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Triple-negative breast cancer (TNBC) is associated with a poor prognosis and the absence of targeted therapy. c-Kit, a receptor tyrosine kinase (RTK), is considered a molecular target for anticancer drugs. Tyrosine kinase inhibitors (TKIs) recognizing c-Kit are used for the treatment of c-Kit-expressing tumors. However, the expression, function, and therapeutic potential of c-Kit have been little explored in TNBC. Here, we studied the expression and effects of c-Kit in TNBC through in vitro and in silico analysis, and evaluated the response to TKIs targeting c-Kit. Analysis of TNBC cells showed the expression of functional c-Kit at the cell membrane. The stimulation of c-Kit with its ligand induced the activation of STAT3, Akt, and ERK1/2, increasing cell migration, but had no effect on cell proliferation or response to Doxorubicin. Analysis of public datasets showed that the expression of c-Kit in tumors was not associated with patient survival. Finally, TNBC cells were susceptible to TKIs, in particular the effect of Nilotinib was stronger than Doxorubicin in all cell lines. In conclusion, TNBC cells express functional c-Kit, which is a targetable molecule, and show a strong response to Nilotinib that may be considered a candidate drug for the treatment of TNBC.
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Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Proliferação de Células , Doxorrubicina/farmacologia , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Receptores Proteína Tirosina Quinases , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Resumen: ANTECEDENTES: La leucemia mieloide crónica es una neoplasia mieloproliferativa; los inhibidores de tirosin cinasa son fármacos eficaces en el tratamiento de esta enfermedad, en el ISSSTE se cuenta con imatinib, nilotinib y dasatinib. OBJETIVOS: Conocer el número de casos de leucemia mieloide crónica de 2005 a 2016, identificar las características clínicas, medir el grado de respuesta y la supervivencia. MATERIAL Y MÉTODO: Estudio retrospectivo, transversal, observacional y explicativo, efectuado de 2005 a 2016, en el que se incluyeron pacientes mayores de 18 años de edad, con diagnóstico de leucemia mieloide crónica, con cualquier fase de la enfermedad y en tratamiento con cualquiera de los inhibidores de tirosin cinasa. RESULTADOS: Se incluyeron 31 casos (55.2% mujeres); la mediana de edad fue 62 años. El 72.4% estaba en fase crónica, 27.6% en fase acelerada y ninguno en fase blástica. La respuesta hematológica fue de 94.1, 90 y 96%; la respuesta citogenética completa a 12 meses fue de 69.2, 60 y 57%; la respuesta molecular mayor se documentó en 62.9, 68.6 y 69.1% para imatinib, nilotinib y dasatinib, respectivamente. La supervivencia libre de enfermedad en este grupo a cinco años fue de 83%. La supervivencia global a cinco años fue de 94%. CONCLUSIONES: Independientemente del inhibidor prescrito se logran respuestas hematológicas superiores a 90%, citogenéticas completas en alrededor de 60% a 12 meses y moleculares mayores de 60% en un hospital del ISSSTE.
Abstract: BACKGROUND: Chronic myeloid leukemia is a myeloproliferative disease; the most effective drugs in the treatment of this disease are imatinib, nilotinib and dasatinib. Those drugs are available at the ISSSTE. OBJECTIVES: To know the number of chronic myeloid leukemia cases, to identify the clinical characteristics and to measure the degree of response to tyrosine kinase inhibitors and the survival. MATERIAL AND METHOD: A retrospective, cross-sectional, observational and explanatory study was done from 2005 to 2016, including patients over 18 years of age, with a diagnosis of chronic myeloid leukemia; with any of the three phases of the disease and treatment with any of the tyrosine kinase inhibitors. RESULTS: There were included 31 cases (55.2% women); the median age was 62 years; 72.4% were in chronic phase, 27.6% in accelerated phase and none in the blast phase. The haematological response was of 94.1%, 90% and 96%; the complete cytogenetic response at 12 months was of 69.2%, 60% and 57% and the mayor mo- lecular response was of 62.9%, 68.6%, 69.1% of the patients treated with imatinib, nilotinib or dasatinib, respectively. Disease-free survival at 5 years was of 83% and global survival at 5 years was of 94%. CONCLUSION: Independently of the inhibitor prescribed, the hematologic response is achieved in more than 90%, the complete cytogenetics around 60% at 12 months and major molecular almost 60% in a ISSSTE hospital.
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ABSTRACT Objective: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. Methods: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. Results: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p < 0.01). Decreased overall survival was associated with advanced-phase disease (p < 0.01), failure to achieve major molecular response in first-line treatment (p < 0.01) and interruption of first-line treatment due to any reason (p = 0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. Conclusion: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies.
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Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Leucemia Mielogênica Crônica BCR-ABL Positiva , Análise de Sobrevida , Mesilato de Imatinib , DasatinibeRESUMO
OBJECTIVE: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. METHODS: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. RESULTS: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p<0.01). Decreased overall survival was associated with advanced-phase disease (p<0.01), failure to achieve major molecular response in first-line treatment (p<0.01) and interruption of first-line treatment due to any reason (p=0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. CONCLUSION: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies.
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BACKGROUND: Cardiovascular events (CVEs) have been observed in patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors. PATIENTS AND METHODS: We retrospectively evaluated the incidence of CVEs on 233 consecutive patients with chronic myeloid leukemia, of which 116 were treated with imatinib, 75 with dasatinib, and 42 with nilotinib. The median follow-up was 2047, 1712, and 1773 days, respectively. RESULTS: The cumulative incidence of CVEs was 4.29%. Three events occurred during dasatinib treatment, 6 during nilotinib treatment, and none during imatinib treatment (P ≤ .001). Arterial occlusive events occurred in 2 (2.6%) of 75 patients treated with dasatinib and in 6 (14.2%) of 42 patients treated with nilotinib (P ≤ .001). Furthermore, all of them occurred in patients with high-risk (n = 2) and very high-risk (n = 6) cardiovascular risk, contributing to 4.3% of mortality. CONCLUSION: CVEs were more frequent in patients treated with second-generation tyrosine kinase inhibitors. Arterial occlusive events were more frequent in patients treated with nilotinib, with high and very high cardiovascular risk.
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Doenças Cardiovasculares/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Inibidores de Proteínas Quinases/efeitos adversos , Adulto , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are effective therapies with demonstrated antineoplastic activity. Nilotinib is a second-generation FDA-approved TKI designed to overcome Imatinib resistance and intolerance in patients with chronic myelogenous leukemia (CML). Interestingly, TKIs have also been shown to be an efficient treatment for several non-malignant disorders such fibrotic diseases, including those affecting skeletal muscles. METHODS: We investigated the role of Nilotinib on skeletal myogenesis using the well-established C2C12 myoblast cell line. We evaluated the impact of Nilotinib during the time course of skeletal myogenesis. We compared the effect of Nilotinib with the well-known p38 MAPK inhibitor SB203580. MEK1/2 UO126 and PI3K/AKT LY294002 inhibitors were used to identify the signaling pathways involved in Nilotinib-related effects on myoblast. Adult primary myoblasts were also used to corroborate the inhibition of myoblasts fusion and myotube-nuclei positioning by Nilotinib. RESULTS: We found that Nilotinib inhibited myogenic differentiation, reducing the number of myogenin-positive myoblasts and decreasing myogenin and MyoD expression. Furthermore, Nilotinib-mediated anti-myogenic effects impair myotube formation, myosin heavy chain expression, and compromise myotube-nuclei positioning. In addition, we found that p38 MAPK is a new off-target protein of Nilotinib, which causes inhibition of p38 phosphorylation in a similar manner as the well-characterized p38 inhibitor SB203580. Nilotinib induces the activation of ERK1/2 and AKT on myoblasts but not in myotubes. We also found that Nilotinib stimulates myoblast proliferation, a process dependent on ERK1/2 and AKT activation. CONCLUSIONS: Our findings suggest that Nilotinib may have important negative effects on muscle homeostasis, inhibiting myogenic differentiation but stimulating myoblasts proliferation. Additionally, we found that Nilotinib stimulates the activation of ERK1/2 and AKT. On the other hand, we suggest that p38 MAPK is a new off-target of Nilotinib. Thus, there is a necessity for future studies to investigate the long-term effects of TKIs on skeletal muscle homeostasis, along with potential detrimental effects in cell differentiation and proliferation in patients receiving TKI therapies.
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Desenvolvimento Muscular/efeitos dos fármacos , Mioblastos Esqueléticos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular/fisiologia , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/enzimologia , Miogenina/biossíntese , Miogenina/genética , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteostase/efeitos dos fármacos , Proteostase/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Although Tyrosine kinase inhibitors (TKIs) that target Bcr-Abl play a key role in Chronic Myeloid Leukemia (CML) therapy, they do not eradicate CML-initiating cells, which lead to the emergence of drug resistance. Here we used the lithium, a GSK-3 inhibitor, to attempt to potentiate the effects of nilotinib against leukemia cells. For this purpose, a K562 leukemia cell line and bone marrow cells from untreated Chronic Myeloid Leukemia (CML) patients, prior to any exposure to TKIs, were used as a model. Our results demonstrated that the combination of lithiumâ¯+â¯nilotinib (Lâ¯+â¯N) induced K562-cell death and cleaved caspase-3 when compared to lithium or nilotinib alone, accompanied by GSK-3ß phosphorylation and Bcr-Abl oncoprotein levels reduction. Interestingly, these events were related to autophagy induction, expressed by increased LC3II protein levels in the group treated with Lâ¯+â¯N. Furthermore, the clonogenic capacity of progenitor cells from CML patients was drastically reduced by Lâ¯+â¯N, as well as lithium and nilotinib when used separately. The number of cell aggregates (clusters), were increased by all treatments (Lâ¯+â¯N, lithium, and nilotinib). This pioneering research has demonstrated that lithium might be of therapeutic value when targeting Bcr-Abl cells with nilotinib because it triggers cell death in addition to exerting classical antiproliferative effects, opening new perspectives for novel target and therapeutic approaches to eradicate CML.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Lítio/uso terapêutico , Pirimidinas/uso terapêutico , Autofagia/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Proteínas de Fusão bcr-abl/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Células K562 , Lítio/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosforilação/efeitos dos fármacos , Pirimidinas/farmacologiaRESUMO
OBJECTIVES: This article reviews clinical experiences in the treatment of chronic myeloid leukemia (CML) in an environment of limited resources. METHODS: We reviewed recent publications on Pub med and abstracts from mayor congresses relevant to the disease. RESULTS: CML is a hematological neoplasm observed more frequently in adults, regardless of their socioeconomic status. Until recently, available treatments improved patients' quality of life but did not modify survival. It was not until interferon appeared that patients received a drug that reduced and even eliminated Philadelphia chromosome-positive (Ph+) cells. DISCUSSION: With the start of the new millennium, the International Randomized Study of Interferon-α plus cytarabine versus STI571 (IRIS) trial demonstrated a dramatic improvement in survival by comparing imatinib versus interferon alpha plus cytarabine. The Food and Drug Administration (FDA) approved imatinib as first-line treatment for newly diagnosed CML in 2001 due to its outstanding effectiveness. Years later, three second-generation (dasatinib, nilotinib, bosutinib) and one third-generation (ponatinib) tyrosine-kinase inhibitors (TKIs) were developed and approved. These highly effective treatment options, however, are not affordable for many low-income patients. Additionally, the use of drugs that effectively treat but do not cure the disease has resulted in an important economic impact for patients and health care systems worldwide, especially those in developing countries. Imatinib is the least expensive and a very effective TKI in many low-income countries. Early allogeneic stem cell transplantation must be considered in the management of selected patients before CML transformation.
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Antineoplásicos/uso terapêutico , Recursos em Saúde/normas , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Antineoplásicos/economia , Recursos em Saúde/economia , Humanos , Mesilato de Imatinib/economia , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/economia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologiaRESUMO
Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP-CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP-CML and enrolling 2,456 patients were included. Follow-up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%(IS)) achievement with second-generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed-treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR(4.5) ≤ 0.0032%(IS)) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new-generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow-up period. It is important to note out that MTC is not a substitute for well-conducted RCTs investigating direct comparisons.
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Antineoplásicos/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Feminino , Humanos , Leucemia Mieloide de Fase Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do TratamentoRESUMO
Nilotinib es un inhibidor altamente selectivo de BCR-ABL tirosina kinasa usado para el tratamiento de Leucemia mieloide crónica. Las reacciones cutáneas fueron uno de los efectos adversos no hematológicos más frecuentemente reportados en relación al uso de esta droga. El presente artículo documenta el caso una paciente femenina de 17 años de edad diagnosticada con Leucemia mieloide crónica que había estado en tratamiento con Nilotinib por 5 meses desarrollando una reacción tipo queratosis pilar. La paciente fue tratada con medidas generales, Urea 15% y antihistamínicos, con cese del prurito. Es importante reconocer las reacciones cutáneas asociadas al uso de Nilotinib para así otorgar alivio oportuno de los síntomas con el fin de lograr una mejor adherencia al tratamiento de la Leucemia mieloide crónica y mejorar la calidad de vida del paciente.
Nilotinib is a highly selective inhibitor of BCR-ABL tyrosine kinase. It is used as a treatment for chronic myelogenous leukemia (CML). Cutaneous reactions are one of the most common non-hematologic reported adverse effects. The present article documents the case of a 17-year-old female patient diagnosed with CML. She was treated with nilotinib for 5 months and developed a keratosis pilaris-like reaction. The patient was treated with general measures, topical 15%-urea and antihistamines with improvement and cessation of pruritus. It is imperative to recognize the cutaneous adverse effects associated with the use of new oncologic treatments such as nilotinib.
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Humanos , Feminino , Adolescente , Pirimidinas/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Ceratose/induzido quimicamente , Pirimidinas/uso terapêutico , ToxidermiasRESUMO
OBJECTIVE: To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib. METHODS: Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing. RESULTS: We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months. CONCLUSIONS: Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome ...
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Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Exame de Medula Óssea , Intervalo Livre de Doença , Proteínas de Fusão bcr-abl/genética , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Resultado do TratamentoRESUMO
Tyrosine kinase inhibitors (TKIs), imatinib, nilotinib and dasatinib, are the current treatment of chronic myeloid leukemia (CML). BCR-ABL1 point mutations are the principal cause of resistance to treatment; however other mechanisms could be involved in failure to TKI therapy. LYN is a src kinase protein that regulates survival and responsiveness of tumor cells by a BCR-ABL1 independent mechanism. PTEN tumor suppressor gene is downregulated by BCR-ABL1 in CML stem cells and its deletion is associated with acceleration of disease. In this study we evaluated the expression of LYN, PTEN and the ratio of both genes in 40 healthy donors (HD) and in 139 CML patients; 88 of them resistant to TKI in different phases of disease and 51 in chronic phase classified as optimal responders (OR) to TKI [40 treated with imatinib or nilotinib (OR-IN) and 11 treated with dasatinib (OR-D) therapy]. When we analyzed the gene expression values of LYN, an increase was observed only in advanced stages of the disease, however, when we analyzed the ratio between LYN and PTEN genes, the group of resistant patients in chronic phase in imatinib or nilotinib treatment (CP-IN) also showed a significant increase. Resistant patients treated with dasatinib, a src kinase inhibitor, presented a similar ratio to the observed in HD. In addition, the LYN/PTEN ratio and the LYN expression showed a direct significant correlation with BCR-ABL1 transcript levels in unmutated resistant patients treated with non-src kinase inhibitors. We were able to identify 8/35 (23%) of cases in CP-IN and 4/12 (33%) in accelerated phase and blast phase (AP/BC-IN), in which resistance could be associated with an increase in the ratio of the LYN/PTEN. Our data suggest that the LYN/PTEN expression ratio may be a sensitive monitor of disease progression in unmutated CML patients under imatinib or nilotinib treatment. This ratio could detect cases when resistance is related to altered LYN expression, suggesting that the treatment change to a src kinase inhibitor would be most suitable to overcome resistance.
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Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , PTEN Fosfo-Hidrolase/genética , Quinases da Família src/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Mutação , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Objetivo: Basados en una evaluación económica de costo-efectividad del dasatinib primera línea en el tratamiento de la leucemia mieloide crónica (LMC) realizada por el Consorcio de York, y previo análisis de transferibilidad de datos, se realizó una adaptación de ésta a Colombia y Venezuela. Se compararon los costos y la relación de costo-efectividad del uso de la dosis de 100 mg/día de dasatinib versus 400 mg/día de imatinib y 600 mg/día de nilotinib para cada fase de la enfermedad, como tratamientos de primera línea, con incrementos a 140 mg/día de dasatinib, 800 mg/día de imatinib y 800 mg/día de nilotinib en una segunda línea de tratamiento. Métodos: El modelo original consideró aquellos pacientes con diagnóstico de LMC que no hubieran recibido tratamiento previo. Para realizar la adaptación de la evaluación económica se asumieron las probabilidades de cambio, para lo cual se consideraron tres fases, crónica, acelerada y muerte, a lo largo de toda la vida y con una tasa de descuento del 3,5 por ciento para los costos y beneficios. Los resultados del modelo incluyeron los costos de cada alternativa de tratamiento con dasatinib, nilotinib o imatinib y los años de vida ajustados a calidad ganada. Los costos se expresan en pesos colombianos y bolívares fuertes del año 2011. Resultados: El dasatinib produjo la mayor cantidad de años de vida ajustados a calidad, tanto para Colombia como para Venezuela con 10,67 y 10,53 QALYs respectivamente, en comparación con 10,10 y 9,97 QALYs en cada caso para el imatinib y 10,50 y 10,36 QALYs para el nilotinib. Los costos esperados por QALY en Colombia fueron de $ 108.174.020 para el dasatinib, $ 80.826.556 para el imatinib y $ 134.747.281 para el nilotinib. En Venezuela fueron de BsF 222.970 para el dasatinib, BsF 213.142 para el imatinib y BsF 269.193 para el nilotinib. El dasatinib fue dominante sobre el nilotinib en ambos países. Conclusiones: El dasatinib fue más efectivo...
Objective: To adapt an economic model of frontline dasatinib treatment for chronic myeloid leukemia developed by the York Consortium to the health care settings in Colombia and Venezuela. Methods: The original model considered treatment of naïve patients with CML and a Markov's model with probabilities of change between chronic, accelerated phases and death, over a patients lifetime. The applied discount rate is 3.5 percent for both costs and benefits. Direct medical and treatment costs, and mortality rates were taken from the local published data and WHO life tables. Costs are expressed in 2011 Colombian pesos and Venezuelan strong bolivars. Results: Dasatinib 100 mg/day as frontline treatment for CML produced the greatest number of QALYs, both in Colombia and Venezuela with 10.67 and 10.53 QALYs respectively, compared with 10.10 and 9.97 QALYs for imatinib and 10.50 and 10.36 QALYs for nilotinib. The expected cost per QALY in Colombia was $ 108.174.020 for dasatinib, $ 80.826.556 for imatinib and $ 134.747.281 for nilotinib. The expected cost per QALY in Venezuela was BsF 222.970 for dasatinib, BsF 213.142 for imatinib and BsF 269.193 for nilotinib. Dasatinib was dominant to nilotinib in both countries. Conclusions: In the frontline treatment for CML in Colombia and Venezuela, dasatinib had greater QALYs than both imatinib and nilotinib, and demonstrated cost-effectiveness relative to nilotinib. There was an increase in overall costs, due to the increase in life years gained and thus a greater use of overall health care resources.
Assuntos
Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Modelos Econômicos , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Antineoplásicos/uso terapêutico , Benzamidas , Colômbia , Análise Custo-Benefício , Inibidores de Proteínas Quinases/economia , Mortalidade , Piperazinas/economia , Pirimidinas/economia , Controle de Qualidade , Tiazóis , VenezuelaRESUMO
Objetivo: con base en una evaluación económica realizada previamente, se realizó una adaptación de ésta a Venezuela y Colombia, previo análisis de transferibilidad de datos.Mediante esta adaptación se compararon los costos y la relación de costo-efectividad deluso de la dosis de 100 mg/día y 140 mg/día de dasatinib, el uso de 800 mg/día de nilotinib y eluso de una dosis mayor de imatinib (800mg/día), para cada fase de la enfermedad, en pacientes que desarrollaron resistencia a la dosis habitual de imatinib.Métodos: para realizar la adaptación de la evaluación económica, se asumieron las probabilidades decambio de acuerdo al modelo de Markov, donde se consideró una cohorte de 10 000 pacientes con LMCen sus tres fases (crónica, acelerada y blástica) a lo largo de toda la vida y con una tasa de descuento del 3,5 % para los costos y beneficios. Los resultados delmodelo incluyeron los costos de cada alternativa de tratamientocon dasatinib, nilotinib o imatinib y los años devida ajustados a calidad ganados. Los costos se expresanen pesos colombianos y bolívares fuertes del año 2009.Resultados: en la fase crónica de la enfermedad, dasatinib100 mg/día produjo la mayor cantidad de añosde vida ajustados a calidad, tanto para Colombia comopara Venezuela (6,88 y 6,54, respectivamente) y la menorrelación de costo-efectividad. En la fase acelerada,dasatinib 140 mg/día también mostró la menor relaciónde costo-efectividad en comparación con imatinib ynilotinib. En la fase blástica, dasatinib mostró menorrelación de costo-efectividad que imatinib. Conclusiones: el dasatinib a dosis de 100 mg/día y 140mg/día mostraron los índices más bajos de costo-efectividad que en las dosis de 800 mg/día de nilotinib para el tratamiento de pacientes con resistencia a la dosis habitual de imatinib en la fase crónica de la LMC, así como en la acelerada y la blástica. Aunque hubo un aumento de los costos en general, especialmente debido al costo de dasatinib.
Objective: Based on a previously performedeconomic evaluation, we adapted a Cost-effectivenessmodel for Venezuela and Colombia, aftera data transferability analysis. We comparedthe costs and cost-effectiveness ratio of using100mg/day and 140 mg/day doses of Dasatinibversus 800 mg/day doses of Nilotinib or an increaseddose of Imatinib (800mg/day), for eachphase of the disease, in patients who developedresistance to habitual doses of Imatinib.Methods: To adapt the economic evaluation, weassumed the transition probabilities based on theMarkov model used for this economic evaluation,which considered a cohort of 10.000 CML patientsin its three phases (chronic, accelerated or blast phase), a lifetime horizon and a 3.5 % discountrate for costs and benefits. Model resultsincluded the costs of each treatment alternativewith Dasatinib, Nilotinib or Imatinib, and the QualityAdjusted Life Years (QALYs) gained. Costs weremeasured in Colombian pesos and Bolivares Fuertes(BsF) of year 2009.Results: In the chronic phase of the disease, dasatinib100 mg/day yielded the highest amount of QALYs both for Colombia and Venezuela (6,88 and6,54 respectively) and the lowest cost-effectivenessratio. In the accelerated phase, Dasatinib 140mg/day also showed the lowest cost-effectivenesscompared to Nilotinib and Imatinib. In the blastphase, dasatinib showed lower cost-effectivenessratio than imatinib.Conclusions: Dasatinib 100 mg/day and 140 mg/day showed the lowest cost-effectiveness ratiosthan doses of 800 mg/day of Nilotinib for thetreatment of patients with CML resistant to usualimatinib doses in the chronic phase, as well as inthe accelerated and blast phases. Although there was an overall cost increase, especially due to thecost of Dasatinib in 140 mg/day doses, this factwas explained by the increase in years of life gainedand, consequently, the use of medical resourcesand drugs in the timeline of treatment.