Blast cells from patients treated for secondary AML (sAML) show less P-glycoprotein (Pgp)-mediated efflux of amonafide compared to daunorubicin: Implications for therapy.

13536 Background: Multidrug resistance (MDR) associated with Pgp overexpression in blasts is common in high-risk AML and is associated with poor outcomes. Erba et al (JCO 2007) reported a 42% complete remission (CR) rate in patients (pts) with sAML [prior MDS or treatment-related AML, (tAML)] (N = 88) treated with amonafide and std dose cytarabine. In laboratory studies of Pgp+ human leukemia cells, amonafide was neither a substrate nor an inhibitor of Pgp-mediated efflux, in contrast to daunorubicin (DNR). We sought to correlate the lack of Pgp effect with treatment outcome.,AML blasts from 15 pts from the Phase 2 trial cited above were retrospectively assessed for Pgp expression and function as well as amonafide and DNR uptake and retention in the presence and absence of the Pgp inhibitor cyclosporin A. Pts: median age, 62 yrs (range 51-87); 7 with prior MDS; 8 had tAML; 10 with unfavorable cytogenetics. Pgp-mediated efflux was assessed by comparing uptake of the Pgp substrate DiOC(3) in the presence and absence of the Pgp inhibitor PSC-833. Pgp- mediated transport (efflux) was calculated as differential uptake and retention of amonafide and DNR with (a) and without (b) PSC-833, normalized to apparent influx, using the formula [(a-b)/a]×100, reported as the mean±s.e.m.,The 15 sAML samples showed significantly less efflux of amonafide (5.2%±3.2) than of DNR (16%±2.1; p=0.0083). The unfavorable cytogenetic subset showed much less efflux of amonafide (0.13%±3.7) compared to DNR (16%±2.1; p=0.0015). CR pts also showed less efflux of amonafide (4.0%±6.7) than of DNR (21%±2.9; p=0.035).,The relative lack of Pgp-mediated efflux of amonafide, compared to DNR, from sAML blasts provides a rationale for its observed clinical efficacy in the Phase 2 trial. Prospective assessment of these MDR parameters is underway in a randomized Phase 3 clinical trial in sAML comparing amonafide to DNR in combination with std dose cytarabine for remission induction. [Table: see text].