients with CML, its evaluation is necessary.It can be performed by direct methods such as detection of drug or metabolite in biological fluids, addition of a biological marker and direct observation of the patient and/or indirect methods, which are simple and easy to perform such as patient diary, questionnaires, drug records, frequency of medication withdrawal in pharmacies, electronic monitoring of medication and manual pill count (Jabbour et al., 2012aJABBOUR, E.J.; KANTARJIAN, H.; ELIASSON, L.; CORNELISON, A.M.; MARIN, D. Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Am. J. Hematol. , v.87, n.7, p.687-91, 2012a.; Pérez-Escamilla et al., 2015PÉREZ-ESCAMILLA, B.; FRANCO-TRIGO, L.; MOULLIN, J.C.; MARTÍNEZ-MARTÍNEZ, F.; GARCÍA-CORPAS, J.P. Identification of validated questionnaires to measure adherence to pharmacological antihypertensive treatments. Patient Prefer. Adherence, v.9, p.569-78, 2015.).

Aim of the review

This review was developed in order to evaluate and compare adherence and/or discontinuation rates to imatinib mesylate in patients with CML in different studies found in scientific literature.

METHODS

An integrative review was performed with original articles published in scientific literature from 2004 to 2014. This type of evaluation allows to incorporate studies with different methods, such as experimental and non-experimental studies, while the systematic review is primarily focused on experimental studies.

Search Strategy

The articles were searched in the PubMed/MEDLINE, Scopus and SciELO databases. The Medical Subject Heading (MeSH) was used to define the descriptors. The descriptor "imatinib" was used in two combinations with the descriptors "medication adherence", "leukemia" and "patient compliance" using the connector AND between the terms: ''medication adherence'' AND ''imatinib'' AND ''leukemia'' and ''patient compliance'' AND "imatinib" AND "leukemia". The limits established to the search were publications between January 1st, 2004 and December 31st, 2014 and in English, Spanish and Portuguese languages.

Inclusion and exclusion criteria

In the first phase, the articles were identified using the search criteria and all the duplicate records were deleted.

In the second stage, a prior reading of the title and abstract of the selected articles was performed in order to include only original articles, which their main objective was to assess adherence rates and/or discontinuation of imatinib in patients with CML. Review articles, notes, correspondence, editorial and letter were excluded. In the last step, articles were excluded if they did not analyze the rates of adherence and/or discontinuation of imatinib. Original articles that addressed the issue of adherence were read in their entirety, in order to assess whether they should be included or not in the study.

Data analysis

Selected articles were subjected to a full analytical reading to identify the variables of interest: authorship, population size, age, disease stage, follow-up, study design, methods used to assess adherence and/or discontinuation, adherence and/or discontinuation rates and predictors related to poor adherence.

The collected data were gathered into a table for further analysis and interpretation. In case of any disagreement, a third researcher was consulted to establish a final agreement on the variable to be collected.

RESULTS AND DISCUSSION

We identified 476 articles through database search. Fourteen articles were included in the study according to the selection criteria (Figure 1).

FIGURE 1
Flowchart of the selected articles for the integrative review according to the criteria used in the study.

The studies in accordance with the inclusion criteria were published in English (n = 13) and Spanish (n = 1). The age range of the patients included in the evaluated studies ranged from 13 to 89 years. Chronic myeloid leukemia can occur in all age groups as observed in this study, but it is more common in adults and rare in childhood. However, no conclusive evidence suggests that age may be a factor involved in adherence to imatinib (Reis et al., 2013REIS, S.R.; QUIXADÁ, A.T.; NUNES, S.T.; CID, D.M.; DE SOUZA, J.H.; DA COSTA, C.M.; SILVEIRA, C.B.; CID, D.A.; DE OLIVEIRA, M.F. Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital. Rev. Bras. Hematol. Hemoter., v.35, n.3, p.174-9, 2013.; Efficace et al., 2014EFFICACE, F .; ROSTI, G.; COTTONE, F. ; BRECCIA, M.; CASTAGNETTI, F. ; IURLO, A.; MANDELLI, F.; BACCARANI, M. Profiling chronic myeloid leukemia patients reporting intentional and unintentional non-adherence to lifelong therapy with tyrosine kinase inhibitors. Leuk. Res., v.38, n.3, p.294-8, 2014.). Some studies suggest higher adherence rates among younger patients (StCharles et al., 2009ST CHARLES, M.; BOLLU, V.K.; HORNYAK, E.; COOMBS, J.; BLANCHETTE, C.M.; DEANGELO, D.J. Predictors of treatment non-adherence in patients treated with imatinib mesylate of chronic myeloid leukemia. In: AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING AND EXPOSITION, 51, 2009, New Orleans. Blood , 2009. Abstracts Washington: ASH, 2009. Abstract no. 2209.; Jabbour et al., 2012bJABBOUR, E.; SAGLIO, G.; RADICH, J.; KANTARJIAN, H. Adherence to BCR-ABL inhibitors: issues for CML therapy. Clin. Lymphoma Myeloma Leuk., v.12, n.4, p.223-9, 2012b.), while others address that adherence is significantly lower among patients with advanced age, which often deal with chronic diseases, present decreased physical and cognitive activities and are more susceptible to complex treatment regimen due to the disease (Townsley et al.; 2005TOWNSLEY, C.; POND, G.R.; PELOZA, B.; KOK, J.; NAIDOO, K.; DALE, D.; HERBERT, C.; HOLOWATY, E.; STRAUS, S.; SIU, L.L. Analysis of treatment practices for elderly cancer patients in Ontario, Canada. 23163802-102005; Russo et al., 2013RUSSO, D.; MALAGOLA, M.; SKERT, C.; FILÌ, C.; BERGONZI, C.; CANCELLI, V.; CATTINA, F. Treatment of chronic myeloid leukemia elderly patients in the tyrosine kinase inhibitor era. Curr. Cancer Drug Targets, v.13, n.7, p.755-67, 2013.; Matikas et al., 2015MATIKAS, A.; ASIMAKOPOULOU, N.; GEORGOULIAS, V.; SOUGLAKOS, J. The place of targeted agents in the treatment of elderly patients with metastatic colorectal cancer. Cancers, v.7, p.439-49, 2015.). In relation to the stage of the disease, two studies included patients in blast crisis, four in accelerated phase and all studies evaluated the drug therapy in patients in the chronic phase of the disease (Table I).

TABLE I
Analysis of published articles that evaluated the adherence and/or discontinuation of imatinib mesylate

The analyzed articles were conducted in developed or developing countries. However, even considering only studies performed in developed countries with similar socioeconomic characteristics, it was observed heterogeneity among the rates of adherence and discontinuation ranging from 19.0 to 97.0% and from 1.8% to 41.0%, respectively. One reason for this heterogeneity may be related to the treatment period when the data collection was performed, since the patient adherence to the treatment at the beginning is higher (Reis et al., 2013REIS, S.R.; QUIXADÁ, A.T.; NUNES, S.T.; CID, D.M.; DE SOUZA, J.H.; DA COSTA, C.M.; SILVEIRA, C.B.; CID, D.A.; DE OLIVEIRA, M.F. Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital. Rev. Bras. Hematol. Hemoter., v.35, n.3, p.174-9, 2013.). Evidences suggest that adherence to imatinib decreases throughout treatment period (Marin et al., 2010MARIN, D.; BAZEOS, A.; MAHON, F.X.; ELIASSON, L.; MILOJKOVIC, D.; BUA, M.; APPERLEY, J.F.; SZYDLO, R.; DESAI, R.; KOZLOWSKI, K.; PALIOMPEIS, C.; LATHAM, V.; FORONI, L.; MOLIMARD, M.; REID, A.; REZVANI, K.; DE LAVALLADE, H.; GUALLAR, C.; GOLDMAN, J.; KHORASHAD, J.S. 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., v.28, n.14, p.2381-8, 2010.; Gater et al., 2012GATER, A.; HERON, L.; ABETZ-WEBB, L.; COOMBS, J. ; SIMMONS, J. ; GUILHOT, F. ; REA, D. Adherence to oral tyrosine kinase inhibitor therapies in chronic myeloid leukemia. 367817-252012).

Among the selected studies, four were cross-sectional, two were descriptive retrospective, four were longitudinal retrospective and four prospective studies. Regarding the longitudinal prospective, two were clinical study. Importantly, longitudinal studies provide answers related to the incidence of adherence and/or discontinuation of the drug prescribed during treatment (Ayres et al., 2014AYRES, L.R.; BALDONI, A.O.; BORGES, A.P. ; PEREIRA, L.R. Adherence and discontinuation of oral hormonal therapy in patients with hormone receptor positive breast cancer. Int. J. Clin. Pharm.,36145-542014).

The indirect methods were used to evaluate adherence and/or discontinuation in the majority of the studies (n = 13), and questionnaire was the most employed instrument (n = 7). The analysis of medical records and Medication Possession Ratio (MPR) records was used in four studies and the evaluation of the hospital pharmacy database in one study. Both clinical studies have used imatinib plasma levels to assess adherence and/or discontinuation. Furthermore, an association among different adherence methods was performed in four studies analyzed, Marin et al. (2010MARIN, D.; BAZEOS, A.; MAHON, F.X.; ELIASSON, L.; MILOJKOVIC, D.; BUA, M.; APPERLEY, J.F.; SZYDLO, R.; DESAI, R.; KOZLOWSKI, K.; PALIOMPEIS, C.; LATHAM, V.; FORONI, L.; MOLIMARD, M.; REID, A.; REZVANI, K.; DE LAVALLADE, H.; GUALLAR, C.; GOLDMAN, J.; KHORASHAD, J.S. 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., v.28, n.14, p.2381-8, 2010.) used Medication Event Monitoring System (MEMS) combined with the drug detection in biological fluids, Noens et al. (2009NOENS, L.; VAN LIERDE, M.A.; DE BOCK, R.; VERHOEF, G.; ZACHÉE, P.; BERNEMAN, Z.; MARTIAT, P.; MINEUR, P.;, VAN EYGEN, K.; MACDONALD, K.; DE GEEST, S.; ALBRECHT, T.; ABRAHAM, I. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood , v.113, n.22, p.5401-11, 2009.) used structured questionnaire with manual tablets count, Eliasson et al. (2011ELIASSON, L.; CLIFFORD, S.; BARBER, N.; MARIN, D. Exploring chronic myeloid leukemia patients' reasons for not adhering to the oral anticancer drug imatinib as prescribed. Leuk. Res. , v.35, n.5, p.626-30, 2011.) combined MEMS with questionnaire e and Chen et al. (2014CHEN, T.C.; CHEN, L.C.; HUANG, Y.B.; CHANG, C.S. Imatinib adherence associated clinical outcomes of chronic myeloid leukaemia treatment in Taiwan. Int. J. Clin. Pharm., v.36, n.1, p.172-81, 2014.) combined MPR with a biological marker detection.

Considering the methods to evaluate adherence, it was evidenced that the adherence rates was lower in studies that used questionnaires as data collection source compared to other assessment methods (Noens et al., 2009NOENS, L.; VAN LIERDE, M.A.; DE BOCK, R.; VERHOEF, G.; ZACHÉE, P.; BERNEMAN, Z.; MARTIAT, P.; MINEUR, P.;, VAN EYGEN, K.; MACDONALD, K.; DE GEEST, S.; ALBRECHT, T.; ABRAHAM, I. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood , v.113, n.22, p.5401-11, 2009.; Efficace et al., 2012EFFICACE, F.; BACCARANI, M.; ROSTI, G.; COTTONE, F.; CASTAGNETTI, F. ; BRECCIA, M. ; ALIMENA, G. ; IURLO, A.; ROSSI, A.R.; PARDINI, S.; GHERLINZONI, F. ; SALVUCCI, M. ; TIRIBELLI, M. ; VIGNETTI, M.; MANDELLI, F. Investigating factors associated with adherence behaviour in patients with chronic myeloid leukemia: an observational patient-centered outcome study. Br. J. Cancer, v.107, n.6, p.904-9, 2012.; Hirji et al., 2013HIRJI, I.; GUPTA, S.; GOREN, A.; CHIROVSKY, D.R.; MOADEL, A.B.; OLAVARRIA, E.; VICTOR, T.W.; DAVIS, C.C. Chronic myeloid leukemia (CML): association of treatment satisfaction, negative medication experience and treatment restrictions with health outcomes, from the patient's perspective. Health Qual. Life Outcomes, v.11, p.167, 2013. DOI: 10.1186/1477-7525-11-167.; Rosa et al., 2013ROSA, V.G.; NICOLAS, F.G.; MORENO RG, ROMERO MV, CARVAJAL TM, PÉREZ RG. Adherencia y toxicidad de los inhibidores de la tirosinquinasa en leucemia mieloide crônica. Farm. Hosp., v.37, n.6, p.434-40, 2013.). Although the questionnaire allows the follow-up of a large number of individuals and it is a low-cost and fast strategy, it is a method subject to bias and may interfere with the measurement of adherence, overestimating or underestimating the current medication adherence rate (Bloch, Melo, Nogueira, 2008BLOCH, K.V.; MELO, N.A.; NOGUEIRA, A.R. Prevalência da adesão ao tratamento anti-hipertensivo em hipertensos resistentes e validação de três métodos indiretos de avaliação da adesão. Cad. Saúde Públ., v.24, n.12, p.2979-84, 2008.; Ben, Neumann, Mengue, 2012BEN, A.J.; NEUMANN, C.R.; MENGUE, S.S. Teste de Morisky Green e Brief Medication Questionnaire para avaliar adesão a medicamentosRev.. Saúde Públ., v.46, n.2, p.279-89, 2012.; Pérez-Escamilla et al., 2015PÉREZ-ESCAMILLA, B.; FRANCO-TRIGO, L.; MOULLIN, J.C.; MARTÍNEZ-MARTÍNEZ, F.; GARCÍA-CORPAS, J.P. Identification of validated questionnaires to measure adherence to pharmacological antihypertensive treatments. Patient Prefer. Adherence, v.9, p.569-78, 2015.).

Additionally a high adherence rate was found in studies that used the association between direct and indirect methods (Marin et al., 2010MARIN, D.; BAZEOS, A.; MAHON, F.X.; ELIASSON, L.; MILOJKOVIC, D.; BUA, M.; APPERLEY, J.F.; SZYDLO, R.; DESAI, R.; KOZLOWSKI, K.; PALIOMPEIS, C.; LATHAM, V.; FORONI, L.; MOLIMARD, M.; REID, A.; REZVANI, K.; DE LAVALLADE, H.; GUALLAR, C.; GOLDMAN, J.; KHORASHAD, J.S. 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., v.28, n.14, p.2381-8, 2010.; Chen et al., 2014CHEN, T.C.; CHEN, L.C.; HUANG, Y.B.; CHANG, C.S. Imatinib adherence associated clinical outcomes of chronic myeloid leukaemia treatment in Taiwan. Int. J. Clin. Pharm., v.36, n.1, p.172-81, 2014.). It is important to mention that MEMS is a very costly method and subject to sampling errors. Despite these disadvantages, it allows to estimate the frequency of daily intake and interval between doses. On the other hand, drug detection in biological fluids, although it is a method of high financial cost, which evaluates only the recent drug use, it can eliminate the interference of patient's report in assessing adherence (Pérez-Escamilla et al., 2015PÉREZ-ESCAMILLA, B.; FRANCO-TRIGO, L.; MOULLIN, J.C.; MARTÍNEZ-MARTÍNEZ, F.; GARCÍA-CORPAS, J.P. Identification of validated questionnaires to measure adherence to pharmacological antihypertensive treatments. Patient Prefer. Adherence, v.9, p.569-78, 2015.). The differences found in adherence and/or discontinuation rates may be justified by the use of different instruments to estimate the incidence and/or prevalence of patient adherence and/or discontinuation (Wetzels et al., 2006WETZELS, G.E.; NELEMANS, P.J.; SCHOUTEN, J.S.; VAN WIJK, B.L.; PRINS, M.H. All that glisters is not gold: a comparison of electronic monitoring versus filled prescriptions-an observational study. BMC Health Serv. Res., v.6, p.8, 2006. DOI:10.1186/1472-6963-6-8. ).

Evidence shows that there is no ideal method for evaluating medication adherence. Each assessment tool has advantages and disadvantages that favor or limit their applicability (Pérez-Escamilla et al., 2015PÉREZ-ESCAMILLA, B.; FRANCO-TRIGO, L.; MOULLIN, J.C.; MARTÍNEZ-MARTÍNEZ, F.; GARCÍA-CORPAS, J.P. Identification of validated questionnaires to measure adherence to pharmacological antihypertensive treatments. Patient Prefer. Adherence, v.9, p.569-78, 2015.). A systematic review of over 6500 citations, with full review of 549 articles published between 1967 and 2001, showed there is no effective approach to assess adherence and that most of the methods used to evaluate adherence in a context of chronic diseases are generally complicated, expensive, and not consistently successful (Jabbour et al., 2012aJABBOUR, E.J.; KANTARJIAN, H.; ELIASSON, L.; CORNELISON, A.M.; MARIN, D. Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Am. J. Hematol. , v.87, n.7, p.687-91, 2012a.). Thus, the authors suggest the combination of methods to monitor medication adherence with the purpose of reducing biases and inherent limitations to each instrument.

Regardind the rates of adherence and discontinuation among patients with CML in all studies included in this review, there was a variation of 19.0 to 97.0% and 1.8 to 41.0%, respectively. Among the 14 studies analyzed, seven referred only to adherence, one referred only to discontinuation, five assess adherence and discontinuation and one included only suboptimal adherers. It was evident that few studies have assessed the achievement of cytogenetic and molecular response, which are important parameters for analyzing the absence of Philadelphia chromosome, as well as reduced levels of BCL-ABL rearrangement (Marin et al., 2010MARIN, D.; BAZEOS, A.; MAHON, F.X.; ELIASSON, L.; MILOJKOVIC, D.; BUA, M.; APPERLEY, J.F.; SZYDLO, R.; DESAI, R.; KOZLOWSKI, K.; PALIOMPEIS, C.; LATHAM, V.; FORONI, L.; MOLIMARD, M.; REID, A.; REZVANI, K.; DE LAVALLADE, H.; GUALLAR, C.; GOLDMAN, J.; KHORASHAD, J.S. 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., v.28, n.14, p.2381-8, 2010.; Cid et al., 2013CID, D.M; MAGALHÃES, S.M.; QUIXADÁ, A.T.; HONÓRIO, R.P.; COSTA, P.F.; REIS, S.R.; CARVALHO, S.M.; CID, D.A.; SUCUPIRA, R.M.; DE OLIVEIRA, M.F. Chronic myeloid leukemia: an overview of the determinants of effectiveness and therapeutic response in the first decade of treatment with imatinib mesylate in a Brazilian hospital. Rev.Bras. Hematol. Hemoter. v.35, n.6, p.389-94, 2013.; Reis et al., 2013REIS, S.R.; QUIXADÁ, A.T.; NUNES, S.T.; CID, D.M.; DE SOUZA, J.H.; DA COSTA, C.M.; SILVEIRA, C.B.; CID, D.A.; DE OLIVEIRA, M.F. Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital. Rev. Bras. Hematol. Hemoter., v.35, n.3, p.174-9, 2013.). In addition, four studies showed adherence rates relatively low to imatinib, such as between 19.0 and 53.0%. It has been shown in clinical trials that reduced adherence rates are associated with lower rates of CCR and CMR (Marin et al., 2010MARIN, D.; BAZEOS, A.; MAHON, F.X.; ELIASSON, L.; MILOJKOVIC, D.; BUA, M.; APPERLEY, J.F.; SZYDLO, R.; DESAI, R.; KOZLOWSKI, K.; PALIOMPEIS, C.; LATHAM, V.; FORONI, L.; MOLIMARD, M.; REID, A.; REZVANI, K.; DE LAVALLADE, H.; GUALLAR, C.; GOLDMAN, J.; KHORASHAD, J.S. 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., v.28, n.14, p.2381-8, 2010.; Cid et al., 2013CID, D.M; MAGALHÃES, S.M.; QUIXADÁ, A.T.; HONÓRIO, R.P.; COSTA, P.F.; REIS, S.R.; CARVALHO, S.M.; CID, D.A.; SUCUPIRA, R.M.; DE OLIVEIRA, M.F. Chronic myeloid leukemia: an overview of the determinants of effectiveness and therapeutic response in the first decade of treatment with imatinib mesylate in a Brazilian hospital. Rev.Bras. Hematol. Hemoter. v.35, n.6, p.389-94, 2013.). In the clinical context, several factors may influence adherence to treatment regimens and these include not only those aspects of the treatment, but also patient characteristics (Partridge et al., 2002PARTRIDGE, A.H.; AVORN, J.; WANG, P.S.; WINER, E.P. Adherence to therapy with oral antineoplastic agents. J. Natl. Cancer Inst., v.94, n.9, p.652-61, 2002.; Efficace et al., 2012EFFICACE, F.; BACCARANI, M.; ROSTI, G.; COTTONE, F.; CASTAGNETTI, F. ; BRECCIA, M. ; ALIMENA, G. ; IURLO, A.; ROSSI, A.R.; PARDINI, S.; GHERLINZONI, F. ; SALVUCCI, M. ; TIRIBELLI, M. ; VIGNETTI, M.; MANDELLI, F. Investigating factors associated with adherence behaviour in patients with chronic myeloid leukemia: an observational patient-centered outcome study. Br. J. Cancer, v.107, n.6, p.904-9, 2012.).

Factors related to poor adherence such as adverse drug reactions (ADRs) and unavailability of drugs were seen as major causes for discontinuation and/or non-adherence to imatinib. Nine studies analyzed showed that adverse reactions to imatinib were related to non-adherence and/or intentional discontinuation. Drug unavailability was a factor related to discontinuation and/or non-adherence in three studies. Low social support, advanced age, poor access to health care, low level of information, prolonged treatment and high daily doses are other examples of factors associated to discontinuation and/or non-adherence.

The ADRs are expected and explained by the the mechanism of action of the drug and can be correlated with changes in the drug dosage (Eliasson et al., 2011ELIASSON, L.; CLIFFORD, S.; BARBER, N.; MARIN, D. Exploring chronic myeloid leukemia patients' reasons for not adhering to the oral anticancer drug imatinib as prescribed. Leuk. Res. , v.35, n.5, p.626-30, 2011.; Efficace et al., 2012EFFICACE, F.; BACCARANI, M.; ROSTI, G.; COTTONE, F.; CASTAGNETTI, F. ; BRECCIA, M. ; ALIMENA, G. ; IURLO, A.; ROSSI, A.R.; PARDINI, S.; GHERLINZONI, F. ; SALVUCCI, M. ; TIRIBELLI, M. ; VIGNETTI, M.; MANDELLI, F. Investigating factors associated with adherence behaviour in patients with chronic myeloid leukemia: an observational patient-centered outcome study. Br. J. Cancer, v.107, n.6, p.904-9, 2012.; Rosa et al., 2013ROSA, V.G.; NICOLAS, F.G.; MORENO RG, ROMERO MV, CARVAJAL TM, PÉREZ RG. Adherencia y toxicidad de los inhibidores de la tirosinquinasa en leucemia mieloide crônica. Farm. Hosp., v.37, n.6, p.434-40, 2013.; Chen et al., 2014CHEN, T.C.; CHEN, L.C.; HUANG, Y.B.; CHANG, C.S. Imatinib adherence associated clinical outcomes of chronic myeloid leukaemia treatment in Taiwan. Int. J. Clin. Pharm., v.36, n.1, p.172-81, 2014.; Gotta et al., 2014GOTTA, V. ; WIDMER, N. ; DECOSTERD, L.A. ; CHALANDON, Y.; HEIM, D.; GREGOR, M.; BENZ, R. ; LEONCINI-FRANSCINI, L.; BAERLOCHER, G.M.; DUCHOSAL, M.A. ; CSAJKA, C. ; BUCLIN, T. Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial. Cancer Chemother. Pharmacol., v.74, n.6, p.1307-19, 2014. ). This was evidenced in two studies included in this work that showed that patients who took an increased dosage of imatinib had significantly lower adherence than patients who remained taking lower doses (Noens et al., 2009NOENS, L.; VAN LIERDE, M.A.; DE BOCK, R.; VERHOEF, G.; ZACHÉE, P.; BERNEMAN, Z.; MARTIAT, P.; MINEUR, P.;, VAN EYGEN, K.; MACDONALD, K.; DE GEEST, S.; ALBRECHT, T.; ABRAHAM, I. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood , v.113, n.22, p.5401-11, 2009.; Marin et al., 2010MARIN, D.; BAZEOS, A.; MAHON, F.X.; ELIASSON, L.; MILOJKOVIC, D.; BUA, M.; APPERLEY, J.F.; SZYDLO, R.; DESAI, R.; KOZLOWSKI, K.; PALIOMPEIS, C.; LATHAM, V.; FORONI, L.; MOLIMARD, M.; REID, A.; REZVANI, K.; DE LAVALLADE, H.; GUALLAR, C.; GOLDMAN, J.; KHORASHAD, J.S. 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., v.28, n.14, p.2381-8, 2010.). These dosage changes may affect therapeutic results, since rising the dose can increase the incidence of ADR, thereby lowering the adherence to the treatment over time (Chen et al., 2014CHEN, T.C.; CHEN, L.C.; HUANG, Y.B.; CHANG, C.S. Imatinib adherence associated clinical outcomes of chronic myeloid leukaemia treatment in Taiwan. Int. J. Clin. Pharm., v.36, n.1, p.172-81, 2014.).

Studies conducted in the USA show that non-adherence to treatment may be associated with high healthcare costs, since it decreases the effectiveness of the treatment and requires a prolonged treatment period culminating in increased costs to the healthcare system (Reinhardt, Hussey, Anderson, 2004REINHARDT, U.E.; HUSSEY, P.S.; ANDERSON, G.F. U.S. health care spending in an international context. Health Aff., v.23, n.3, p.10-25, 2004.; Halpern et al., 2009HALPERN, R.; BARGHOUT, V.; ZAROTSKY, V.; WILLIAMS, D.E. Costs and utilization associated with imatinib adherence in patients with chronic myeloid leukemia or gastrointestinal stromal tumors. JCOM, v.16, n.5, p.215-23, 2009.). Another important aspect related to the non-adherence and/or discontinuation to be considered is relative to the availability of medicines in developing countries. The unstructured healthcare systems and failures in pharmaceutical care policies of the developing countries impair the access to medicines and can contribute to non-intentional discontinuation of the treatment by the patients. Studies performed in Brazil showed that less than half of people who have prescription drugs in the public healthcare system have access to all of them (Boing et al., 2013BOING, A.C.; BERTOLDI, A.D.; BOING, A.F.; BASTOS, J.L.; PERES, K. G. Access to medicines in the public sector: analysis of users of the Brazilian Unified National Health System. Cad. Saúde Públ. , v.29, p.691-701, 2013.) and the most frequent reason for non-adherence is the unavailability of the drug at the healthcare system (Reis et al., 2013REIS, S.R.; QUIXADÁ, A.T.; NUNES, S.T.; CID, D.M.; DE SOUZA, J.H.; DA COSTA, C.M.; SILVEIRA, C.B.; CID, D.A.; DE OLIVEIRA, M.F. Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital. Rev. Bras. Hematol. Hemoter., v.35, n.3, p.174-9, 2013.). Moreover, studies show that the lack of access to medicines can generate not only a direct impact on clinical, social and economic conditions of the patient, but also an increase in spending on secondary and tertiary care (Reis, Perini, 2008REIS, A.M.M.; PERINI, E. Desabastecimento de medicamentos: determinantes, conseqüências e gerenciamento. Ciênc. Saúde Colet., v.13, p.608-10, 2008.).

Knowing the current rates of adherence and/or discontinuation is essential to develop strategies to improve pharmacotherapeutic results. Thus, it is worth noting that the follow-up of patients that take oral medication for CML plays a key role in promoting and improving adherence to treatment and also to identify, prevent and solve other drug related problems. Well-trained pharmacists can solve those problems through interventions such as medication management, providing information and guidance that improve adherence to drug therapy and that increase the effectiveness and medication safety (Partridge et al., 2002PARTRIDGE, A.H.; AVORN, J.; WANG, P.S.; WINER, E.P. Adherence to therapy with oral antineoplastic agents. J. Natl. Cancer Inst., v.94, n.9, p.652-61, 2002.; Weingart et al., 2008WEINGART, S.N.; BROWN, E.; BACH, P.B. ; ENG, K.; JOHNSON, S.A.; KUZEL, T.M.; LANGBAUM, T.S.; LEEDY, R.D.; MULLER, R.J.; NEWCOMER, L.N.; O'BRIEN, S.; REINKE, D.; RUBINO, M.; SALTZ, L.; WALTERS, R.S. NCCN task force report: oral chemotherapy. J. Natl. Compr. Canc. Netw., v.6, Suppl.3, p.S1-14, 2008.).

CONCLUSION

In this study, we observed diverse rates of adherence and/or discontinuation of imatinib, ranging from 19.0 to 97.0% and from 1.8 and 41.0%, respectively. This can be due to the use of various tools to access adherence, different treatment period when data collection of the studies was conducted and by socioeconomic differences among countries, health systems, age range and changes in dosage. Few studies evaluated cytogenetic and molecular responses to imatinib treatment being necessary further efforts of the clinical research community in this aspect. Besides that, there is a lack of studies of the predictors for adherence and/or discontinuation of imatinib. Therefore, health professionals should also be able to identify predictors of poor adherence to imatinib,which allows them to seek for strategies that improves adherence and consequently leads to better clinical outcomes. Therefore, this study showed that patient education combined with a follow-up by pharmacists or other health professionals can maximize patient adherence and minimize discontinuation of pharmacotherapy.

ACKNOWLEDGEMENTS

The authors would like to thank the University of São João Del Rei for its support during the research.

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Publication Dates

  • Publication in this collection
    Dec 2016

History

  • Received
    20 Jan 2016
  • Accepted
    05 Oct 2016
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br