The prognostic impact of BCRP mRNA and FLT3-ITD in adult AML patients – a Polish study

High expression of the Breast Cancer Resistance Protein (BRCP) Messenger RNA (mRNA) and Fms-like Tyrosine Kinase 3 – Internal Tandem Duplication (FLT3-ITD) are poor risk factors for patients with intermediate and normal karyotype Acute Myeloid Leukemia (AML) that’s according to a study published ahead of print in the European Journal of Hematology.

Expression of the Multidrug Resistance (MDR) proteins; P-glycoprotein (encoded by the MDR1 gene), Multidrug Resistance-Associated Protein-1 (MRP1 [encoded by the MRP-1 gene]) and BRCP have been shown to be associated with clinical resistance to chemotherapy.

Barbara Nasilowska –Adamska from the Institute of Hematology and Transfusion Medicine, Warsaw, Poland and colleagues analyzed the significance of MDR-1, MRP-1, BCRP mRNA expression in correlation with FLT3-ITD in peripheral blood or bone marrow samples of 100 previously untreated AML adult patients (median age = 51.6 years) with intermediate and normal karyotype AML using Real-Time Quantitative (RQ)- Polymerase Chain Reaction (PCR). The endpoints of this study were Disease Free Survival (DFS) and Overall Survival (OS).

Patients were either FLT3-ITD positive (FLT3-ITD+, n = 36) or FLT3-ITD negative (FLT3-ITD-, n = 64). The median mRNA expression for MDR1, MRP-1 and BCRP were 0.0884 (range, 0.0302–3.7321), 0.7846 (range, 0.0199–4.9246) and 0.4061 (0.0043–29.8571) respectively. For statistical purposes, expressions of MDR1 mRNA ≥ 0.3415, MRP-1 mRNA ≥ 1.6818 and BCRP mRNA ≥ 1.1892 were defined as the highest gene expression.

The key results of the study were:

• Median DFS in patients with low (< 1.1892 [n = 77]) and high (≥ 1.1892 [n =23]) BRCP mRNA expression; 22.6 vs 7.6 months, P = 0.004
• Median DFS in patients that were FLT3-ITD+ and FLT3-ITD-; 7.6 vs 22.6 months, P = 0.005
• Median OS in patients with low and high BRCP mRNA expression; 13.7 vs 10.3 months, P = 0.01
• Median OS in patients that were FLT3-ITD+ and FLT3-ITD-; 35.5 vs 11.2 months, P = 0.01
• DFS was negatively influenced by BCRP mRNA expression ≥ 1.1892 (HR = 2.2, P = 0.011) and FLT3-ITD (HR = 1.8, P = 0.057)
• OS was negatively influenced independently by BCRP mRNA expression ≥ 1.1892 (HR = 2.0, P = 0.035) and FLT3-ITD (HR = 2.4, P = 0.006)
• MDR1 mRNA expression did not influence the survival outcomes of patients with intermediate and normal karyotype AML

In summary, high BCRP mRNA expression and FLT3-ITD are associated with poor survival outcomes in AML patients with intermediate or normal karyotype.

The authors concluded by suggesting that “combined analysis of MDR genes and leukemia-associated aberrations allows to identify a different risk groups of AML patients with normal and intermediate karyotype”. They further suggested that additional studies should be carried out “in order to determine its real clinical value and to establish the position of drug resistance genes/proteins in AML”.

Abstract

PURPOSE:

FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) is aberration associated with poor prognosis in AML. We have analyzed the expression of MDR-1, MRP-1 and BCRP mRNA in relation to FLT3-ITD in 100 AML adult patients with normal and intermediate karyotype.

METHODS:

The RQ-PCR method was performed to assess the expression of MDR-1, MRP-1 and BCRP mRNA and the results were presented as coefficients calculated using an intermediate method according to Pfaffl's rule.

RESULTS:

According to univariate analysis, the following pre-treatment variables negatively influenced DFS: WBC count ≥25 x109 /L (p=0,037), MRP-1 mRNA ≥ 1,6818 (p=0,028), BCRP mRNA ≥ 1,1892 (p=0,004), FLT3-ITD (p=0,005) and OS: WBC count ≥25 x109 /L (p=0,031), MRP-1 mRNA ≥ 1,6818 (p=0,01), BCRP mRNA ≥ 1,1892 (p=0,01), FLT3-ITD (p=0,001). When all prognostic variables were pooled into a multivariate model, we found that WBC count ≥25 x109 /L (p=0,026), BCRP mRNA ≥ 1,1892 (p=0,011) and FLT3-ITD (p=0,057) negatively influenced DFS. On the OS negatively, independently influenced BCRP mRNA ≥1,1892 (p=0,035) and FLT3-ITD (p=0,006).

CONCLUSIONS:

The high expression of BCRP mRNA calculated with Pfaffl´s rule and FLT3-ITD are independent poor risk factors in adult patients with AML and intermediate or normal karyotype.