The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has gen- erated a need for early molecular parameters associated with inadequate responses to Imatinib (IM). We correlated quantitative determination of BCR-ABL transcripts at diagnosis with the outcome of 230 newly diag- nosed CML patients receiving IM 400 mg/die. BCR-ABL transcripts were measured from peripheral blood samples drawn at diagnosis using Real- Time Quantitative PCR (RQ-PCR). All molecular determinations were performed twice (in triplicates) on the same sample using either ABL or glucuronidase-beta (GUS) as reference genes. BCR-ABL values were then reported on the international scale (IS). High BCR-ABL/ABLIS levels at diagnosis were associated with inferior IM efficacy (p=0.007). Correla- tions between high BCR-ABL transcripts at diagnosis and unsatisfacto- ry IM responses were strengthened by the use of GUS. Indeed, high BCR-ABL/GUSIS at diagnosis was associated with lower rates of complete cytogenetic response (CCyR) after 12 months of treatment (p<0.0001), and with inferior probabilities of failure-free survival (p<0.0001), event-free survival (p<0.0001) and optimal response as defined by the 2009 European Leukemia Net recommendations (p<0.0001). Elevated BCR-ABL/GUSIS levels were also associated with suboptimal responses and IM failure (p<0.0001) and with inferior rates of disease transformation to the accelerated phase or blast crisis (p=0.012). Using receiver operating characteristic curves and the achieve- ment of an optimal response as a specific endpoint, we found that 15.96% BCR-ABL/GUSIS at diagnosis defined a threshold distinguish- ing low risk from high risk patients. High BCR-ABL transcripts at diag- nosis measured by RQ-PCR employing GUS as a reference gene allow the identification of CML patients unlikely to benefit from IM that should receive alternative forms of treatment.

HIGH BCR-ABL LEVELS AT DIAGNOSIS ARE ASSOCIATED WITH UNFAVORABLE RESPONS- ES TO IMATINIB

VIGNERI, PAOLO;Massimino M;MANZELLA, LIVIA;DI RAIMONDO, FRANCESCO
2013

Abstract

The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has gen- erated a need for early molecular parameters associated with inadequate responses to Imatinib (IM). We correlated quantitative determination of BCR-ABL transcripts at diagnosis with the outcome of 230 newly diag- nosed CML patients receiving IM 400 mg/die. BCR-ABL transcripts were measured from peripheral blood samples drawn at diagnosis using Real- Time Quantitative PCR (RQ-PCR). All molecular determinations were performed twice (in triplicates) on the same sample using either ABL or glucuronidase-beta (GUS) as reference genes. BCR-ABL values were then reported on the international scale (IS). High BCR-ABL/ABLIS levels at diagnosis were associated with inferior IM efficacy (p=0.007). Correla- tions between high BCR-ABL transcripts at diagnosis and unsatisfacto- ry IM responses were strengthened by the use of GUS. Indeed, high BCR-ABL/GUSIS at diagnosis was associated with lower rates of complete cytogenetic response (CCyR) after 12 months of treatment (p<0.0001), and with inferior probabilities of failure-free survival (p<0.0001), event-free survival (p<0.0001) and optimal response as defined by the 2009 European Leukemia Net recommendations (p<0.0001). Elevated BCR-ABL/GUSIS levels were also associated with suboptimal responses and IM failure (p<0.0001) and with inferior rates of disease transformation to the accelerated phase or blast crisis (p=0.012). Using receiver operating characteristic curves and the achieve- ment of an optimal response as a specific endpoint, we found that 15.96% BCR-ABL/GUSIS at diagnosis defined a threshold distinguish- ing low risk from high risk patients. High BCR-ABL transcripts at diag- nosis measured by RQ-PCR employing GUS as a reference gene allow the identification of CML patients unlikely to benefit from IM that should receive alternative forms of treatment.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/100107
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