A Randomized Comparison of Induction Therapy for Untreated Acute Myeloid Leukemia (AML) in Patients &lt; 60 Years Using P-Glycoprotein (Pgp) Modulation with Valspodar (PSC833): Preliminary Results of Cancer and Leukemia Group B Study 19808.
Authors: Kolitz Jonathan E. , George Stephen L. , Marcucci Guido , Vij Ravi , Powell Bayard L. , Allen Steven L. , De Angelo Daniel J. , Shea Thomas , Stock Wendy , Hars Vera , Hoke Eva , Vardiman James W. , Bloomfield Clara D. , Larson Richard A. 
Published: April 2020

In order to assess whether Pgp modulation with PSC833 improves disease-free (DFS) and overall (OS) survival in untreated patients (pts) with AML &lt; 60 years, a phase 3 trial (CALGB 19808) was undertaken comparing two induction regimens: Ara-C (A), Daunorubicin (D), and Etoposide (E), with (ADEP) or without (ADE) PSC833. All pts received A 100 mg/m2 by CIV daily for 7 days. In ADE, D 90 mg/m2 and E 100 mg/m2 were each given daily by short IV infusion on days 1–3; the corresponding doses in ADEP were D 40 mg/m2 and E 40 mg/m2. PSC833 10 mg/m2 was given by CIV over 72 hrs after a loading dose of 2.8 mg/kg IV over 2 hrs. These doses were based on findings from parallel phase I trials that showed comparable efficacy and toxicity for the 2 regimens (JCO2004; 22:4290). Pts in complete remission (CR) received consolidation therapy according to cytogenetic risk (ASH2001, 688a) and were then randomized to a phase 3 immunotherapy sequence comparing interleukin-2 with observation. The Pgp modulation portion of the trial ended when PSC833 became unavailable after 302 of a planned 600 pts had been randomized. Prior myelodysplasia or therapy-related AML were exclusion criteria. The median age was 45 years; the arms were comparable with respect to cytogenetic risk groups (Core-Binding Factor (CBF) leukemia vs. others). Response by intent-to-treat on the part of 296 evaluable pts and toxicity data are tabulated below. The median follow-up is 2.2 years. None of the differences in CR rate, OS, or DFS are statistically significant.

ADE (n=149) ADEP (n=147) CR 77% 78% CR - CBF AML 100% (21/21) 100% (25/25) CR With One Induction Course 89% 88% Induction Mortality 7% 7% Median OS (months) 21 20 Median DFS (months) 19 15 Median OS -pts ≤ 45 yrs (months) 29 Not Reached Median DFS pts ≤ 45 yrs (months) Not Reached 13 Grade 3 and 4 Toxicities Dysphagia/Esophagitis 6% 17% Stomatitis 9% 24% Bilirubin 6% 25% Rash 1% 10% Left Ventricular Function 2% 1%

The high dose daunorubicin regimen was given safely, without excess induction mortality or cardiotoxicity. Hepatotoxicity due to ADEP consisted of generally reversible hyperbilirubinemia. PSC833 did not cause significant neurotoxicity. Compared with the induction regimen used in the previous group study in this pt population in which 474 pts received D 45 mg/m2 x 3 days and A 200 mg/m2 x 7 days without E or PSC833, (CALGB 9222, Blood2005; 105:3420), the CR rates in this study were higher (78% vs 72%), the number of pts achieving CR with 1 induction higher (89% vs. 77%), and the induction mortality comparable (7% vs 9%). These preliminary findings suggest that similar outcomes occur following an induction regimen using 2.25-fold higher D and 2.5-fold higher E doses (ADE) relative to a regimen employing a Pgp modulator (ADEP). PSC833 is known to delay the hepatic clearance of D and E. These data cannot distinguish between the possibilities that PSC833 augments the anti-leukemia activity of the lower dose ADE regimen or whether there is, in fact, no clinically meaningful dose-response relationship with D and E within the evaluated dose ranges. The findings of this trial to date suggest that Pgp-mediated drug efflux may not be the major or sole mechanism of drug resistance in AML or that PSC833 is an inadequate inhibitor of Pgp activity or both.