RESUMO
BACKGROUND AND OBJECTIVES: The introduction and widespread use of effective and well-tolerated tyrosine kinase inhibitors for chronic myeloid leukemia have been associated with marked increments in life expectancy and disease prevalence. These changes have been accompanied by elevations in costs of tyrosine kinase inhibitors, which typically must be taken ad vitam after diagnosis and tend to be more expensive than medical therapies for many other hematologic malignancies. The aims of this review included evaluating the potential associations and consequences of healthcare resource utilization and costs of tyrosine kinase inhibitors and possible clinical management approaches to mitigate them. METHODS: A PubMed search of English-language US study reports was conducted that covered the interval of 2001 (US approval of imatinib) through 17 April, 2023 augmented by manual reviews of published bibliographies from the referenced articles and searches of other databases: Google Scholar and Scopus. RESULTS: On the basis of this analysis of chiefly real-world evidence (administrative claims database studies), healthcare resource utilization and costs can be considered indicators of ineffective chronic myeloid leukemia management, including potentially mutation-driven treatment resistance and costly tyrosine kinase inhibitor switches, non-adherence, and suboptimal tolerability, which may culminate in the progression of disease from the chronic to an accelerated or blast phase, with additional excess costs. Costs of tyrosine kinase inhibitors are also associated with reduced treatment adherence. At a willingness-to-pay threshold of $50,000-$200,000 per quality-adjusted life-year, tyrosine kinase inhibitors can be considered cost effective from a US payer perspective. Potential clinical approaches to mitigate costs include regular molecular monitoring with proactive assessments of BCR::ABL1 gene mutations to avoid costly treatment switches, as well as interventions to enhance treatment adherence and tyrosine kinase inhibitor tolerability. CONCLUSIONS: Healthcare resource utilization and costs of chronic myeloid leukemia care may be considered barometers of ineffective management, including mutation-driven tyrosine kinase inhibitor resistance and switching as well as non-adherence and intolerance. Future prospective research is warranted to help determine whether costs can be reduced and other treatment outcomes optimized via more proactive and effective diagnostic interventions (i.e., regular molecular monitoring and proactive mutational testing) and treatment approaches. The strengths and limitations of this review include its emphasis on observational research, which, on one hand, offers a naturalistic "real-world" perspective on current chronic myeloid leukemia management, but, on the other hand, is associational in nature and cannot be used to determine causality and/or its direction.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mesilato de Imatinib/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Atenção à Saúde , Antineoplásicos/uso terapêuticoRESUMO
The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at "high-risk". Beyond the onset, a re-evaluation of the risk status is mandatory, monitoring the response to TKI treatment. Moreover, novel critical insights are emerging into the role of genomic factors, present at diagnosis or evolving on therapy. This review presents the current knowledge regarding prognostic factors in CML and their potential role for an improved risk classification and a subsequent enhancement of therapeutic decisions and disease management.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Aberrações Cromossômicas , Crise Blástica , Medição de RiscoRESUMO
Tyrosine kinase inhibitor (TKI) use is critical in the care of patients with chronic myeloid leukemia (CML). Quantitative polymerase chain reaction (qPCR) testing for BCR-ABL1 every 3 months during the first year of TKI treatment is recommended to assure achievement of milestone response goals. Real-world evidence for the patterns of qPCR monitoring and TKI adherence in the older patient population is lacking. Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 1192 patients aged ≥66 years (median age, 74 years) with newly diagnosed CML who were followed up for ≥13 months from TKI initiation. In total, 965 patients (81.0%) had ≥1 test, with 425 (35.7%) and 540 (45.3%) of the patients tested during 1, 2, and ≥3 quarters (optimal monitoring) of the first year from TKI initiation, respectively. In multivariable analysis, diagnosis in later years and influenza vaccination before diagnosis, a proxy for health care access, were associated with optimal qPCR monitoring. Use of low-income subsidy and residing in census tracts with the lowest socioeconomic status were associated with less optimal monitoring. Patients with optimal monitoring were 60% more likely to be TKI adherent (odds ratio, 1.60; 95% CI, 1.11-2.31; P = .01) and had improved 5-year survival (hazard ratio, 0.66; 95% CI, 0.49-0.90; P < .01) than those without such monitoring. In this large, real-world study of CML management patterns, many older patients had suboptimal molecular monitoring, which was associated with decreased TKI adherence and worse survival.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Idoso , Estados Unidos , Medicare , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Doença CrônicaRESUMO
Chronic myeloid leukemia (CML) is a myeloproliferative disease and the first line treatment is through the administration of Imatinib, a first generation tyrosine kinase inhibitor. Thrombocytosis and bleeding irregularities are common in CML, however, the morphological variations in CML patients' platelets are not well documented. In this study, ex vivo platelet morphology of control participants, as well as CML patients were assessed before and after Imatinib treatment. The topographical and structural morphology of platelets were determined via scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Qualitative data of SEM and TEM revealed that CML patient's platelets were prone to aggregation and coagulation at time of diagnosis; the samples that were not aggregated at time of diagnosis showed typical discoid shaped platelets, which was comparable to control participants' platelets. TEM results of CML patients' platelets at diagnosis showed that internal granular constituents including dense bodies were decreased in comparison to control participants. In all CML patients, platelets appeared activated after 6 months of treatment with Imatinib with membrane structure abnormalities and constituent variations. Research to date has primarily focused on the effects of CML on leukocyte populations, however, the results of the current study implicate the impact of CML pathogenesis on platelets, seemingly as a result of alterations in normal hematopoiesis. In addition, the impact of Imatinib treatment on platelet morphology was also established, indicating an increase in platelet activation. Recognizing and understanding the impact of CML disease progression on platelets is of importance to aid improved patient treatment. RESEARCH HIGHLIGHTS: In the study, results from SEM and TEM indicated that CML patient's platelets were prone to aggregation at time of diagnosis, and activation after Imatnib treatment. Platelet samples that did not aggregate had decreased internal granular constituents.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Plaquetas , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
The clinical outcome of chronic myeloid leukaemia patients has vastly improved since the introduction of tyrosine kinase inhibitor treatment, with a significant proportion of patients able to achieve treatment-free remission. However, studies have shown that patients with the e13a2 transcript were less likely to achieve major molecular response compared to those with e14a2 transcripts. Most quantitative polymerase chain reaction (PCR) assays for detection of the BCR-ABL1 fusion gene do not differentiate between the two transcripts and we therefore hypothesised that technical bias linked to the qPCR assay could partially explain the discrepancy in outcomes. We designed an e14a2-specific assay and identified no difference in results compared to an e13a2 standard assay. We then demonstrated that the commercial e14a2 standards were causing a significant overestimation of the e13a2 transcripts. Finally, we reviewed patient management after the qPCR values were corrected, using our new evaluation. We concluded that despite statistically significant differences in qPCR results, there was no impact on patient management or outcome. We conclude that, at least in our institution, it would be inappropriate to perform separate assays for patients with e13a2 or e14a2.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Reação em Cadeia da Polimerase em Tempo Real , TecnologiaRESUMO
AIM: This study was carried out to assess the minimal residual disease in Tunisian patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors in routine clinical practice, to recognize potentially eligible carrier for treatment discontinuation, based on a molecular response (MR). PATIENTS AND METHODS: A retrospective study was carried out in the Hospital University of Sfax, south of Tunisia from January 2016 to October 2020, including all CML patients in the chronic phase at diagnosis, treated with TKI (tyrosine kinase inhibitors) for a minimum duration of 6 months. Quantitative assessment of the BCR-ABL transcript was performed using the Cepheid Xpert BCR-ABL ultra-assay. Molecular response and outcome were evaluated, according to the European Leukemia Net guidelines. RESULTS: A total of 162 CML patients were carried out. The median age was 50 years, the sex ratio M/F was 1.62. The rate of cumulative EMR; MMR and DMR was 80.8%; 73.8% and 55.9% respectively. According to the ELN criteria, 141 CML patients were evaluable. Optimal, suboptimal response and failure were noted in 81 (57.4%), 33(23.4%), and 27(19.1%) patients, respectively. Overall survival (OS) and progression-free survival (PFS) were 96.3% and 85%. Risk factors for an event (death/progression) were lack of EMR, MMR, and DMR (P < 0.05). Among 149 patients with sustained DMR; 14 (8.6%) CML patients have discontinued TKI therapy. CONCLUSION: Despite the limit of our study (duration and size), the available real-life molecular responses with TKI therapy should be considered to identify potentially CML patients eligible for discontinuation of TKI therapy.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Intervalo Livre de Progressão , Fatores de Risco , Resultado do TratamentoRESUMO
Cancer treatment is constantly evolving from a one-size-fits-all towards bespoke approaches for each patient. In certain solid cancers, including breast and lung, tumor genome profiling has been incorporated into therapeutic decision-making. For chronic phase chronic myeloid leukemia (CML), while tyrosine kinase inhibitor therapy is the standard treatment, current clinical scoring systems cannot accurately predict the heterogeneous treatment outcomes observed in patients. Biomarkers capable of segregating patients according to outcome at diagnosis are needed to improve management, and facilitate enrollment in clinical trials seeking to prevent blast crisis transformation and improve the depth of molecular responses. To this end, gene expression (GE) profiling studies have evaluated whether GE signatures at diagnosis are clinically informative. Patient material from a variety of sources has been profiled using microarrays, RNA sequencing and, more recently, single-cell RNA sequencing. However, differences in the cell types profiled, the technologies used, and the inherent complexities associated with the interpretation of genomic data pose challenges in distilling GE datasets into biomarkers with clinical utility. The goal of this paper is to review previous studies evaluating GE profiling in CML, and explore their potential as risk assessment tools for individualized CML treatment. We also review the contribution that acquired mutations, including those seen in clonal hematopoiesis, make to GE profiles, and how a model integrating contributions of genetic and epigenetic factors in resistance to tyrosine kinase inhibitors and blast crisis transformation can define a route to GE-based biomarkers. Finally, we outline a four-stage approach for the development of GE-based biomarkers in CML.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Biomarcadores , Crise Blástica/tratamento farmacológico , Epigênese Genética , Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Abnormal mRNAs of the hybrid BCR-ABL gene in the majority of cases initiate the synthesis of proteins with a mass of 210 kDa (p210), 190 kDa (p190), and 230 kDa (p230). Expression of the p210 variant is most common in CML (95% of cases), while the p190 and p230 variants are less common (1-4%). On the contrary, p190 predominates in ALL. Measurement of BCR/ABL gene expression is included in clinical guidelines for the diagnosis of CML and ALL as sequential tests in accordance with their occurrence. At the same time, in the context of primary patients testing with suspected hematological malignancies with a low prevalence of BCR-ABL positive patients in the cohort of examined individuals, sequential testing is associated with low cost-effectiveness. Purpose: approbation of a parallel algorithm for detecting all three (p210, p190 and p230) using the multiplex RT-PCR format implemented in the «BCR/ABL-MULTITEST¼ reagent kit. We used anonymized blood samples from patients with suspected CML, as well as samples from ALL patients before starting therapy. Testing of blood samples was carried out using two variants of the algorithm: sequential determination of individual BCR-ABL transcripts and parallel determination using the developed set of reagents «BCR/ABL-MULTITEST¼. To detect the p210 transcript, a commercial kit «AmpliSens® Leukemia Quantum M-bcr-FRT¼ (Central Research Institute of Epidemiology of Rospotrebnadzor, Russia) was used. Simultaneously, a test was used to detect all three variants of BCR-ABL transcripts using the «BCR/ABL - MULTITEST¼ reagent kit based on a monochrome multiplex reaction «in one test tube¼. Reverse transcription were carried out using the REVERTA-L reagent kit (Central Research Institute of Epidemiology of Rospotrebnadzor, Russia) in accordance with the manufacturer's instructions. Using the reagent kits «BCR/ABL-MULTITEST¼ and «AmpliSens® Leukemia Quantum M-bcr-FRT¼ there is a high level of correlation of quantitative results of determining the chimeric transcript BCR-ABL Ñ210 (r = 0.99). When using the proposed parallel algorithm with the primary use of the «BCR/ABL-MULTITEST¼ reagent kit, out of 95 patients with suspected CML, 9 samples with p210 transcript were identified, one with p190 BCR / ABL, and in one case a transcript variant characteristic of chronic neutrophilic leukemia - p230 BCR / ABL. The estimated cost for detecting one positive case of BCR-ABL when using the parallel diagnostic algorithm «BCR/ABL-MULTITEST¼ with a focused flow of studies is reduced by about 2 times due to a decrease in the amount of laboratory plastic used and the volume of the reaction mixture, as well as the absence of the need for repeated separate tests to detect p190 and p230. The use of the multiplex PCR-RT test system «BCR/ABL-MULTITEST¼ allows detecting in one test tube all three main variants of BCR-ABL transcripts - p210, p190, p230 and achieving significant resource savings when examining a cohort of patients with suspected CML and ALL and low frequency of positive samples.
Assuntos
Laboratórios , Leucemia Mielogênica Crônica BCR-ABL Positiva , Algoritmos , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , RNA MensageiroRESUMO
Most cancer cases occur in areas of low resources. The diagnosis, treatment and monitoring of cancers is especially challenging in these locations. Unique partnerships exist between non-profit organisations and pharmaceutical companies to provide free drugs to CML patients throughout the world if the diagnosis can be rigorously and unambiguously established. But there lies the rub: How do you perform molecular diagnostics in areas where even electricity is unreliable? Here we describe the evolution of testing patients from low resource areas, which, when merged with a remarkable effort to bring tyrosine kinase inhibitors to patients across the globe, have led to survival outcomes similar to cases in industrialised countries.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Antineoplásicos/uso terapêutico , Países em Desenvolvimento , Teste em Amostras de Sangue Seco/economia , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Técnicas de Diagnóstico Molecular/economia , Reação em Cadeia da Polimerase em Tempo Real/economia , Resultado do TratamentoAssuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Tomada de Decisão Clínica , Gerenciamento Clínico , Desenvolvimento de Medicamentos , Monitoramento de Medicamentos , Europa (Continente) , Preservação da Fertilidade , Custos de Cuidados de Saúde , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fatores Sexuais , Resultado do TratamentoRESUMO
The growing use of oral systemic therapies and transition of some cancer treatments to the outpatient setting makes capturing all cancer case patients more difficult. We aim to develop algorithms to identify potentially missed incident case patients and estimate impact on incidence rates. We reviewed claims from SEER-Medicare 5% noncancer control patient sample to identify potentially missed chronic myeloid leukemia (CML) and bladder case patients based on diagnosis codes, cancer-related treatments, and oncology consultations. Observed rates of definite missed CML and definite and probable missed bladder case patients were calculated and the impact of missed case patients of these two cancers on SEER 65+ incidence rates were estimated. From 2008 to 2015, the algorithm estimated 781 definite CML case patients missed, increasing the number by 10.7%. From 2007 to 2015, the algorithm estimated 4629 definite and 5772 probable bladder case patients missed, increasing the number by 3.8% to 8.1%. Our algorithms offer potential methods for identifying missed case patients and validating the completeness of cancer registries.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Medicare , Programa de SEER , Neoplasias da Bexiga Urinária , Idoso , Humanos , Incidência , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Estados Unidos/epidemiologia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/epidemiologiaRESUMO
Treatment-free remission (TFR), in which patients discontinue pharmacotherapy and remain in molecular remission, is an emerging treatment goal for patients with chronic myeloid leukemia (CML). Attainment of TFR requires an increased frequency of molecular monitoring, to ensure that patients maintain a deep molecular response. The objective of this analysis was to assess the economic impact of stopping nilotinib among Japanese TFR-eligible patients. A Markov model evaluated the economic impact of TFR among the study population, TFR-eligible CML patients diagnosed since 2012. The model compared patients who had discontinued tyrosine kinase inhibitor (TKI) treatment (ie, attempted TFR) with patients that continued TKI treatment. A 3-y time horizon was modeled from a Japanese public payer perspective. Costs associated with drug treatment, hospital/physician visits, and molecular monitoring were considered. TFR-eligible patients were calculated from Japanese CML incidence rates and efficacy was derived from nilotinib trials. Japanese co-payment maximums were utilized to assess the patient perspective. An estimated 761 and 140 patients were eligible for first- and second-line nilotinib, respectively, in 2019. Assuming that 100% of eligible patients complied, TFR was associated with cost savings of ¥7 625 174 640 (US$66 567 775) over 3 y. In scenarios with reduced willingness to attempt TFR, cost savings persisted. Achievement of TFR was estimated to markedly reduce out-of-pocket expenses for CML patients, regardless of the timing of relapse. Stopping nilotinib for TFR-eligible patients in Japan may result in significant cost savings to both payers and patients. Monitoring costs contributed little to overall annual costs and decreased over time.
Assuntos
Orçamentos , Análise Custo-Benefício , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Custos de Cuidados de Saúde , Humanos , Japão/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Cadeias de Markov , Modelos Teóricos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Indução de Remissão , Resultado do TratamentoRESUMO
Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gerenciamento Clínico , Feminino , Proteínas de Fusão bcr-abl/genética , Custos de Cuidados de Saúde , Pesquisas sobre Atenção à Saúde , Humanos , Itália/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Masculino , Pessoa de Meia-Idade , Gravidez , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Indução de Remissão , Retratamento , Resultado do Tratamento , Adulto JovemRESUMO
Subsequent to the development and global availability of BCR/ABL-targeted tyrosine kinase inhibitors (TKIs), the prognosis of patients with chronic myeloid leukemia (CML), at least those in the chronic phase, has markedly improved, and in the developed world, the average lifespan of these patients is now close to that of age- and sex-matched subjects without the disease. However, the situation in low- and middle-income countries (LMICs) may not be so rosy. Many important differences in hematological cancers, including CML, have been highlighted in various publications in LMICs vs developed countries. These include differences in incidence and prevalence rates, age and stage of disease at diagnosis, response rates, and survival. Some of the possible reasons proposed for these are varying socioeconomic milieu (impacting availability of effective drugs and essential monitoring), environmental factors (mainly exposure to viral infections and pesticides), nutritional factors with interplay of malnutrition and diet on drug absorption and blood levels, and possible unknown genetic factors. Although generic first-generation TKIs (imatinib) are available in many parts of the world, several challenges remain in providing optimal treatment to patients with CML in resource-poor countries. Some of these include availability of optimal and high-quality BCR/ABL testing, availability and expense related to use of second- and third-generation TKIs (nilotinib, dasatinib, bosutinib, and ponatinib) and hematopoietic stem cell transplantation, issues with compliance and toxicities of drugs, and ensuring a minimal standard-of-care treatment and monitoring for every patient diagnosed with CML. For the purpose of this article, the more objective country label-LMIC-coined by the World Bank will be used (gross national income per capita between $1026 and $3995; World Bank, June 2019). Some of these issues will be discussed in this article in greater detail by experts in the field in 3 different but interconnected sections.
Assuntos
Países em Desenvolvimento , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Transplante de Células-Tronco Hematopoéticas/economia , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Adulto , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/economia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Inibidores de Proteínas Quinases/economia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
CONTEXTO: O diagnóstico das leucemias Ph+ é feito pela demonstração da presença do cromossomo Philadelphia (22q-) com translocação t (9;22) (q34; q11) ou rearranjo BCR-ABL, identificado por citogenética (já disponível no SUS), ISH ou método molecular (RT-PCR), em pacientes com leucocitose (e ocasionalmente trombocitemia) persistente. Além disso, o Leukemianet recomenda que RT-qPCR seja utilizado no monitoramento do tratamento; nos casos de falha ou progressão da doença, para a detecção de mutações; e nos casos que requerem maior atenção. PERGUNTA: Qual a acurácia diagnóstica da Reação em Cadeia da Polimerase Transcriptase Reversa (RT-PCR) qualitativa e quantitativa (RT-qPCR) e da Hibridização in situ (ISH) para o diagnóstico e monitoramento das leucemias Philadelphia positivo em adultos e crianças/adolescentes? TECNOLOGIA: Hibridização in situ (ISH), Reação em Cadeia da polimerase por transcriptase reversa qualitativa (RT-PCR) e Reação em Cadeia da polimerase por transcriptase reversa quantitativa (RT-qPCR). EVIDÊNCIAS CIENTÍFICAS: As bases Medline (via Pubmed) e Embase foram pesquisadas e onze estudos foram elegíveis para responder a pergunta de pesquisa. Esses estudos foram agrupados de acordo com os respectivos testes índice e referência. Nenhum dos estudos incluídos foi realizado em populações com suspeita de leucemias Ph+ (triagem). Todos os estudos incluem pacientes com diagnóstico confirmado de leucemias ou outras doenças hematológicas, proliferativas ou não, e avaliam a acurácia com base na detecção dos casos positivos (detecção do transcrito BCR-ABL) e negativos (doenças hematológicas não relacionadas ao BCR-ABL, leucemias Ph- ou indivíduos sadios). Alguns estudos inclusive avaliam a capacidade de detecção e quantificação de transcritos de um teste após a terapia com imatinibe, interferon ou transplante de medula óssea (TMO) (avaliação da resposta molecular). De modo geral, houve boa acurácia entre as técnicas de ISH e RT-PCR (quali e quantitativo), RT-qPCR e RT-PCR qualitativo, tipos diferentes de RT-PCR e RT-qPCR conduzido em amostras de sangue periférico e medula óssea (MO). A maioria dos resultados de sensibilidade e especificidade foi superior a 80%. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO (AIO): O cenário simulado com o menor preço de mercado apresentou o menor impacto orçamentário. No contexto do diagnóstico, esses custos poderiam variar entre R$ 1.313.872,46 e R$ 2.920.036,56, a depender da combinação da frequência de uso das tecnologias, no período entre 2019 e 2023. No contexto do monitoramento, no qual apenas a técnica de RT-PCR quantitativo é utilizada, os valores variaram de R$ 67.281.142,19, para 4 avaliações/ano, até R$ 16.820.285,55, para uma avaliação/ano. CONSIDERAÇÕES FINAIS: O diagnóstico de leucemias Ph+ típica é simples e consiste em documentar, na presença de leucocitose persistente (ou ocasionalmente trombocitose), a presença da anormalidade cromossômica Filadélfia (Ph), o t (9; 22) (q34; q11), por citogenética de rotina, ou anormalidades moleculares BCR-ABL1 relacionadas ao Ph, por hibridização fluorescente in situ (FISH) ou por estudos moleculares. Estudos de acurácia diagnóstica evidenciam bons resultados de sensibilidade e especificidade para os testes ISH e RT-PCR (qualitativo e quantitativo). Ademais, um desses estudos mostra que existe boa correlação entre os resultados obtidos por RT-qPCR em amostras de sangue periférico e em MO. Os testes diagnósticos pleiteados nesse relatório eram anteriormente fornecidos aos pacientes com LMC e LLA Ph+ pelas empresas fabricantes dos inibidores de tirosinoquinase, fato que não acontece atualmente e que pode deixar os usuários sem a integralidade assistencial necessária. Esse relatório pleiteia, portanto, a ampliação do uso de ISH e RT-PCR para LMC e LLA Ph+, no âmbito do SUS, haja vista que, atualmente, esses procedimentos são fornecidos apenas para portadores de doenças raras, que não incluem as leucemias. A AIO mais atrativa considerou os menores valores praticados no mercado. No contexto do diagnóstico, houve variação entre R$ 1.313.872,46 e R$ 2.920.036,56, no período entre 2019 e 2013. No contexto do monitoramento, os valores variaram de R$ 67.281.142,19, para 4 avaliações/ano, até R$ 16.820.285,55, para uma avaliação/ano. RECOMENDAÇÃO PRELIMINAR DA CONITEC: A Conitec, em sua 78ª reunião ordinária, realizada no dia 05 e 06 de junho de 2019, recomendou a incorporação a incorporação dos testes diagnósticos ISH e RT-PCR (qualitativo e quantitativo), para o diagnóstico e o monitoramento das leucemias Ph+ (LMC e LLA Ph+) em adultos e em crianças/adolescentes. A matéria foi disponibilizada para consulta pública. CONSULTA PÚBLICA: Foram apresentadas as características das 641 (seiscentas e quarenta e uma) contribuições recebidas, das quais 400 foram de experiência e opinião e 241 técnico científicas. Do total de contribuições, 99% dos participantes concordaram totalmente com a recomendação preliminar da Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde. RECOMENDAÇÃO FINAL DA CONITEC: Os membros presentes deliberaram, por unanimidade, recomendar a incorporação, ao SUS, dos testes de reação em cadeia da polimerase transcriptase reversa (RT-PCR) qualitativa e quantitativa (RT-qPCR) e hibridização in situ (ISH) para o diagnóstico e monitoramento da leucemia mieloide crônica (LMC) e da leucemia linfoblástica aguda cromossoma Philadelphia positivo (LLA Ph+). Foi assinado o Registro de Deliberação nº 464/2019. DECISÃO: Incorporar a reação em cadeia da polimerase - transcriptase reversa (RT-PCR) qualitativa e quantitativa (RT-qPCR) e hibridização in situ (ISH) para o diagnóstico e monitoramento da leucemia mieloide crônica (LMC) e da leucemia linfoblástica aguda cromossoma Philadelphia positivo (LLA Ph+), no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 57, publicada no Diário Oficial da União nº 224, seção 1, página 79, em 20 de novembro de 2019.
Assuntos
Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa/instrumentação , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economiaRESUMO
BACKGROUND: Recent investigations in chronic myeloid leukemia (CML) have focused on the identification and characterization of leukemic stem cells (LSCs). These cells reside within the CD34+ /CD38â /Linâ fraction and score positive for CD26 (dipeptidylpeptidase IV) a marker, expressed in both bone marrow (BM) and peripheral blood (PB) samples, that discriminates CML cells from normal hematopoietic stem cells (HSCs) or from LSCs of other myeloid neoplasms. CD26 evaluation could be a useful tool to improve the identification of CML LCSs by using flow-cytometry assay. METHODS: CD26+ LSCs have been isolated from EDTA PB and BM samples of patients with leucocytosis suspected for CML. Analysis of LSCs CML has been performed by using custom-made lyophilized pre-titrated antibody mixture test and control tube and a CD45+ /CD34+ /CD38- /CD26+ panel as a strict flow cytometric gating strategy. RESULTS: The expression of CD26 on CD34+ /CD38- population was detectable in 211/211 PB and 84/84 BM samples of subsequently confirmed BCR-ABL+ CP-CML patients. None of the 32 samples suspicious for CML but scoring negative for circulating CD26+ LSCs were diagnosed as CML after conventional cytogenetic and molecular testing. To validate our results, we checked for PB CD26+ LSCs in patients affected by other hematological disorders and they all scored negative for CD26 expression. CONCLUSIONS: We propose flow cytometry evaluation of CD26 expression on PB CD34+ /CD38- population as a new rapid, reproducible, and powerful diagnostic tool for the diagnosis of CML. © 2019 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Citometria de Fluxo , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Células-Tronco Neoplásicas/patologia , Estudos de Coortes , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/isolamento & purificação , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Células-Tronco Neoplásicas/metabolismoRESUMO
Healthcare costs are rising due to an increase in chronic diseases, including chronic myeloid leukemia (CML) due to improved survival. In CML care, patient adherence and physician adherence are key elements. We assessed the potential health gain and cost savings when both are improved, using a decision analytic model that integrated various sources of evidence. The current situation was compared to a theoretical situation in which either patient or physician adherence is improved, in terms of costs and quality-adjusted life years (QALYs). Current patient adherence rate is 74%, improvement to 100% resulted in 0.1031 QALYs gained and a saving of 17,509 per patient over a 25-year period. Improving physician adherence from 72% to 100%, resulted in 0.0380 QALYs and 7606. Enhancement of either adherence results in substantial health gain and cost savings. Regarding the rising healthcare costs, new strategies should focus on improving adherence to keep healthcare affordable in the future.
Assuntos
Redução de Custos , Fidelidade a Diretrizes , Custos de Cuidados de Saúde , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Adesão à Medicação , Análise Custo-Benefício , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/epidemiologia , Países Baixos/epidemiologia , Avaliação de Resultados da Assistência ao Paciente , Qualidade da Assistência à SaúdeRESUMO
We evaluated the impact of molecular monitoring earlier as compared to later in the course of chronic myeloid leukemia (CML) on disease progression and healthcare costs in the real-world setting in the US. Patients with a diagnosis of CML were identified from the MarketScan claims databases (1 January 2006 to 30 June 2016). Multivariable regression analyses were used to control for differences in patient cohorts with earlier versus later monitoring. Of the 2730 CML patients in the study population, 60% (n = 1633) received earlier monitoring and 40% (n = 1097) received later monitoring only. After adjusting for differences in patient characteristics, patients with earlier monitoring had a lower likelihood of CML progression during the follow-up period (odds ratio: 0.72, confidence interval: 0.53-0.96; p = .03) and lower total healthcare costs ($6794 versus $9782 per-patient-per-month, p < .001) than patients with later monitoring. Patients who are monitored earlier in the course of CML may have better outcomes and lower total costs of care.
Assuntos
Custos de Cuidados de Saúde , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Conduta Expectante , Adulto , Idoso , Comorbidade , Progressão da Doença , Feminino , Pesquisas sobre Atenção à Saúde , Recursos em Saúde , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
Objectives: As pathologists and laboratorians, we can enhance patient care by promoting the appropriate ordering of diagnostic tests. Our goal was to improve the ordering of BCR-ABL1 tests by using the EPIDEM model of quality improvement. Methods: We applied the EPIDEM model, which emphasizes understanding local context, culture, and resources, to explore inappropriate BCR-ABL1 ordering, promote and implement a new reflexive testing strategy in-house, document and evaluate effectiveness, and make stepwise modifications. Results: Multiple quality improvement interventions correlated with cost savings and decreased total errors and incorrect orders for both BCR-ABL1 major and minor positive patients. Furthermore, our laboratory built stronger collaborative relationships with colleagues within and outside of pathology. Conclusions: Our molecular pathology laboratory successfully used the EPIDEM model of quality improvement to improve the ordering of BCR-ABL1 tests and promote better patient care by focusing on educational efforts and modification of laboratory workflow.