Clinical Relevance of Multidrug Resistance Proteins Expression in Patients with De Novo Acute Myeloid Leukaemia.

Background. Early occurrence of the multidrug resistance (MDR) in de novo acute myeloid leukaemia (AML) may contribute to the treatment failure.The aim of this study was to investigate prospectively the clinical significance of the MDR proteins overexpression and their functional augmenting, in the context of other AML prognostic factors, such as age, immunophenotype and cytogenetic profile. We examined expression of MDR proteins: MDR1, MRP1, MDR3, BCRP, LRP and GSTπ and performed drug resistance functional assay in peripheral blood blasts of 25 patients with de novo AML at diagnosis and after the first chemotherapy cycle consisting of a 3 + 7 combination of DNR/Ara-C. MDR proteins presence and their functional activity (measured by fluorescent Rh123 dye efflux) were estimated by flow cytometry.

Results: Thirteen out of the 25 AML patients (52%) attained a CR with induction treatment, one had PR and eleven did not achieve remission. Out of 10 patients without CR, 2 died in aplasia and 9 were classified as an early death due to disease progression. All patients who achieved remission were younger than 55 years. Among 11 patients without remission, 9 expressed CD34; 6 of them had intermediate and 5 unfovorable cytogenetic profiles. In 10 out of 25 patients (40%) overexpression od MDR1 was shown at diagnosis, and was irreversible in 9 of them, those with poor clinical outcome (6 did not achieve CR, 1 had PR and one who obtained CR relapsed), whereas one patient who reversed achieved CR. The functional MDR assay showed the increased Rh123 efflux, both at diagnosis and after the first chemotherapy cycle in 12 patients (48%) and it influenced patients’ outcome in similar manner as MDR1 expression. At diagnosis other MDR proteins were also elevated in some AML patients:GSTπin 19 (76%), LRP in 9 (36%), MRP in 4 (16%) and MDR3 in 2 (8%). Seven AML patients (20%), both at diagnosis and after the first chemotherapy cycle co-expressed MDR1 with other multidrug resistance proteins and had enhanced Rh123 efflux. This co-expression resultes in 6 of them in chemotherapy resistance; the remaining one who achieved remission was young and had favorable cytogenetic profile. The results obtained demonstrate that the advanced age, unfavorable cytogenetic profile, overexpression of MDR1 at diagnosis and co-expression of other MDR proteins together with their functional activity contribute to the treatment failure in de novo AML.