High BCR-ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib.
Clin Cancer Res
; 23(23): 7189-7198, 2017 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-28928163
ABSTRACT
Purpose:
The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses.ExperimentalDesign:
We correlated BCR-ABL/GUSIS and BCR-ABL/ABL transcripts at diagnosis with the outcome-defined by the 2013 European LeukemiaNet recommendations-of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined BCR-ABL/GUSIS and BCR-ABL/ABL levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS).Results:
With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as "warnings," 22.4% failed imatinib, and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), seven (2.5%) attributable to disease progression. We found that higher BCR-ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (P < 0.001), FFS (P < 0.001), and EFS (P < 0.001). Elevated BCR-ABL/GUSIS levels were also associated with lower rates of TFS (P = 0.029) but not with OS (P = 0.132). Similarly, high BCR-ABL/ABL levels at diagnosis were associated with inferior rates of OR (P = 0.03), FFS (P = 0.001), and EFS (P = 0.005), but not with TFS (P = 0.167) or OS (P = 0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates.Conclusions:
Our data suggest that high BCR-ABL transcripts at diagnosis measured using GUS as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. Clin Cancer Res; 23(23); 7189-98. ©2017 AACR.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide de Fase Crônica
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Regulação Leucêmica da Expressão Gênica
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Proteínas de Fusão bcr-abl
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Mesilato de Imatinib
Tipo de estudo:
Clinical_trials
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Diagnostic_studies
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Guideline
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adolescent
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Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Clin Cancer Res
Ano de publicação:
2017
Tipo de documento:
Article