CPOP-R Versus CHOP-R As First-Line Therapy for Diffuse Large B-Cell Lymphoma (DLBCL): A Phase 2, Randomized, Open-Label, Multicenter Study

CHOP-R is standard therapy for patients with untreated DLBCL. Pixantrone dimaleate (P) is a novel aza-anthracenedione that, unlike doxorubicin (D), forms stable DNA adducts and has enhanced efficacy compared to D in preclinical lymphoma models. Due to its inability to bind iron or form alcohol metabolites, P has substantially less cardiotoxicity than D or mitoxantrone in preclinical studies. In a Phase I-II study in 65 patients with relapsed aggressive B cell NHL after CHOP (±R), patients treated with CPOP (P replaced D in CHOP) had CR/CRu rate of 52% and an overall response rate (ORR) of 77% with median progression-free survival (PFS) of 8.2 months and overall survival (OS) of 17.9 months (Leuk Lymph 2011;52: 620–8). The present Phase II study evaluated efficacy and safety, particularly cardiotoxicity, of CPOP-R vs CHOP-R as first-line therapy in patients with DLBCL.

Patients with untreated DLBCL (CD20+, stage II-IV disease) were randomized to CPOP-R or CHOP-R (1: 1). CHOP-R was administered at standard doses; in CPOP-R, P (150 mg/m²) was substituted for D. After 4 cycles, patients with a partial response (PR) received 4 more cycles of treatment; those with CR received 2 more cycles. Follow-up after treatment was 36 months. Response was assessed by an independent assessment panel. A primary objective to evaluate non-inferiority of CPOP-R to CHOP-R, measured by CR/CRu rates, required 280 patients. Secondary endpoints included ORR, PFS, OS, and time to progression (TTP) and safety. Enrollment was stopped after 124 patients because of resource constraints; the study was no longer powered to detect non-inferiority.

Of the 124 patients enrolled, 61 were randomized to CPOP-R and 63 to CHOP-R. Treatments were administered to 122 patients (98%). Demographics and baseline disease characteristics were balanced between arms. Median age was 68 years in both arms, 79% of patients in CPOP-R vs 78% in CHOP-R were Ann Arbor stage 3–4, 48% vs 54% had IPI ≥3, and 20% vs 11% had ≥3 comorbid conditions. Median number of cycles delivered was 8 for CPOP-R vs 6 for CHOP-R. CR/CRu rate in the ITT population was 72.1% for CPOP-R vs 79.4% for CHOP-R (95% CI for the difference = −7.8%, 22.3%) and ORR (CR+CRu+PR) was 82.0% vs 87.3%. PFS appeared similar for CPOP-R and CHOP-R (HR=1.08). TTP was also similar (median not reached in either arm). Median OS was not reached in either arm (HR=2.34, 95% CI=1.05, 5.22, P =.032). The 3-year survival rates were 66% in CPOP-R vs 85% in CHOP-R. Three-year survival for patients with IPI ≤2 was 82% for CPOP-R vs 86% for CHOP-R; IPI ≥3, survival was 50% vs 84%. It was unusual that in the CHOP-R arm, patients with the modal IPI score=3 (n=25) had a better survival than patients with IPI ≤2 with only 8% mortality at 3 years. This historically high survival rate for CHOP-R patients with IPI=3 appeared responsible for the disparate survival rates between CPOP-R and CHOP-R.

Eight patients in CPOP-R and 2 in CHOP-R had a history of coronary artery disease, congestive heart failure (CHF), or myocardial infarction. Overall, adverse events (AEs) were similar between arms; grade 3/4 AEs occurred in about 85% of patients in both arms. Incidence of grade 3/4 AEs was similar for neutropenia (61.0% vs 60.3%), febrile neutropenia (15.3% vs 15.9%), thrombocytopenia (5.1% vs 6.3%), and infections (16.9% vs 17.5%). Stomatitis was less common in CPOP-R (6.8% vs 17.5%). LVEF was measured prospectively at intervals through 24 months. LVEF values were generally stable in CPOP-R, but declined significantly from baseline in CHOP-R (P <.05). One patient in CPOP-R vs 8 in CHOP-R had LVEF declines ≥20% (P<.05). In CPOP-R, 6.7% of patients vs 35.2% in CHOP-R developed elevated troponin T levels (P<.05). No patients in CPOP-R vs 4 in CHOP-R developed CHF. Three deaths occurred within 30 days of last dose in CPOP-R vs none in CHOP-R. Most deaths after treatment in both arms were related to progressive disease.

This study compared CPOP-R, a pixantrone-containing regimen, with CHOP-R as first-line therapy for DLBCL and showed comparable efficacy as measured by response, PFS, and TTP. Hematopoietic toxicities were similar; however, CPOP-R had reduced cardiotoxicity as determined by overall and serious declines in LVEF, elevations in troponin T, and CHF occurrence. Non-inferiority of CPOP-R to CHOP-R could not be established.

Herbrecht:Cell Therapeutics, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cernohous:Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment. van der Jagt:Cell Therapeutics, Inc: Consultancy, Research Funding.