Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and P-glycoprotein expression simultaneously determined by flow cytometry

Summary. We analysed the expression of three drug transporter proteins [p-glycoprotein (PGP), lung resistance-related protein (LRP) and multidrug resistanceassociated protein (MRP1)] involved in anthracycline resistance that are frequently overexpressed in poor-risk adult acute non-lymphocytic leukaemia (ANLL), in 23 acute promyelocytic leukaemia (APL) patients at onset managed at a single institution. Cellular daunorubicin accumulation was also evaluated. At onset, no case had PGP or MRP1 expression that exceeded that of nonmultidrug-resistant (MDR) cell lines. Only one case showed LRP overexpression. No peculiar MDR features distinguished the seven patients who relapsed from those who maintained complete remission. In the onset vs. first relapse, only one patient showed an increased (threefold) PGP expression at relapse. At second relapse, three out of four patients showed a PGP expression two-to threefold higher than baseline values. These results are consistent with the view that low PGP, LRP and MRP1 expression and the absence of defects in intracellular drug accumulation may account for the peculiarly high sensitivity of APLs to anthracycline. It does not support the screening of MDR markers in APL patients at onset as predicting factors of early relapse. The results suggest that no significant changes in PGP, LRP or MRP1 expression are likely to occur at first relapse. In contrast, PGP expression is likely to increase later in the patient history as a result of additional chemotherapy courses.

Section: Discussionsupporting

confidence: 92%

P‐glycoprotein (PGP), lung resistance‐related protein (LRP) and multidrug resistance‐associated protein (MRP) expression in acute promyelocytic leukaemia

Michieli

Damiani²,

Ermacora³

et al. 2000

“…In untreated de novo AML patients MDR 1 is expressed in 19-75% of the patients (Campos et al, 1992;Leith et al, 1995;Boekhorst et al, 1995Boekhorst et al, , 1993Holmes et al, 1994;Guerci et al, 1995). In these patients, MDR 1 is frequently associated with an immature phenotype (CD34) and autonomous AML growth in vitro (Boekhorst et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia

Heuvel

Hol²,

Broekhorst

et al. 1997

Summary. The Multidrug Resistance gene (MDR 1) is frequently expressed in acute myeloid leukaemia (AML).MDR 1 is associated with resistance to chemotherapy in vitro and with a poor response rate in AML. We have investigated the prognostic value of MDR 1 expression in relation to other patient characteristics with respect to response and survival.One hundred and thirty patients aged 0-88 years were treated for de novo AML with standard induction and consolidation chemotherapy. MDR 1 expression was determined by immunocytochemistry. Univariate and multivariate analyses were conducted to identify prognostic factors for reaching complete remission (CR) and for overall survival from diagnosis, in order to compare MDR 1 with known prognostic factors. Univariate analysis showed that higher MDR 1 expression was an adverse prognostic factor for CR (P < 0 . 001), as was higher age (P < 0 . 001) and unfavourable karyotype (P < 0 . 01). These factors were also negative prognostic factors for overall survival (P < 0 . 001, P < 0 . 05 and P < 0 . 005, respectively). In the multivariate analysis MDR 1 (P < 0 . 001), higher age (P < 0 . 001) and karyotype (P < 0 . 01) were independent adverse prognostic factors for CR as well as for overall survival (P < 0 . 001, P < 0 . 005, P < 0 . 001, respectively). Our data indicate that MDR 1 expression is a disease-related unfavourable prognostic factor which has a significant impact on complete remission and overall survival in AML. Analysis of MDR 1 may be used to determine prognosis in individual patients.

“…Paradoxically, we did not ®nd an association between IDA and treatment outcome, although there was a trend for earlier relapse and shorter survival in patients with low IDA, but this could be caused by the relatively small number of patients in our study. Other studies have also not found a correlation between IDA and outcome (Campos et al, 1992;Kessel et al, 1984;Kokenberg et al, 1988;Pallis et al, 1999), although Guerci et al (1995) did show a positive association. In this study, both LRP and Pgp function, but not MRP, were predictive of response to chemotherapy and overall survival.…”

Section: Discussionmentioning

confidence: 87%

P‐glycoprotein and multidrug resistance‐associated protein, but not lung resistance protein, lower the intracellular daunorubicin accumulation in acute myeloid leukaemic cells

Borg¹,

Burgess²,

Green

et al. 2000

Summary. The in vitro intracellular daunorubicin accumulation (IDA) of blast cells from 69 patients with newly diagnosed acute myeloid leukaemia (AML) was correlated with the expression and functional activity of the multidrug resistance (MDR) proteins, P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP) and lung-resistance protein (LRP). An inverse and signi®cant association was found between IDA and Pgp-related ef¯ux activity (r À0´31, P 0´01) and also MRP (r À0´25, P 0´04) but not with LRP (r À0´13, P 0´28). Coexpression of the MDR proteins had an additive effect in further lowering of IDA levels, suggesting that the clinical MDR phenotype is dependent on the sum of multiple MDR factors available to the leukaemic cell. Thus, the median IDA of leukaemic cells without any MDR proteins was signi®cantly higher than that of blasts carrying two MDR proteins (0´466 vs. 0´296, P 0´046). Seven patients with no expression of Pgp, MRP and LRP still had low IDA levels, suggesting the presence of ef¯ux MDR mechanisms other than those studied. The relation of IDA to clinical parameters known to be associated with poor prognosis, such as age, secondary AML, karyotype, peripheral blood blast and CD34 counts, was also studied, but no signi®cance was found on multifactorial analysis. There was a non-signi®cant trend for earlier relapse in patients with low IDA levels (leukaemia-free survival of 16´3 months compared with 21´1 months in patients with high IDA levels). Our data suggest that, while the IDA assay is a quick and relatively easy test for the combined ef¯ux MDR phenotype, it is unable to detect other MDR mechanisms, such as LRP, which may be important to the clinical outcome of patients with AML.