Adult acute myeloid leukemia (AML) with intermediate cytogenetic remains a very heterogeneous group of patients with highly variable individual prognosis. Emerging data suggest that some molecular markers could help to refine cytogenetic stratification. Here we focused on ABCB1 (MDR1/Pgp) ATP-binding cassette transporter activity and fms-like tyrosine kinase mutations (Flt3/ITD) because their individual prognosis value is well demonstrated and because they may lead to targeted therapy. Therefore we assessed Pgp activity using JC-1 probe and Flt3 exon 14 mutational status by standard PCR and realised a multivariate analysis in 171 adult AML patients treated in the EORTC protocols. Flt3/ITD (ITD+) and high Pgp activity (Pgp+) were found in 26/171 (15%) and 55/171 (32%) of the patients, respectively. The repartition was remarkable in that, as defined with our criteria, both were negative in 94/171 (55%, Pgp-ITD- group) or mutually exclusive in 73/171 (43%, Pgp-ITD+ and Pgp+ITD- groups) and only 4/171 (2%, Pgp+ITD+ group) were positive for both. In univariate analysis complete remission (CR) rates for ITD+ were 38% vs 61% for ITD- patients (p=0.034) and 47% vs 62% (p=0.06) for Pgp+ vs Pgp- patients. Individually, both parameters were strong predicators for overall survival (OS) (p=0,02) but not for disease free survival. In multivariate analysis Pgp+ITD+ (p<0.0001) and age (p=0.0022) were independent prognostic factors for CR achievement. For OS, CR achievement (p<0.0001), WHO performance status (p=0.0007) and Pgp+ITD+ (p=0.0014) were also independent prognostic factors. In 98 patients with intermediate cytogenetic CR rates for ITD+ were 40% vs 62% for ITD- patients (p=0.099) and 41% vs 67% (p=0.014) for Pgp+ vs Pgp- patients. In the Pgp-ITD- group (47/98 patients), CR rate was 70% vs 44% for others (p= 0.012). The 4 years OS achieved 48% vs 16% (p<0.0001) and DFS was 56% versus 27% (p=0.024). Furthermore, OS curves of the intermediate cytogenetic-Pgp-ITD- group were not significantly different from the favorable cytogenetic group. In conclusion Flt3-ITD and P-gp activity are independent and additive prognostic factors, which provide a powerful risk classification that can be used to stratify the treatment of intermediate cytogenetic AML patients.

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Topics:
flt3 gene, ms-like tyrosine kinase 3, p-glycoprotein, impedance threshold device, prognostic factors, biological markers, complete remission, leukemia, myelocytic, acute, membrane transport proteins, molecular targeted therapy

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2005, The American Society of Hematology
2005
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