RESUMO
Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting treatment with tyrosine kinase inhibitors strongly predicts clinical outcomes for patients with chronic myeloid leukemia. In this work, we asked whether the prognostic value of the 3-month transcript level could be improved by combining the 3- and 6-month results. We classified patients treated with imatinib and patients treated with dasatinib according to their transcript levels at 3 months and 6 months. The patients who met the 3-month landmark but failed the 6-month one had outcomes identical to those of patients who met both landmarks, whereas the patients who failed the first landmark but met the second one had prognoses similar to those who failed both landmarks. In summary, early intervention strategies can be based robustly just on the transcript level at 3 months. This trial was registered at www.clinicaltrials.gov as # NCT01460693.
Assuntos
Benzamidas/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genética , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Acebutolol/metabolismo , Antineoplásicos/uso terapêutico , Dasatinibe , Testes Genéticos/métodos , Humanos , Mesilato de Imatinib , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
We studied the relation between adherence to imatinib measured with microelectronic monitoring systems and the probabilities of losing a complete cytogenetic response (CCyR) and of imatinib failure in 87 CCyR chronic myeloid leukemia patients receiving long-term therapy. We included in our analysis the most relevant prognostic factors described to date. On multivariate analysis, the adherence rate and having failed to achieve a major molecular response were the only independent predictors for loss of CCyR and discontinuation of imatinib therapy. The 23 patients with an adherence rate less than or equal to 85% had a higher probability of losing their CCyR at 2 years (26.8% vs 1.5%, P = .0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, P = .006) than the 64 patients with an adherence rate more than 85%. In summary, we have shown that poor adherence is the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long-term therapy.
Assuntos
Aberrações Cromossômicas , Resistencia a Medicamentos Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Cooperação do Paciente , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Benzamidas , Aberrações Cromossômicas/efeitos dos fármacos , Aberrações Cromossômicas/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente/estatística & dados numéricos , Indução de Remissão , Fatores de Tempo , Falha de TratamentoRESUMO
We analyzed a cohort of 26 patients with chronic myeloid leukemia who had failed imatinib and a second tyrosine kinase inhibitor but were still in first chronic phase and identified prognostic factors for response and outcomes. The achievement of a prior cytogenetic response on imatinib or on second-line therapy were the only independent predictors for the achievement of complete cytogenetic responses on third-line therapy. Younger age and the achievement of a cytogenetic response on second line were the only independent predictors for overall survival (OS). At 3 months, the 9 patients who had achieved a cytogenetic response had better 30-month probabilities of complete cytogenetic responses and OS than the patients who had failed to do so. Factors measurable before starting treatment with third line therapy and cytogenetic responses at 3 months can accurately predict subsequent outcome and thus guide clinical decisions.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Salvação , Fatores Etários , Benzamidas , Estudos de Coortes , Dasatinibe , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Indução de Remissão , Tiazóis/administração & dosagem , Resultado do TratamentoRESUMO
Activation of the EVI-1 oncogene has been reported in acute myeloid leukemia, chronic myeloid leukemia (CML) in blast crisis, and less commonly, in chronic-phase CML patients. We screened an unselected cohort of 75 chronic-phase CML patients who had failed imatinib for expression of EVI-1 and sought a correlation with subsequent outcome on the second-generation tyrosine kinase inhibitors dasatinib (n = 61) or nilotinib (n = 14). The 8 patients (10.7%) who expressed EVI-1 transcripts detectable by real-time polymerase chain reaction had significantly lower event-free survival, progression-free survival, and overall survival than patients with undetectable transcript. The predictive value of EVI-1 expression was validated in an independent cohort. In a multivariate analysis, EVI-1 expression status and the best cytogenetic response obtained on imatinib were the only independent predictors for overall survival, progression-free survival, and event-free survival. Our data suggest that screening for EVI-1 expression at the time of imatinib failure may predict for response to second-line TKI therapy and consequently aid clinical management.
Assuntos
Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide de Fase Crônica/mortalidade , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proto-Oncogenes/genética , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Fatores de Transcrição/genética , Benzamidas , Crise Blástica , Proteínas de Ligação a DNA/metabolismo , Dasatinibe , Feminino , Humanos , Mesilato de Imatinib , Hibridização in Situ Fluorescente , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genética , Proteína do Locus do Complexo MDS1 e EVI1 , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Tirosina Quinases/antagonistas & inibidores , RNA Mensageiro/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Terapia de Salvação , Taxa de Sobrevida , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Second-generation tyrosine kinase inhibitors induce cytogenetic responses in approximately 50% of patients with chronic myeloid leukemia in chronic phase in whom imatinib treatment has failed. However, it has not yet been established which of the patients in whom imatinib treatment fails are likely to benefit from therapy with second-generation tyrosine kinase inhibitors. DESIGN AND METHODS: We analyzed a cohort of 80 patients with chronic myeloid leukemia who were resistant to imatinib and who were treated with dasatinib or nilotinib while still in first chronic phase. We devised a scoring system to predict the probability of these patients achieving complete cytogenetic response when treated with second-generation tyrosine kinase inhibitors. RESULTS: The system was based on three factors: cytogenetic response to imatinib, Sokal score and recurrent neutropenia during imatinib treatment. We validated the score in an independent group of 28 Scottish patients. We also studied the relationship between cytogenetic responses at 3, 6 and 12 months and subsequent outcome. We classified the 80 patients into three categories, those with good risk (n=24), intermediate risk (n=27) and poor risk (n=29) with 2.5-year cumulative incidences of complete cytogenetic response of 100%, 52.2% and 13.8%, respectively (P<0.0001). Moreover, patients who had less than 95% Philadelphia chromosome-positive metaphases at 3 months, those with 35% or less Philadelphia chromosome-positive metaphases at 6 months and patients in complete cytogenetic response at 12 months all had significantly better outcomes than patients with lesser degrees of cytogenetic response. CONCLUSIONS: Factors measurable before starting treatment can accurately predict response to second-generation tyrosine kinase inhibitors. Cytogenetic responses at 3, 6 and 12 months may influence the decision to continue treatment with second-generation tyrosine kinase inhibitors.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Benzamidas , Estudos de Coortes , Análise Citogenética , Dasatinibe , Resistência a Medicamentos , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Pessoa de Meia-Idade , Piperazinas/farmacologia , Prognóstico , Pirimidinas/farmacologiaAssuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Adulto , Idoso , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics. PATIENTS AND METHODS: We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere. RESULTS: Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively). CONCLUSION: A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.
Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genética , Piperazinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Benzamidas , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/biossíntese , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Transcrição Gênica , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: There is a considerable variability in the level of molecular responses achieved with imatinib therapy in patients with chronic myeloid leukemia (CML). These differences could result from variable therapy adherence. METHODS: Eighty-seven patients with chronic-phase CML treated with imatinib 400 mg/d for a median of 59.7 months (range, 25 to 104 months) who had achieved complete cytogenetic response had adherence monitored during a 3-month period by using a microelectronic monitoring device. Adherence was correlated with levels of molecular response. Other factors that could influence outcome were also analyzed. RESULTS: Median adherence rate was 98% (range, 24% to 104%). Twenty-three patients (26.4%) had adherence Assuntos
Antineoplásicos/uso terapêutico
, Análise Citogenética
, Regulação Leucêmica da Expressão Gênica
, Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
, Adesão à Medicação
, Piperazinas/uso terapêutico
, Inibidores de Proteínas Quinases/uso terapêutico
, Pirimidinas/uso terapêutico
, Subfamília B de Transportador de Cassetes de Ligação de ATP
, Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Antineoplásicos/farmacocinética
, Benzamidas
, Monitoramento de Medicamentos/instrumentação
, Feminino
, Proteínas de Fusão bcr-abl/genética
, Humanos
, Mesilato de Imatinib
, Estimativa de Kaplan-Meier
, Leucemia Mielogênica Crônica BCR-ABL Positiva/genética
, Modelos Logísticos
, Masculino
, Sistemas Microeletromecânicos/instrumentação
, Pessoa de Meia-Idade
, Mutação
, Fator 1 de Transcrição de Octâmero/genética
, Piperazinas/farmacocinética
, Polimorfismo Genético
, Modelos de Riscos Proporcionais
, Inibidores de Proteínas Quinases/farmacocinética
, Pirimidinas/farmacocinética
, RNA Mensageiro/metabolismo
, Medição de Risco
, Fatores de Risco
, Fatores de Tempo
, Resultado do Tratamento
, Adulto Jovem