Abstract

The CHOP-R regimen is the standard regimen for first-line therapy of patients with DLBCL. Pixantrone (BBR 2778) is a novel aza-anthracenedione with structural similarities to mitoxantrone. In a phase 1/2 study of CPOP in 65 patients with relapsed NHL who had received a first-line anthracycline-containing regimen, patients received pixantrone at 80–180 mg/m2. This study indicated substantial activity with an overall response rate of 77% and complete response (CR) rate of 54% with acceptable toxicity. Studies in indolent NHL demonstrated that the combination of pixantrone with rituximab is well tolerated and more active than rituximab alone (

JCO
,
24
(18S),
2006
:
7578
). To evaluate the safety and activity of CPOP-R with special regard to cardiac safety in the first-line setting, a randomized phase 2 study in untreated patients with DLBCL comparing CPOP-R to CHOP-R is being conducted. Patients with untreated, histologically confirmed CD20-positive DLBCL receive CHOP-R or CPOP-R every 21 days for 6–8 cycles. An interim analysis for efficacy was prospectively planned to be performed when 40 patients had completed 4 cycles of therapy to test whether the CR rate of CPOP-R (pixantrone dose of 150 mg/m2) is, with 95% confidence, not more than 15% less than the CR rate of CHOP-R. We report the results of this analysis, which included 40 patients (21 CPOP-R and 19 CHOP-R) who had completed 4 cycles or had prematurely withdrawn from the study. Preliminary safety data (CPOP-R=27 patients, CHOP-R=30 patients) were also evaluated. CR rates after 4 cycles based on investigators’assessment were similar between arms (CPOP-R=33%, CHOP-R=37%). In general, adverse events were equal between arms. There were no more grade 3–4 adverse events (41% CPOP-R vs 50% CHOP-R) and no more grade 3–4 treatment-related adverse events (33% in CPOP-R vs 40% in CHOP-R) in the CPOP-R arm compared to the CHOP-R arm. 8 patients in each arm had asymptomatic absolute LVEF declines of ≥10%. 3 patients in the CPOP-R arm had a LVEF decline of >15% and ≤20% compared to 5 patients in the CHOP-R arm. No patients in the CPOP-R arm had a >20% LVEF decline compared to 2 patients in the CHOP-R arm. No heart failure or deaths resulting from heart failure have been reported. Infections reported as serious adverse events occurred in 1 patient (4%) in the CPOP-R arm and 3 patients (10%) in the CHOP-R arm. Grade 3–4 neutropenia was similar (CPOP-R = 34%, CHOP-R = 30%). Febrile neutropenia was less frequent in the CPOP-R arm (4% vs 23%). There were 2 deaths within 30 days of the last dose of study drug on CPOP-R arm. Both patients were > 80 years; 1 of the events was attributed to study treatment secondary to neutropenic infection. No deaths were reported in the CHOP-R arm. Based on this preliminary analysis, we conclude that for 1st-line therapy of patients with DLBCL, CPOP-R has similar activity to CHOP-R with no more toxicity. Further follow-up is required.

Author notes

Disclosure:Employment: Igor Gorbatchevsky is an employee of Cell Therapeutics, Inc. Ownership Interests:; Igor Gorbatchevky has stock and stock options in Cell Therapuetics, Inc.