Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônica
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/20928 |
Resumo: | Chronic Myeloid Leukemia (CML) is associated with the chromosome Philadelphia. This abnormal chromosome forms the chimeric BCR-ABL1 gene, which is responsible for producing a protein with tyrosine kinase activity. Tyrosine kinase inhibitors drugs (ITKs) used in Brazil are imatinib mesylate (IM), dasatinib and nilotinib. The response to these tests can be rated at three levels: hematological, cytogenetic and molecular. This last one is more sensitive and evaluated with Reaction in Chain of Real Time Polimerase (RQ-PCR). The treatment aims at achieving the Major Molecular Response (MMR), whose ratio of bcr-abl1 chimeric transcript levels and endogenous control are less than or equal to 0.1%. European Leukemia Net (ELN) establishes guidelines for molecular responses according to the quantification of transcripts and the time of treatment with ITQs, classifying them as optimal response, alert and failure. According to the literature, it is known that approximately 15-25% of patients treated with MI do not reach optimal response. Due to the low number of studies that show how the molecular monitoring of CML in Brazil is we decided to evaluate the molecular response to treatment with the ITQs of CML patients treated in HUSM through RQ-PCR monitoring for quantification of transcripts of the BCR-ABL1 fusion gene. The analysis was did through the database of the Hematology-Oncology Service of the HUSM and the quantification of the transcripts and the mutation search in the ABL gene were performed in an external laboratory. 117 medical records were reviewed, of which 58.11% were male. The mean age at diagnosis was 48.1 years and 9.4% of the patients died. Six patients were analyzed separately for different characteristics of the others. Thus, of the 111 patients, 52.25% of the patients received exclusively MI, 42.30% reached MMR at 12 months and 73.40% had MMR at some point during IM treatment. 54.25% of the patients who exclusively used IM reached the MMR and maintained it to the end. Of the 47.74% that changed ITQ, 58.82% reached MMR shortly after the exchange and maintained this response to the end. Of the 19 (37.25%) patients who failed during the exchange, 14 went to the third line of therapy. Currently, 91.06% of patients who use IM are with MRM, as are 65.37% of patients using nilotinib and 58.81% of those who use dasatinib. Of the patients who were tested for mutation in the ABL gene, 40% had presence. According to the criteria of the EUROSKI study, five patients would be eligible to enter a study protocol for Treatment-Free Referral. We observed an improvement in monitoring over time, as well as good MMR results compared to the three ITQs currently used in HUSM. Our results are in agreement with the literature and the HUSM has been |
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Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônicaMonitoring of molecular response to thyrosino-kynase inhibitors in patients with chronic myeloid leukemiaLeucemia mieloide crônicaMonitoramento molecularBCR-ABL1Resistência ao imatinibeChronic myeloid leukemiaMolecular monitoringResistance to imatinibCNPQ::CIENCIAS DA SAUDE::FARMACIAChronic Myeloid Leukemia (CML) is associated with the chromosome Philadelphia. This abnormal chromosome forms the chimeric BCR-ABL1 gene, which is responsible for producing a protein with tyrosine kinase activity. Tyrosine kinase inhibitors drugs (ITKs) used in Brazil are imatinib mesylate (IM), dasatinib and nilotinib. The response to these tests can be rated at three levels: hematological, cytogenetic and molecular. This last one is more sensitive and evaluated with Reaction in Chain of Real Time Polimerase (RQ-PCR). The treatment aims at achieving the Major Molecular Response (MMR), whose ratio of bcr-abl1 chimeric transcript levels and endogenous control are less than or equal to 0.1%. European Leukemia Net (ELN) establishes guidelines for molecular responses according to the quantification of transcripts and the time of treatment with ITQs, classifying them as optimal response, alert and failure. According to the literature, it is known that approximately 15-25% of patients treated with MI do not reach optimal response. Due to the low number of studies that show how the molecular monitoring of CML in Brazil is we decided to evaluate the molecular response to treatment with the ITQs of CML patients treated in HUSM through RQ-PCR monitoring for quantification of transcripts of the BCR-ABL1 fusion gene. The analysis was did through the database of the Hematology-Oncology Service of the HUSM and the quantification of the transcripts and the mutation search in the ABL gene were performed in an external laboratory. 117 medical records were reviewed, of which 58.11% were male. The mean age at diagnosis was 48.1 years and 9.4% of the patients died. Six patients were analyzed separately for different characteristics of the others. Thus, of the 111 patients, 52.25% of the patients received exclusively MI, 42.30% reached MMR at 12 months and 73.40% had MMR at some point during IM treatment. 54.25% of the patients who exclusively used IM reached the MMR and maintained it to the end. Of the 47.74% that changed ITQ, 58.82% reached MMR shortly after the exchange and maintained this response to the end. Of the 19 (37.25%) patients who failed during the exchange, 14 went to the third line of therapy. Currently, 91.06% of patients who use IM are with MRM, as are 65.37% of patients using nilotinib and 58.81% of those who use dasatinib. Of the patients who were tested for mutation in the ABL gene, 40% had presence. According to the criteria of the EUROSKI study, five patients would be eligible to enter a study protocol for Treatment-Free Referral. We observed an improvement in monitoring over time, as well as good MMR results compared to the three ITQs currently used in HUSM. Our results are in agreement with the literature and the HUSM has beenA Leucemia Mieloide Crônica (LMC) está associada ao cromossomo Philadelphia. Este cromossomo anormal forma o gene quimérico BCR-ABL1, o qual é responsável por produzir uma proteína com atividade de tirosino quinase. Os fármacos inibidores desta proteína (ITQs) usados no Brasil são: mesilato de imatinibe (MI), dasatinibe e nilotinibe. A resposta a estes tratamentos farmacológicos pode ser expressa em três níveis: hematológica, citogenética e molecular. Esta última é a mais sensível e é avaliada por Reação em Cadeia da Polimerase em Tempo Real (RQ-PCR). O tratamento visa o alcance da Resposta Molecular Maior (RMM), cuja razão dos níveis do transcrito quimérico bcr-abl1 e o controle endógeno são menores ou iguais a 0,1%. O European Leukemia Net (ELN) estabelece diretrizes para as respostas moleculares de acordo com a quantificação dos transcritos e o tempo de tratamento com ITQs, classificando-as como resposta ótima, alerta e falha. Segundo a literatura, sabe-se que aproximadamente 15-25% dos pacientes tratados com MI não alcançam a resposta ótima. Em virtude do baixo número de trabalhos que mostram o monitoramento molecular da LMC no Brasil, avaliamos a resposta molecular ao tratamento com os ITQs de pacientes com LMC tratados no HUSM através do monitoramento por RQ-PCR para quantificação dos transcritos do gene de fusão BCR-ABL1. A análise se deu através do banco de dados do Serviço de Hematologia-Oncologia do HUSM e a quantificação dos transcritos e a pesquisa de mutação no gene ABL foram realizadas em laboratório externo. Foram revisados 117 prontuários, sendo que 58,11% eram da população masculina. A média de idade ao diagnóstico foi de 48,1 anos e 9,4% dos pacientes foram a óbito. Seis pacientes foram analisados à parte por características diferenciadas dos demais. Assim, dos 111 pacientes, 52,25% dos pacientes receberam exclusivamente MI, 42,30% atingiram a RMM aos 12 meses e 73,40% tiveram RMM em algum momento durante o tratamento com MI. 54,25% dos pacientes que usaram exclusivamente o MI alcançaram a RMM e a mantiveram até o fim. Dos 47,74% que mudaram de ITQ, 58,82% alcançaram a RMM logo após a troca e mantiveram até o fim esta resposta. Dos 19 (37,25%) pacientes que falharam ao longo da troca, 14 foram para a terceira linha de terapia. Atualmente 91,06% dos pacientes que usam MI estão com RMM, assim como 65,37% dos pacientes que usam nilotinibe e 58.81% dos que usam dasatinibe. Dos pacientes que foram testados para mutação no gene ABL, 40% tinham presença. Segundo os critérios do estudo EURO-SKI cinco pacientes seriam elegíveis para entrar num protocolo de estudo de Remissão Livre de Tratamento. Observamos uma melhora no monitoramento ao longo do tempo, bem como bons resultados de RMM frente aos três ITQs usados no HUSM atualmente. Nossos resultados estão em acordo com a literatura e o HUSM tem sido bem visto no cenário brasileiro com o monitoramento molecular que tem com seus pacientes para avaliar as respostas do uso de ITQs.Universidade Federal de Santa MariaBrasilFarmáciaUFSMPrograma de Pós-Graduação em Ciências FarmacêuticasCentro de Ciências da SaúdeSilva, José Edson Paz dahttp://lattes.cnpq.br/1177504021154172Leal, Daniela Bitencourt RosaSantos, Karen FreitasVilla, Bárbara2021-05-19T17:36:53Z2021-05-19T17:36:53Z2019-02-28info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/20928porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2022-10-07T18:08:16Zoai:repositorio.ufsm.br:1/20928Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-10-07T18:08:16Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônica Monitoring of molecular response to thyrosino-kynase inhibitors in patients with chronic myeloid leukemia |
title |
Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônica |
spellingShingle |
Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônica Villa, Bárbara Leucemia mieloide crônica Monitoramento molecular BCR-ABL1 Resistência ao imatinibe Chronic myeloid leukemia Molecular monitoring Resistance to imatinib CNPQ::CIENCIAS DA SAUDE::FARMACIA |
title_short |
Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônica |
title_full |
Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônica |
title_fullStr |
Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônica |
title_full_unstemmed |
Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônica |
title_sort |
Monitoramento da resposta molecular aos inibidores de tirosino-quinase em pacientes com leucemia mieloide crônica |
author |
Villa, Bárbara |
author_facet |
Villa, Bárbara |
author_role |
author |
dc.contributor.none.fl_str_mv |
Silva, José Edson Paz da http://lattes.cnpq.br/1177504021154172 Leal, Daniela Bitencourt Rosa Santos, Karen Freitas |
dc.contributor.author.fl_str_mv |
Villa, Bárbara |
dc.subject.por.fl_str_mv |
Leucemia mieloide crônica Monitoramento molecular BCR-ABL1 Resistência ao imatinibe Chronic myeloid leukemia Molecular monitoring Resistance to imatinib CNPQ::CIENCIAS DA SAUDE::FARMACIA |
topic |
Leucemia mieloide crônica Monitoramento molecular BCR-ABL1 Resistência ao imatinibe Chronic myeloid leukemia Molecular monitoring Resistance to imatinib CNPQ::CIENCIAS DA SAUDE::FARMACIA |
description |
Chronic Myeloid Leukemia (CML) is associated with the chromosome Philadelphia. This abnormal chromosome forms the chimeric BCR-ABL1 gene, which is responsible for producing a protein with tyrosine kinase activity. Tyrosine kinase inhibitors drugs (ITKs) used in Brazil are imatinib mesylate (IM), dasatinib and nilotinib. The response to these tests can be rated at three levels: hematological, cytogenetic and molecular. This last one is more sensitive and evaluated with Reaction in Chain of Real Time Polimerase (RQ-PCR). The treatment aims at achieving the Major Molecular Response (MMR), whose ratio of bcr-abl1 chimeric transcript levels and endogenous control are less than or equal to 0.1%. European Leukemia Net (ELN) establishes guidelines for molecular responses according to the quantification of transcripts and the time of treatment with ITQs, classifying them as optimal response, alert and failure. According to the literature, it is known that approximately 15-25% of patients treated with MI do not reach optimal response. Due to the low number of studies that show how the molecular monitoring of CML in Brazil is we decided to evaluate the molecular response to treatment with the ITQs of CML patients treated in HUSM through RQ-PCR monitoring for quantification of transcripts of the BCR-ABL1 fusion gene. The analysis was did through the database of the Hematology-Oncology Service of the HUSM and the quantification of the transcripts and the mutation search in the ABL gene were performed in an external laboratory. 117 medical records were reviewed, of which 58.11% were male. The mean age at diagnosis was 48.1 years and 9.4% of the patients died. Six patients were analyzed separately for different characteristics of the others. Thus, of the 111 patients, 52.25% of the patients received exclusively MI, 42.30% reached MMR at 12 months and 73.40% had MMR at some point during IM treatment. 54.25% of the patients who exclusively used IM reached the MMR and maintained it to the end. Of the 47.74% that changed ITQ, 58.82% reached MMR shortly after the exchange and maintained this response to the end. Of the 19 (37.25%) patients who failed during the exchange, 14 went to the third line of therapy. Currently, 91.06% of patients who use IM are with MRM, as are 65.37% of patients using nilotinib and 58.81% of those who use dasatinib. Of the patients who were tested for mutation in the ABL gene, 40% had presence. According to the criteria of the EUROSKI study, five patients would be eligible to enter a study protocol for Treatment-Free Referral. We observed an improvement in monitoring over time, as well as good MMR results compared to the three ITQs currently used in HUSM. Our results are in agreement with the literature and the HUSM has been |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-02-28 2021-05-19T17:36:53Z 2021-05-19T17:36:53Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/20928 |
url |
http://repositorio.ufsm.br/handle/1/20928 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmácia UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmácia UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
_version_ |
1805922096360980480 |