ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.
J Clin Oncol
; 23(18): 4100-9, 2005 Jun 20.
Article
em En
| MEDLINE
| ID: mdl-15867198
ABSTRACT
PURPOSE:
Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. PATIENTS ANDMETHODS:
Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months.RESULTS:
Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045).CONCLUSION:
Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.
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Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Pirimidinas
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Leucemia Mieloide de Fase Crônica
/
Genes abl
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Mutação Puntual
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Resistencia a Medicamentos Antineoplásicos
/
Análise Citogenética
/
Antineoplásicos
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
/
Risk_factors_studies
/
Systematic_reviews
Limite:
Adult
/
Aged
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Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article