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High P-Glycoprotein Function but Not Multidrug Resistance Protein Function at Diagnosis Correlates with Minimal Residual Disease in Acute Myeloid Leukemia



High P-Glycoprotein Function but Not Multidrug Resistance Protein Function at Diagnosis Correlates with Minimal Residual Disease in Acute Myeloid Leukemia



Blood 100(11): Abstract No. 1244



Although chemotherapy induces morphologic complete remission in most acute myeloid leukemia (AML) patients, many will eventually relapse due to the persistence of minimal residual disease (MRD). Various studies suggests that the expression/function of ABC-transporters P-glycoprotein (Pgp) and Multidrug Resistance Protein (MRP) at diagnosis contribute to treatment failure. In a previous study (ASH 2001, 1300) we showed that the function of these transporters did not change after chemotherapy and therefore we hypothesized that functional Pgp and/or MRP might directly correlate with MRD. This was tested in the present study. Firstly, Pgp and MRP function at diagnosis were detected with Syto16/PSC833 and calcein-AM/probenecid, respectively as specific substrate/modulator combination. Pgp and MRP activity (shift gtoreq1.1) was detected in 76% (76/100) and 56% (40/72) of the patients, respectively. It was found that elderly patients (gtoreq60 y) showed significantly higher Pgp activities than younger patients (median ratio of 2.2 vs 1.3, respectively). Furthermore, elderly patients with a Pgp ratio gtoreq3.0 showed both shorter DFS and OS when compared with patients showing lower Pgp activity (median 4 vs 11 months, logrank: p=0.0137 and 8 vs 14 months, p=0.0252, respectively). In addition, for younger patients at a cut-off Pgp ratio of gtoreq1.5 a trend towards shorter OS (p=0.0752) was found. For MRP activity no significant correlations were found with outcome. Secondly, for MRD detection a flow cytometric method was used that at diagnosis defines leukemia-associated phenotypes, this method was applicable in up to 80% of AML patients (van der Pol et.al., Leukemia. 2001;15:1554). Thirty-five bone marrow (BM) samples obtained after the 1st (MRD1) and 37 after the 2nd (MRD2) course of chemotherapy were examined for the presence of MRD using LAP detection. At both time points, MRD levels correlated significantly with both DFS and OS (MRD1: p=0.0334 and 0.0262, respectively; MRD2: p=0.011 and 0.007, respectively). Thirdly, in the correlation of ABC-transporter activity at diagnosis and MRD levels after therapy it was found that patients with Pgp activity gtoreq1.1 showed higher MRD levels in MRD1 samples (p=0.193) and, statistically significant, in MRD2 samples (p=0.043). The other way around, MRD frequencies higher than 0.03-0.1% corresponded with higher initial Pgp activities in MRD1 samples (pltoreq0.091) and, statistically significant, in MRD2 samples (pltoreq0.026). No such correlations were found for MRP activity. Taken together, the results show that i) high MRD levels in BM after induction chemotherapy correlate with short DFS and OS and ii) high Pgp but not MRP activity at diagnosis correlates with higher MRD levels after chemotherapy. These findings strongly suggest that in AML high Pgp but not MRP activity contributes to high MRD frequencies which in turn determines treatment failure.

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