Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers

Wyndham H. Wilson, Kieron Dunleavy, Stefania Pittaluga, Upendra Hegde, Nicole Grant, Seth M. Steinberg, Mark Raffeld, Martin Gutierrez, Bruce A. Chabner, Louis Staudt, Elaine S. Jaffe, John Edward Janik

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Abstract

Purpose: To assess the clinical outcome and the influence of biomarkers associated with apoptosis inhibition (Bcl-2), tumor proliferation (MIB-1), and cellular differentiation on the outcome with dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab (R) infusional therapy in diffuse large B-cell lymphoma (DLBCL) with analysis of germinal center B-cell (GCB) and post-GCB subtypes by immunohistochemistry. Patients and Methods: Phase II study of 72 patients with untreated de novo DLBCL who were at least 18 years of age and stage II or higher. Radiation consolidation was not permitted. Results: Patients had a median age of 50 years (range, 19 to 85) and 40% had a high-intermediate or high International Prognostic Index (IPI). At 5 years, progression-free survival (PFS) and overall survival (OS) were 79% and 80%, respectively, with a median potential follow-up of 54 months. PFS was 91%, 90%, 67%, and 47%, and OS was 100%, 90%, 74%, and 37%, for 0 to 1, 2, 3, and 4 to 5 IPI factors, respectively, at 5 years. The Bcl-2 and MIB-1 biomarkers were not associated with PFS or OS. Based on DA-EPOCH historical controls, rituximab only benefited Bcl-2 positive tumors. Bcl-6 expression was associated with higher PFS whereas GCB exhibited a marginally significant higher PFS compared with post-GCB DLBCL. Conclusion: DA-EPOCH-R outcome was not affected by tumor proliferation and rituximab appeared to overcome the adverse effect of Bcl-2. Bcl-6 may identify a biologic program associated with a superior outcome. Overall, DA-EPOCH-R shows promising outcome in low and intermediate IPI groups. A molecular model of treatment outcome with rituximab and chemotherapy is presented.

Original languageEnglish (US)
Pages (from-to)2717-2724
Number of pages8
JournalJournal of Clinical Oncology
Volume26
Issue number16
DOIs
StatePublished - Sep 15 2008

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Germinal Center
Lymphoma, Large B-Cell, Diffuse
Disease-Free Survival
Biomarkers
B-Lymphocytes
Survival
Neoplasms
Molecular Models
Vincristine
Etoposide
Prednisone
Doxorubicin
Cyclophosphamide
Immunohistochemistry
Rituximab
Radiation
Apoptosis
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. / Wilson, Wyndham H.; Dunleavy, Kieron; Pittaluga, Stefania; Hegde, Upendra; Grant, Nicole; Steinberg, Seth M.; Raffeld, Mark; Gutierrez, Martin; Chabner, Bruce A.; Staudt, Louis; Jaffe, Elaine S.; Janik, John Edward.

In: Journal of Clinical Oncology, Vol. 26, No. 16, 15.09.2008, p. 2717-2724.

Research output: Contribution to journalArticle

Wilson, WH, Dunleavy, K, Pittaluga, S, Hegde, U, Grant, N, Steinberg, SM, Raffeld, M, Gutierrez, M, Chabner, BA, Staudt, L, Jaffe, ES & Janik, JE 2008, 'Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers', Journal of Clinical Oncology, vol. 26, no. 16, pp. 2717-2724. https://doi.org/10.1200/JCO.2007.13.1391
Wilson, Wyndham H. ; Dunleavy, Kieron ; Pittaluga, Stefania ; Hegde, Upendra ; Grant, Nicole ; Steinberg, Seth M. ; Raffeld, Mark ; Gutierrez, Martin ; Chabner, Bruce A. ; Staudt, Louis ; Jaffe, Elaine S. ; Janik, John Edward. / Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 16. pp. 2717-2724.
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abstract = "Purpose: To assess the clinical outcome and the influence of biomarkers associated with apoptosis inhibition (Bcl-2), tumor proliferation (MIB-1), and cellular differentiation on the outcome with dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab (R) infusional therapy in diffuse large B-cell lymphoma (DLBCL) with analysis of germinal center B-cell (GCB) and post-GCB subtypes by immunohistochemistry. Patients and Methods: Phase II study of 72 patients with untreated de novo DLBCL who were at least 18 years of age and stage II or higher. Radiation consolidation was not permitted. Results: Patients had a median age of 50 years (range, 19 to 85) and 40{\%} had a high-intermediate or high International Prognostic Index (IPI). At 5 years, progression-free survival (PFS) and overall survival (OS) were 79{\%} and 80{\%}, respectively, with a median potential follow-up of 54 months. PFS was 91{\%}, 90{\%}, 67{\%}, and 47{\%}, and OS was 100{\%}, 90{\%}, 74{\%}, and 37{\%}, for 0 to 1, 2, 3, and 4 to 5 IPI factors, respectively, at 5 years. The Bcl-2 and MIB-1 biomarkers were not associated with PFS or OS. Based on DA-EPOCH historical controls, rituximab only benefited Bcl-2 positive tumors. Bcl-6 expression was associated with higher PFS whereas GCB exhibited a marginally significant higher PFS compared with post-GCB DLBCL. Conclusion: DA-EPOCH-R outcome was not affected by tumor proliferation and rituximab appeared to overcome the adverse effect of Bcl-2. Bcl-6 may identify a biologic program associated with a superior outcome. Overall, DA-EPOCH-R shows promising outcome in low and intermediate IPI groups. A molecular model of treatment outcome with rituximab and chemotherapy is presented.",
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T1 - Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers

AU - Wilson, Wyndham H.

AU - Dunleavy, Kieron

AU - Pittaluga, Stefania

AU - Hegde, Upendra

AU - Grant, Nicole

AU - Steinberg, Seth M.

AU - Raffeld, Mark

AU - Gutierrez, Martin

AU - Chabner, Bruce A.

AU - Staudt, Louis

AU - Jaffe, Elaine S.

AU - Janik, John Edward

PY - 2008/9/15

Y1 - 2008/9/15

N2 - Purpose: To assess the clinical outcome and the influence of biomarkers associated with apoptosis inhibition (Bcl-2), tumor proliferation (MIB-1), and cellular differentiation on the outcome with dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab (R) infusional therapy in diffuse large B-cell lymphoma (DLBCL) with analysis of germinal center B-cell (GCB) and post-GCB subtypes by immunohistochemistry. Patients and Methods: Phase II study of 72 patients with untreated de novo DLBCL who were at least 18 years of age and stage II or higher. Radiation consolidation was not permitted. Results: Patients had a median age of 50 years (range, 19 to 85) and 40% had a high-intermediate or high International Prognostic Index (IPI). At 5 years, progression-free survival (PFS) and overall survival (OS) were 79% and 80%, respectively, with a median potential follow-up of 54 months. PFS was 91%, 90%, 67%, and 47%, and OS was 100%, 90%, 74%, and 37%, for 0 to 1, 2, 3, and 4 to 5 IPI factors, respectively, at 5 years. The Bcl-2 and MIB-1 biomarkers were not associated with PFS or OS. Based on DA-EPOCH historical controls, rituximab only benefited Bcl-2 positive tumors. Bcl-6 expression was associated with higher PFS whereas GCB exhibited a marginally significant higher PFS compared with post-GCB DLBCL. Conclusion: DA-EPOCH-R outcome was not affected by tumor proliferation and rituximab appeared to overcome the adverse effect of Bcl-2. Bcl-6 may identify a biologic program associated with a superior outcome. Overall, DA-EPOCH-R shows promising outcome in low and intermediate IPI groups. A molecular model of treatment outcome with rituximab and chemotherapy is presented.

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