Analysis of the Interaction of Induction Regimens with P-Glycoprotein Expression In Patients with Acute Myeloid Leukaemia: Results From the MRC AML15 Trial
Authors: Pallis Monica , White Paul , Hills Robert , Grundy Martin , Russell Nigel H. , Burnett Alan 
Published: October 2019

Abstract
Abstract 2724
P-glycoprotein (pgp), the product of the MDR1 (ABCB1) gene is a cellular drug efflux pump associated with primary disease resistance in several studies of adult AML. Previous attempts to improve the outcome of this group of patients using pgp reversal agents have not been successful. Retrospective analyses in non-randomised cohorts supported by in vitro studies have suggested that fludarabine/Ara-C-containing regimens may be more effective anti-leukaemic therapy than daunorubicin-containing regimens in pgp+ve AML, as fludarabine and AraC are not pgp substrates and idarubicin is only weakly effluxed compared to daunorubicin. We prospectively measured pgp protein and function by flow cytometry (MRK) in CD45-gated blasts from 461 trial patients randomised to remission induction therapy with two courses of FLAG-Ida or DA/ADE in the AML15 clinical trial. A further randomisation to Mylotarg was not included in this analysis: previous work showed no interaction for outcomes of the Mylotarg randomisation with pgp. Patients were primarily under 60, although 13% of the cohort studied for pgp was older. 34% of cases were positive for pgp protein and 38% for function (23% low and 15% high). Overall, pgp protein-positive cases had a higher incidence of resistant disease (14% v 5%), OR 2.67 (1.14-6.24 adjusted for age, WBC, sex, secondary disease, performance status and cytogenetics). There was a trend towards a lower risk of relapse at 5 years for pgp-negative cases (50% v 61%), adjusted HR 1.42 (0.98-2.07)(p=0.06) but this did not translate into a significant survival benefit (HR 1.13 (0.82-1.55) p=0.5).The impact of individual regimens on initial treatment outcomes is shown below.
Table 1. Death in complete remission by year CR/CRi Resistant disease MRK−ve MRK +ve MRK−ve MRK+ve DA/ADE 90% (142/148) 78% (62/80) 6% (9/158) 18% (14/80) FLAG/Ida 86% (38/44) 86% (74/86) 3% (3/86) 7% (3/44)
The adjusted p value for the interaction between pgp and CR rate was 0.06. For primary resistant disease the P value was 0.8, but with such a low incidence of primary resistant disease in the trial, this comparison was underpowered for statistical analysis.
The results for AML15 previously reported (Burnett et al ASH 2009) showed no significant differences in response rates between individual treatments, although FLAG-Ida resulted in a reduced relapse rate but with no benefit on overall survival. Looking at the interaction with pgp, the risk of relapse was reduced in both pgp –ve and +ve patients receiving FLAG-Ida, but there was no interaction between treatment received and overall expression. Data for pgp function followed similar trends. Our data suggest that FLAG-Ida may improve the remission rate for pgp+ve AML, but the malignant clone is reduced rather than eradicated such that the relapse rate remains high in pgp positive patients, irrespective of remission-induction therapy. However, outcome for pgp positive younger adult patients was considerably better than that reported in the literature, regardless of regimen.

Disclosure:
Pallis: Tragara Pharmaceuticals: Research Funding.