Monitoring of BCR-ABL levels in chronic myeloid leukemia patients treated with imatinib in the chronic phase: the importance of a major molecular response

BACKGROUND: Real time PCR has become the most common technique to monitor BCR-ABL transcript levels of patients treated with kinase inhibitors. The aim of this study was to evaluate BCR-ABL levels of chronic myeloid leukemia patients treated with imatinib in the chronic phase and correlate the response to therapy and event-free survival. METHODS: BCR-ABL levels were measured in peripheral blood cell samples using Real time PCR at diagnosis and then every 3 months after starting therapy with imatinib. Major molecular response was defined as a three-log reduction from the standardized baseline value. Major molecular response values were adjusted to international scale using a conversion factor of 1.19. The results are reported as a BCR-ABL/ABL ratio (%). RESULTS: Hematological, major cytogenetic and complete cytogenetic responses were achieved by 57 (95%), 45 (75%) and 38 (63%) patients, respectively. Twenty-four out of sixty patients achieved a major molecular response (40%) in a median time of 8.5 months. Overall survival and event free survival were higher for patients with (100%) versus patients without (77%) a complete cytogenetic response (p-value = 0.01) at 48 months. Patients with complete cytogenetic response and major molecular response had a higher event free survival compared to patients with complete cytogenetic response but without major molecular response (p-value = 0.007). CONCLUSION: In conclusion, the prognostic impact of achieving complete cytogenetic response and a major molecular response and also the importance of molecular monitoring in the follow-up of chronic myeloid leukemia patients were demonstrated.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Early progression as a predictor of survival in marginal zone lymphomas: An analysis from the FIL-NF10 study

Marginal zone lymphomas (MZLs) are indolent nonfollicular B-cell lymphomas (INFLs) and have heterogeneous clinical behavior. Recently, time to progression of disease at 24 months (POD24) was identified to stratify overall survival (OS) in follicular non-Hodgkin lymphoma and in INFL. Here, we examined the ability of POD24 to predict subsequent OS in a large, international cohort of MZL as part of the NF10 prospective international registry headed by Fondazione Italiana Linfomi (FIL). POD24 was only calculated for MZL patients requiring immediate therapy and was defined as experiencing lymphoma progression within 24 months from diagnosis. Among the 1325 patients enrolled in the NF10 study, we identified 321 patients with MZL for whom immediate therapy was planned right after lymphoma diagnosis. Overall, POD24 was confirmed in 59 patients (18%). Three-year OS for patients with POD24 was 53% with a hazard ratio of 19.5 (95% confidence interval, 8.4-45) compared with patients without POD24 (3-year OS, 95%). Association of POD24 with OS was confirmed for the subgroup of splenic and extranodal MZLs. Assessment of POD24 stratifies subsequent outcome inMZL and identifies a high-risk population

Influence of the polymorphisms CYP1A1 A4889G, CYP1A1 T6235C, NQO1 C609T and GSTP1 Ile105Val and homozygous deletions of GSTM1 and GSTT1 on risk and prognosis in patients with diffuse large B-cell lymphoma

Orientadores: Carmen Silvia Passos Lima, Carmino Antonio de SouzaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Polimorfismos de nucleotídeo único (SNPs) em genes que codificam proteínas de detoxificação de xenobióticos foram investigados na suscetibilidade ao linfoma não-Hodgkin difuso de grandes células B (LDGCB) e no prognóstico de portadores do tumor em poucos e inconclusivos estudos. O objetivo deste estudo foi o de avaliar a influência dos SNPs CYP1A1 T6235C e A4889G, NQO1 C609T, GSTP1 Ile105Val, GSTM1 e GSTT1 no risco do LDGCB, características clínico patológicas e sobrevidas dos pacientes com o tumor. Cento e quarenta e quatro pacientes com LDGCB diagnosticados entre julho de 2010 a junho de 2015 e 256 indivíduos saudáveis foram inseridos no estudo. Os pacientes foram tratados com RCHOP. Os genótipos foram identificados por meio da reação em cadeia da polimerase e digestão enzimática em amostras de sangue periférico. Indivíduos com o genótipo CYP1A1 4889AA e o genótipo CYP1A1 4889AA combinado ao GSTM1 presente estiveram sob riscos 1,73 vezes (IC95%: 1,03-2,90, P= 0,03) e 2,71 vezes (IC95%: 1,22-5,98, P= 0,01) maiores de apresentar LDGCB do que os demais. O genótipo NQO1 CT+TT foi mais comum em pacientes com sintomas B (83% vs. 63%, P= 0,01) e ECOG? 2 (22% vs. 8%, P= 0,02) do que nos outros pacientes e tumores volumosos ocorreram em geral em pacientes com o genótipo NQO1 4889TT comparados aos demais (39% vs. 25%, P= 0,10). Os pacientes com o genótipo GSTP1Ile/Ile tiveram chances 2,94 (IC95%: 1,28-6,76 P= 0,01), 2,18 (IC95%: 1,05-4,56 P= 0,03) e 2,80 (IC95%: 1,36-5,76 P=0,005) maiores de apresentar toxicidade de graus III-IV, resposta parcial ou progressão da doença e evoluir para o óbito, respectivamente. As taxas de sobrevida livre de doença (76% vs. 88%, P= 0,02), sobrevida livre de eventos (47% vs. 70%, P= 0,003) e sobrevida global (51% vs. 74%, P= 0,005) foram menores em pacientes com o genótipo GSTP1Ile/Ile do que nos demais pacientes em cinco anos de seguimento (Kaplan Meier) e estes resultados foram confirmados em análises uni e multivariada de Cox. Pacientes com o genótipo GSTP1Ile/Ile estiveram sob riscos cerca de 2 vezes (IC95%: 1,31-4,40 P= 0,004) maiores de apresentar recidiva do tumor, progressão do tumor ou evoluir para o óbito. O método bootstrap, baseado em 1.000 amostras, confirmou a associação do genótipo GSTP1Ile/Ile com a toxicidade, tipo de resposta ao RCHOP e a sobrevida dos pacientes. Nossos resultados indicam que alterações herdadas no metabolismo de xenobióticos, relacionadas aos SNPS CYP1A1 A4889G, NQO1 C609T, GSTM1 e GSTP1 Ile105Val, influenciam o risco, manifestações clínicas e o prognóstico do LDGCBAbstract: Single nucleotide polymorphisms (SNPs) in genes encoding proteins of xenobiotic detoxification were investigated in susceptibility and prognosis of diffuse non-Hodgkin B cell lymphoma (DBCL) in a few patients and inconclusive studies. The aim of this study was to evaluate the influence of CYP1A1 T6235C and A4889G, NQO1 C609T, GSTP1 Ile105Val, GSTM1 and GSTT1 on risk of DLBCL, clinic pathologic features and survival of these patients. One hundred forty-four patients with DLBCL diagnosed between July 2010 to June 2015 and 256 healthy subjects were enrolled in the study. Patients were treated with RCHOP. Genotypes were identified by polymerase chain reaction and enzymatic digestion in peripheral blood samples. Subjects with the CYP1A1 4889AA genotype and CYP1A1 4889AA genotype combined with GSTM1 present were under risk 1.73 times (95% CI: 1.03-2.90, P=0.03) and 2.71 times (95% CI: 1.22-5.98, P=0.01) higher than present DLBCL than others. The NQO1 CT + TT genotype was more common in patients with B symptoms (83% vs. 63%, P=0.01) and ECOG? 2 (22% vs. 8%, P=0.02) than in the other patients and bulky disease occurred in general in patients with NQO1 4889TT genotype compared to the others (39% vs. 25%, P=0.10). Patients with GSTP1Ile/Ile genotype had chances 2.94 (95% CI: 1.28-6.76, P=0.01), 2.18 (95% CI: 1.05-4.56, P=0.03) and 2.80 (95% CI: 1.36-5.76, P=0.005) higher to present toxicity of grade III-IV partial response or disease progression and evolve to death, respectively. Free survival rates of disease (76% vs. 88%, P=0.02), event-free survival (47% vs. 70%, P=0.003) and overall survival (51% vs. 74%, P=0.005) were lower in patients with GSTP1Ile/Ile genotype than in the other patients at five years of follow-up (Kaplan Meier) and these results were confirmed by Cox univariate and multivariate. Patients with GSTP1Ile/Ile genotype were under risk 2.3 times (95% CI: 1.31-4.40, P=0.004) higher to present tumor recurrence progression or progress to death. The bootstrap method, based on 1,000 samples, confirmed the association of GSTP1Ile/Ile genotype with toxicity, type of response to RCHOP and survival of patients. Our results indicate that changes inherited in xenobiotic metabolism, related to CYP1A1 A4889G, NQO1 C609T, GSTM1 and GSTP1 Ile105Val SNPs¿ influence the risk, clinical manifestations and prognosis of DLBCLDoutoradoClinica MedicaDoutora em Ciência

Correlação entre a quantidade de celulas CD34+ circulantes e a coleta por aferese de CPP em pacientes onco-hematologicos

Orientador: Irene Lorand-MetzeDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: As Células Progenitoras Periféricas Hemopoiética(CPPH) são hábeis para restaurar a hemopoiese após tratamento quimioterápico mieloablativo. O tratamento com megaquimioterapiaacompanhadopor resgate de CPPH é uma importante abordagem terapêutica utilizada hoje em pacientes com neoplasias hematológicas como Linfoma Não-Hodgkin (LNH),Doença de Hodgkin (LH) e Mieloma Múltiplo (MM). O regime quimioterápicomais efetivo e de intensidademais adequada ainda deve ser definido e pode ser claramente demonstrado que a Célula Progenitora Hemopoiética pode ser influenciada por tratamentos prévios. Vários outros parâmetros também podem influenciar na coleta de CPPH após a quimioterapia de mobilização. A proposta do nosso estudo foi estabelecerparâmetros que possam melhor predizer o dia para iniciar a coleta de CPPH com o objetivo de coletar mais células CD34+ com um menornúmero de procedimentos de leucoaféreses. Nós analisamos,retrospectivamente,pacientes com neoplasias hematológicas tratados em nosso Serviço,que foram submetidos à mobilizaçãopara obter CPPH a fim de realizar o transplante autólogo de medula óssea. Os pacientes foram mobilizados com Ciclofosfamida (4 ou 7g/m2)e G-CSF na dose de 300/lg, sub-cutâneo, diariamente, com o propósito de coletar 5 x 106 células CD34+/Kg. Nós investigamos a influência da idade, sexo, diagnóstico,número de linhas quimioterápicasprévias, hemograma do sangue periférico no dia da mobilização, dia quando os neutrófilos < Ix I09/L e o dia do nadir (incluindo o intervalo de dias destes dois dias - delta). Foi elaboradoum modelo matemático utilizando a correlação linear multivariada com o objetivo de predizer o melhor dia da coleta. Nós analisamos 134pacientes: 36 com DH, 65 LNH, 33 MM. A mediana de idade foi de 28 , 40 e 48 anos respectivamente. O teste de Pearson mostrou uma correlação para o dia dos leucócitos > 1 x 109/L com os valores de hemoglobina no dia O,dia dos neutrófiolos 1 x1O9/L.Nestes pacientes, a correlação encontrada entre o dia da coleta e hemoglobina,dia dos neutrófilos < 1 x 109/L e o dia do nadir. foi estatisticamente significativa e possibilitou desenvolver um modelo matemáticoseparando os pacientes conforme a doença de base: DH: dia da aférese = delta x 1.5 + 9.1 LNH: dia da aférese = delta x 0.66 + 10.8 MM: dia da aférese = delta x 1.6+ 8.8 De acordo com nosso estudo, cada doença apresenta sua dinâmica de mobilização, possivelmente relacionada com o número de linhas quimioterápicas prévias ou pelo status do microambiente medular. O parâmetro mais importante encontrado e comum a todos os pacientes foi a velocidade de queda dos neutrófilos após a quimioterapia de mobilizaçãoAbstract: Mobilized peripheral blood progenitor cells (PBPC) are able to engraft and restore hemopoiesis after myeloablative therapy. Intense chemotherapy with PBPC rescue is currently an important therapeutic approach in hematological malignancies such as non- Hodgkin's lymphoma(NHL),Hodgkin's disease (HD) and multiple myeloma (MM). The most effective regimen and the adequate intensity of mobilization chemotherapy still remains to be defined and it has been c1earlyshown that the progenitor cell yield can be influenced by intensity of previous treatments. Several other parameters may affect the harvesting of PBPC after mobilizationchemotherapy. The purpose of our study was to establish the parameters that best predict the day to start harvesting of PBPC in order to collect most CD34+ cells with few aphereses. We analysed retrospective data ofpatients with hematological malignancies treated in our Institution,who underwent mobilizationto obtain PBPC in order to perforrn autologous bone marrow transplantation. Patients were mobilized with Cyc1ophosphamide(4 or 7g1m2) and G-CSF 300Jlg,sc,dai1y,aiming to collect 5x1O6cells/Kg. We investigated the influence of age, sex, diagnosis, number of previous chemotherapy lines (nCHT), peripheral blood counts on day of mobilization, day of neutrophils < 1 xl09/L and day of nadir (inc1uding the interval between these two days) on harvesting. Multivariate linear correlation models were built in order to predict the day of best harvesting. We analysed 134 patients: 36HL, 65 NHL and 33 MM. Median age: 28,40 and 48 respectively. The Pearson's test showed a correlation for day of leucocytes > 1 xl 09/L with hemoglobin value of day O, day of neutrophils 1 xl 09/L. In these patients, a correlation was found between the day of harvesting and hemoglobin, day of neutrophils <lx1O9/L and day ofnadir. Separating the patients for disease: HL: day of apheresis =delta x 1.5 +9.1 NHL: day of apheresis = delta x 0.66 + 10.8 MM:day of apheresis=deltax 1.6+8.8. According to this study, each disease has its own pattem of mobilization dynamics, possibly related to the amount of previous chemotherapy or the status of bone marrow microenviroment. The most important parameter, cornrnonto alI patients, was the velocity of decline of the neutrophil count afier mobilization chemotherapyMestradoClinica MedicaMestre em Clinica Medic

Increased risk of Hodgkin lymphoma in males with inherited T lymphocyte receptor programed death-1 deficiency

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Polymorphisms in key regulator genes of the intrinsic apoptosis pathway in risk and clinical presentation of diffuse large B-cell lymphoma

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