A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype

Abstract

Background: A phase II trial of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) from the National Cancer Institute showed promising activity in untreated diffuse large B-cell lymphoma. The Cancer and Leukemia Group B conducted a study to determine if these results could be reproduced in a multi-institutional setting.

Design and methods: The study included 69 patients with untreated diffuse large B-cell lymphoma at least 18 years of age and at least stage II. Radiaton therapy was not permitted on study. Median age was 58 years (range 23-83) and 40% had high-intermediate or high International Prognostic Index risk. Immunohistochemical biomarkers for cell of origin and proliferation were performed.

Results: With a median follow up of 62 months, time to progression and overall survival were 81% and 84%, respectively, and time to progression was 87%, 92% and 54% for low/low-intermediate, high-intermediate and high International Prognostic Index risk groups, respectively, at 5-years and beyond. The time to progression and event-free survival of germinal center B-cell lymphoma were 100% and 94%, respectively, and non-germinal center B-cell GCB diffuse large B-cell lymphoma were 67% and 58%, respectively, at 62 months (germinal center vs. non-germinal center B cell P=0.008). DA-EPOCH-R was tolerated without significant grade 4 non-hematologic toxicities.

Conclusions: These results provide the first confirmation by a multi-institutional group that DA-EPOCH-R provides high durable remissions in diffuse large B-cell lymphoma and is effective in both germinal center and non-germinal center B-cell subtypes. The trial was registered at ClinicalTrials.Gov (NCT00032019).

Figure 1.

Kaplan-Meier plots of survival outcomes of all patients. Outcomes are reported at 5 years (95% Confidence Interval (CI)) and CI range is shown on the curves. (A) PFS 81% (69, 88). (B) EFS 75% (63, 84). (C) OS 84% (73, 91). (D) PFS for IPI risk groups: low/low-intermediate (------------------------) 87% (72, 94), high-intermediate (- - - - - - - - ) 92% (57, 99) and high risk (--- . . --- . . --- ) 54% (25, 76) (P=0.0085). (E) EFS for IPI risk groups: low/low-intermediate 85% (69, 93), high-intermediate 85% (51, 96) and high risk 43% (18, 66) (P<0.0013). (F) OS for IPI risk groups: low/low-intermediate 95% (80, 99), high-intermediate 92% (57, 99) and high risk 43% (18, 66) (P<0.0001).

Figure 2.

Kaplan-Meier plots of survival outcomes patients with biomarkers. (A) PFS of GCB (-------------------------------) and non-GCB ( - - - - - - - - ) DLBCL (P=0.008). (B) EFS of GCB and non-GCB DLBCL (P=0.008). (C) OS of GCB and non-GCB DLBCL (P=0.04). (D) PFS of Ki67 < 60% (---------------------------) and Ki67 ≥ 60% ( - - - - - - - - - ) in non-GCB DLBCL (P=0.03). (E) EFS of Ki67 < 60% and Ki67 ≥ 60% in non-GCB DLBCL (P=0.04). (F) OS of Ki67 < 60% and Ki67 ≥ 60% in non-GCB DLBCL (P=0.05).