Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Abstract

BACKGROUND: ABCG2 protein overexpression and FLT3 internal tandem duplication (ITD) correlate with higher relapse rate and shorter disease-free survival (DFS) in acute myeloid leukemia (AML), but no data are available on the possible effect of concomitant presence of these 2 factors. METHODS: The authors analyzed the outcome of 166 cases of adult AML patients who were homogeneously treated with a fludarabine-based induction therapy. RESULTS: ABCG2 overexpression and FLT3-ITD were detected in 83 (50%) and 47 (28%) patients, respectively. A significant correlation was found between ABCG2 positivity and FLT3 mutation, with 33 (40%) ITD in 83 ABCG2-positive patients compared with 14 (17%) ITD in 83 ABCG2-negative patients (P ¼ .002). Complete remission (CR) after induction therapy was achieved in 95 (57%) patients. Neither ABCG2 overexpression nor FLT3-ITD had any impact on achievement of CR. Relapse occurred in 42 of 95 (44%) patients at a median time of 28 months. Time to relapse was shortened in patients overexpressing ABCG2 (P ¼ .0004). DFS was not affected by FLT3-ITD alone, but FLT3 mutation significantly worsened long-term outcome of ABCG2-positive patients. DFS at 1 and 3 years in patients with overexpression of both ABCG2 and FLT3-ITD was only 36% and 28%, respectively; in ABCG2-positive/FLT3-negative patients, DFS at 1 and 3 years was 65% and 48%, respectively; and in ABCG2-negative cases (regardless of FLT3 status), DFS at 1 and 3 years was greater than 85% and 75%. CONCLUSIONS: Concomitant overexpression of ABCG2 and FLT3-ITD is relatively frequent and identifies a subgroup of AML patients with a significantly worse prognosis. The possible interactions between these 2 prognostic factors need to be defined. Cancer 2011;117:2156-62.

Drug resistance: Still a daunting challenge to the successful treatment of AML

“…Co-ordinate regulation of ABCG2 with ABCB1 (and a member of the ABCC family such as ABCC3) and possibly other transporters or resistance mechanisms, could explain why inhibition of a single transporter may not be an effective therapeutic strategy (Marzac et al, 2011; van den Heuvel-Eibrink et al, 2005). Along this same line, a recent report suggested that ABCG2 can be overexpressed in leukemias with a FLT3 internal tandem duplication, with an association between ABCG2 overexpression and reduced disease-free and overall survival but not with response rate (Tiribelli et al, 2011). This finding suggests an association of ABCG2 with the intrinsic biology of the leukemia rather than with drug efflux mediating resistance per se.…”

Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance

“…Tiribelli et al [161] found a significant positive correlation between BCRP overexpression and fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) (p=0.002), and while CR attainment correlated with neither, DFS was shorter in patients with blast BCRP expression (p=0.046), and shortest in those with both BCRP expression and FLT3-ITD (p=0.023). FLT3 signaling inhibitors are in clinical trials in AML for patients with a FLT3-ITD.…”

Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

“…MDR1 expression was associated with lower CR rates but not decreased OS rates in a study of 405 patients with AML (Illmer et al, 2002); the homozygous wild-type genotype was associated with a decreased OS rate and an increased risk of relapse, which suggests that mechanisms in addition to P-gp expression are involved. An analysis of MDR1 expression and FLT3-ITD mutation status among 166 adult patients with AML demonstrated shorter times to relapse for MDR1-overexpressing patients and poor disease-free survival rates for patients with both MDR1 overexpression and FLT3-ITD ϩ status (Tiribelli et al, 2011). The parameter of P-gp expression also has been shown to be associated with responses and outcomes.…”