Analysis of the interaction of induction regimens with p-glycoprotein expression in patients with acute myeloid leukaemia: results from the MRC AML15 trial

Abstract

Retrospective analyses in non-randomised cohorts suggest that regimens containing fludarabine/Ara C and/or idarubicin/ara C may be more effective than daunorubicin/AraC (DA)-containing regimens in cases of acute myeloid leukaemia (AML) overexpressing p-glycoprotein (Pgp). We prospectively measured Pgp protein and function by flow cytometry in CD45-gated blasts from 434 AML15 trial patients randomised to remission induction therapy with two courses of FLAG-Ida or DA±etoposide (DA/ADE). In all, 34% were positive for Pgp protein and 38% for function. Pgp protein-positive cases had a higher incidence of resistant disease (14% vs 5%), adjusted odds ratio 2.67 (1.14–6.24). There was a trend towards a higher cumulative incidence of relapse at 5 years for Pgp-positive cases (46% vs 55%), adjusted hazard ratio 1.42 (0.98–2.07) (P=0.06). For patients treated with FLAG-Ida, the complete remission (CR) rate was 86% for both Pgp-positive and Pgp-negative patients. In patients treated with DA/ADE, 78% of Pgp-positive and 90% of Pgp-negative cases achieved CR (P=0.06). In analyses of overall survival, there was no interaction between treatment received and Pgp expression. Data for Pgp function followed similar trends. Our data suggest that FLAG-Ida may improve the remission rate for Pgp-positive AML, but the malignant clone is reduced rather than eradicated such that the relapse rate remains high in Pgp-positive patients.

Erlotinib antagonizes ABC transporters in acute myeloid leukemia

“…3,4 In line with this notion, increased expression and functionality of ABC transporters on the surface of AML cells have been correlated with poor prognosis due to chemoresistance. 5,6 Notably, ABC transporters are frequently overexpressed in AML cases that exhibit additional risk factors, such as an unfavorable karyotype erlotinib was originally developed as an epidermal growth factor receptor (eGFR)-specific inhibitor for the treatment of solid malignancies, yet also exerts significant eGFR-independent antileukemic effects in vitro and in vivo. The molecular mechanisms underlying the clinical antileukemic activity of erlotinib as a standalone agent have not yet been precisely elucidated.…”

Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy

“…There is some controversy regarding the role of MDR1 in AML chemoresistance. Although various studies have failed to detect any association between MDR1 expression and the response of AML patients to treatment with induction therapy [ 17 , 18 ], other reports have indicated that high MDR1 expression can predict the lack of response in these patients [ 19 , 32 , 33 ]. Our results support this concept.…”

“…However, the ability of ABC pumps to transport idarubicin has not been clearly elucidated. Several studies have found an association between MDR1 overexpression and poor outcome after idarubicin treatment [ 16 ], while others describe no such relationship [ 17 , 18 ]. Our results in cells expressing MDR1 suggested that this pump can export doxorubicin, but not idarubicin, supporting the hypothesis that MDR1 upregulation in blasts from NR patients is involved in the mechanisms of chemoresistance developed by AML cells to overcome response to treatment.…”

“…On the other hand, the contribution of ABC proteins in idarubicin efflux is unclear. Several studies have reported an association between multidrug resistance protein 1 (MDR1) overexpression and the poor outcome of patients treated with idarubicin [ 15 , 16 ], while others described no such association [ 17 , 18 ]. High expression of MRP1 and MRP2, along with breast cancer resistance protein (BCRP or ABCG2), have been proposed as independent predictors of treatment outcome in AML, and the presence of polymorphisms in these genes has been associated with anthracycline response and cardiotoxicity [ 19 , 20 , 21 , 22 , 23 ].…”

Role of drug transport and metabolism in the chemoresistance of acute myeloid leukemia

“…In recent years, high MDR1 expression has been considered as one of the most unfavorable prognostic factors for the responses of adult AML patients to induction regimens based on anthracyclines such as daunorubicin or idarubicin,74,75 but not mitoxantrone 76. Nevertheless, induction regimens containing idarubicin afford better CR rates than daunorubicin in AML patients expressing high MDR1 levels 77,78. By contrast, studies that have investigated the relationship between MDR1 over-expression and adverse treatment outcome have suggested that this connection is uncertain, at least in infant patients with AML 79.…”