Multidrug Resistance (mdr1) in Adult Acute Leukemia at Diagnosis: Correlation with Response to Induction Chemotherapy

Abstract

<i>Background:</i> Multidrug resistance is caused by overexpression of P-glycoprotein (P-gp, encoded by the mdrl gene), a transmembrane energy-dependent efflux pump which acts by expelling a wide variety of cytostatic drugs from the cytosol, thus decreasing intracellular drug accumulation. The multidrug-resistant phenotype has been identified as a major cause of treatment failure in many malignancies. In acute leukemia, overexpression of P-gp has been observed at diagnosis as well as in patients with resistant disease. The aim of the present study was to correlate response to induction therapy with mdrl gene expression in newly diagnosed acute leukemia. <i>Material and Methods:</i> The mdrl gene product P-gp expression was studied in 51 adult patients with newly diagnosed leukemia (9 acute lymphoblastic leukemias, 42 acute nonlymphoblastic leukemias) by means of immunocytochemistry and the alkaline phosphatase/anti-alkaline phosphatase method, using the two monoclonal antibodies C219 and MRK16. In all patients induction therapy was performed according to currently ongoing German multicenter trials. <i>Results:</i> At diagnosis, the mdr phenotype was observed in 47% of the patients. Following induction therapy, 56% of the P-gp-positive patients were induced into remission, compared to 78% of the P-gp-negative patients. The surface marker CD34, known to be associated with a poor prognosis in acute leukemia, was expressed in 58% of the samples. In cases where both markers were positive, the complete remission rate was only 50% as compared to 82% when both markers were negative. 8 of 11 P-gp-positive patients refractory to initial chemotherapy expressed both markers, thus indicating the existence of a possible subgroup with a very poor prognosis. <i>Conclusions:</i> Our data are concurrent with other reports and support increasing evidence that mdrl gene expression contributes to chemoresistance in newly diagnosed acute leukemia as an independent factor.