Daunorubicin and Cytarabine Compared with Daunorubicin, Cytarabine and the MDR1 Reversal Agent PSC-833 in Elderly Patients with Acute Myelogenous Leukemia.
Authors: van der Holt Bronno , Sonneveld Pieter , Burnett Alan K. , Vossebeld Paula J.M. , Beverloo Berna , Rosenkranz Gerd , Dugan Margaret , van Putten Wim L.J. , Wheatley Keith , Lowenberg Bob 
Published: October 2019

Older patients (pts) have a high incidence of P-glycoprotein (P-gp) positive AML blast cells. P-gp acts as drug efflux pump for a variety of agents including daunorubicin (DNR). The P-gp inhibitor PSC-833 can inhibit the function of P-gp in AML cells and restore sensitivity to DNR. Combining PSC-833 with DNR may improve response rate and survival in AML pts. However, previous intervention studies have produced conflicting results. From 1997 to 1999 we conducted a multi-center phase 3 study in pts of older age with previously untreated AML, in which we prospectively investigated the effect of PSC-833 combined with standard antileukemic treatment in relation to the flowcytometric P-gp status at diagnosis. Pts were randomized to receive two cycles of DNR (45 mg/m2, days 1-3) and Ara-C (200 mg/m2, 7 days) or the same regimen with a lower dose of DNR (35 mg/m2, days 1–3) plus PSC-833 (2 mg/kg loading dose followed by 10 mg/kg/24h for 72 hours). Pts who attained a complete remission (CR) were to receive a common consolidation cycle of Ara-C (1 g/m2, days 1–4), mitoxantrone (6 mg/m2, days 1–4) and etoposide (80 mg/m2, days 1–4).

Results. 428 pts were randomized (214 in each arm) with 419 eligible and evaluable. Median age was 67 years (range 58–85). Baseline characteristics were comparable between the two arms. Cytogenetics was successfully performed in 293 pts; 5 had favorable and 66 had unfavorable abnormalities. P-gp expression was assessed in fresh, purified bone marrow samples of 309/419 pts (74%) by determining the Rhodamin123 efflux ratio with/without PSC-833 in vitro and by assessment of the UIC2 and MRK16 expression ratios. Upon P-gp assessment combining the 3 tests, pts were classified as P-gp negative (27%), low positive (29%), positive (28%) or highly positive (17%). Median follow up is 56 months. CR and 5-year survival rates with 95% confidence intervals are in the table below. Increased P-gp expression was associated with a lower CR rate (P=0.02), worse event-free survival (EFS) and overall survival (OS), P=0.01. There was also no significant effect of PSC-833 on the CR rate, OS, EFS or disease-free survival (DFS) when P-gp status was included in a multivariate analysis. In the planned subgroup analysis of pts with P-gp expression, who were expected to benefit most from PSC-833, CR rate was somewhat higher in the PSC arm (61% vs. 51%, P=0.07), however, OS, EFS and DFS were not different (P=0.8, 0.9 and 0.15). Analysis of frequently occurring polymorphisms of P-gp in exons 12, 21 and 26 revealed that pts who had wildtype genotype alleles in all 3 exons had a relatively poor survival as compared with those with heterozygous or homozygous mutant alleles in all 3 exons.

Conclusions. Addition of PSC-833 to DNR and Ara-C does not improve CR rate nor long-term OS, EFS and DFS in elderly AML pts. P-gp expression remains an independent adverse prognostic factor in AML pts treated with P-gp reversal.

Results by treatment arm

control (n=211) PSC-833 (n=208) P-value CR 48% (41–55) 54% (47–61) 0.22 EFS 8% (5–13) 7% (4–11) 0.46 DFS 17% (11–26) 13% (8–20) 0.06 10% (6–15) 10% (6–15) 0.52