RESUMEN
BACKGROUND AND OBJECTIVES: Imatinib induces complete cytogenetic responses (CCR) in the majority of patients with chronic myeloid leukemia (CML) in chronic phase (CP). However, a subgroup of patients is refractory at the cytogenetic level. Clinically, it would be advantageous to identify such patients a priori, since they may benefit from more aggressive therapy. DESIGN AND METHODS: To elucidate mechanisms underlying cytogenetic refractoriness, we used Affymetrix oligonucleotide arrays to determine the transcriptional signature associated with cytogenetic refractoriness in unselected white blood or bone marrow cells from 29 patients with CML in first CP prior to treatment with imatinib. Patients with CCR within 9 months were defined as responders (n = 16) and patients lacking a major cytogenetic response (> 35% Philadelphia-positive metaphases) after 1 year were defined as non-responders (n = 13). RESULTS: Differences in gene expression between responders and non-responders were subtle. Stringent statistical analysis with multiple comparison adjustments revealed very few differentially expressed genes. Differentially expressed genes could not be confirmed in an independent test set. INTERPRETATION AND CONCLUSIONS: We conclude that transcriptional profiling of unselected white cells is of limited value for identifying genes consistently associated with cytogenetic refractoriness to imatinib.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Benzamidas , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucocitos/efectos de los fármacos , Leucocitos/fisiología , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , ARN Neoplásico/sangre , ARN Neoplásico/genética , ARN Neoplásico/aislamiento & purificación , ARN Ribosómico/sangre , ARN Ribosómico/genética , ARN Ribosómico/aislamiento & purificaciónRESUMEN
Since its introduction 5 years ago, imatinib mesylate has shown remarkable efficacy in treating patients with chronic myeloid leukaemia. Here we shall review the clinical results seen with imatinib at all stages of the disease, current views on the best way to monitor patients' responses and potential ways of predicting response to treatment. We shall also briefly cover the reasons why quiescent stem cells pose a theoretical threat to successful treatment.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Benzamidas , Supervivencia sin Enfermedad , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Neoplasia Residual/diagnóstico , Células Madre Neoplásicas/efectos de los fármacos , Pronóstico , Resultado del TratamientoRESUMEN
This article briefly recaps the key clinical trials that involve imatinib and focuses on the ongoing results and implications of these studies for future research in imatinib-based therapy in chronic myeloid leukemia (CML). Imatinib by no means has replaced allografting in the treatment of CML, although clearly, there has been a radical shift in thinking in considering which patients should undergo transplant. The route to cure with minimal toxicity may involve creative use of drug and transplant technologies.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Benzamidas , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Técnicas de Diagnóstico Molecular , Piperazinas/administración & dosificación , Pronóstico , Pirimidinas/administración & dosificación , Inducción de Remisión , Resultado del TratamientoRESUMEN
Mutations in the kinase domain (KD) of BCR-ABL are the leading cause of acquired imatinib resistance. In some cases, identical mutations were detected at relapse and in pretherapeutic specimens, consistent with selection of resistant clones in the presence of drug. However, the incidence of KD mutations in imatinibnaive patients, irrespective of response to therapy, is unknown. We studied mutation frequency in 66 patients with chronic myelogenous leukemia (CML), using cDNA sequencing and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) assays for 8 common mutations. Thirteen patients were positive by ASO-PCR only, 1 by ASO-PCR and sequencing, and 1 by sequencing only (overall frequency, 22.7%). T315I was most frequent (12% of patients). Eleven of the 14 patients with positive ASO-PCR had follow-up samples available for sequencing. Wild-type sequence was detected in 6 of 11, 2 different mutations in 1 of 11, and identical mutations in 4 of 11 patients, 2 of whom had achieved major cytogenetic response. In multivariate analysis mutation detection was associated with clonal cytogenetic evolution, exposure to 6-Thioguanine, and a low platelet count, but not with response to imatinib, event-free survival, and overall survival. KD mutants present at low levels do not invariably lead to relapse, and additional factors are required to induce a fully drug-resistant phenotype.