ABC Proteins Activity Remains An Independent Prognostic Factor In 206 AML When Compared to Other Molecular Markers, FLT3, NPM1, CEBPα, and BAALC

Many clinical and biological features are commonly used in order to predict the probability of response to standard treatment in adult acute myeloid leukaemia (AML). Although cytogenetic analysis provides the major information for prognosis, many molecular alterations like FLT3/ITD, mutations of NPM1, mutations of CEBPα, or BAALC over expression have been described these last years, in order to guide therapeutic choices, especially in patients with normal karyotype. In the other hand, prognostic implications of ABC proteins' expression and functionality, like ABCB1 (Pgp) and others, have been known for years but relationships between ABC proteins and those molecular markers haven't been fully studied.

In this retrospective study, we explore the relationships between ABC proteins and these molecular markers, and evaluate whether ABC proteins' activity is an independent prognosis factor in 206 AML, homogenously treated in EORTC protocols. ABC proteins' activity has been assessed with JC1 functional test performed at the time of diagnosis, and all patients were screened from frozen bone marrow or peripheral blood samples for FLT3/ITD, NPM1 mutations, CEBPα mutations, and expression of BAALC. 206 patients aged from 16 to 81 years and treated either in EORTC AML 10, AML 12 or AML 13 from 1996 to 2008 have been included, with a median follow up time for alive patients of five years.

In the whole population, 42 patients (20%) showed a high ABC functional assay (JC1+). High ABC activity was associated with NPM1 wild type (p=0.03) and higher BAALC expression (p=0.007). FLT3-ITD was detected in only 2 patients with high ABC functional assay. There was no relationship between high ABC functionality and CEBPα mutational status.

In multivariate analysis including age, leukocyte count, cytogenetic, existence of a pre leukemic phase, NPM1, FLT3/ITD, CEBPα and BAALC status and JC1 assay, high ABC proteins' activity was an independent prognosis factor for OS in the whole population (p=0.03). Others independent prognosis factors for OS were age (p=0.0004), cytogenetic (p=0,045), FLT3/ITD (p=0.0096), and NPM1 mutation (p= 0.07). When interesting to normal cytogenetic population (112 patients), high ABC proteins' activity was an independent prognosis factor for DFS (p=0.0107) and OS (p=0.0038). Age (p=0.0012), and FLT3/ITD (p=0.0173) were the only other prognosis factors for OS. In patients with normal cytogenetic, and both NPM1 WT and no FLT3/ITD, only age (p=0.0008) and high ABC proteins' activity (p=0.004) were independent prognosis factors for OS.

ABC proteins' activity remains an independent prognosis factor in adult AML, when compared to these molecular factors. Because of its relatively high frequency (around 20 % of patients), and the easiness to perform this test, we think JC1 probe should be used in every AML patients in order to refine the treatment strategy at the time of diagnosis.

No relevant conflicts of interest to declare.