Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: A pharmacodynamic approach with high efficacy

Wyndham H. Wilson, Michael L. Grossbard, Stefania Pittaluga, Diane Cole, Deborah Pearson, Nicole Drbohlav, Seth M. Steinberg, Richard F. Little, John Edward Janik, Martin Gutierrez, Mark Raffeld, Louis Staudt, Bruce D. Cheson, Dan L. Longo, Nancy Harris, Elaine S. Jaffe, Bruce A. Chabner, Robert Wittes, Frank Balis

Research output: Contribution to journalArticle

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Abstract

We hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug selection, schedule, and pharmacokinetics would improve outcome in patients with large B-cell lymphomas. A prospective multi-institutional study of administration of etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone (EPOCH therapy) was done in 50 patients with previously untreated large B-cell lymphomas. The doses of etoposide, doxorubicin, and cyclophosphamide were adjusted 20% each cycle to achieve a nadir absolute neutrophil count below 0.5 x 109/L. The median age of the patients was 46 years (range, 20-88 years); 24% were older than 60 years; and 44% were at high-intermediate or high risk according to International Prognostic Index (IPI) criteria. There was a complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and over-all survival (OS) rates were 70% and 73%, respectively. Neither IPI risk factors nor the index itself was associated with response, PFS, or OS. Doses were escalated in 58% of cycles, and toxicity levels were tolerable. Significant inverse correlations were observed between dose intensity and age for all adjusted agents, and drug clearance of doxorubicin and free etoposide was also inversely correlated with age (r = -0.54 and P2 = .08 and r = -0.45 and P2 = .034, respectively). Free-etoposide clearance increased significantly during successive cycles (P2 = .015). Lymphomas with proliferation of at least 80% had somewhat lower progression and those expressing bcl-2 had significantly higher progression (P2 = .04). Expression of bcl-2 may discriminate the recently described activated B-like from germinal-center B-like large-cell lymphomas and provide important pathobiologic and prognostic information. Dose-adjusted EPOCH may produce more cell kill than CHOP-based regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in younger patients, and compensate for increased drug clearance over time.

Original languageEnglish (US)
Pages (from-to)2685-2693
Number of pages9
JournalBlood
Volume99
Issue number8
DOIs
StatePublished - Apr 15 2002

Fingerprint

Pharmacodynamics
Chemotherapy
B-Cell Lymphoma
Doxorubicin
Etoposide
Cyclophosphamide
Cells
Vincristine
Drug Therapy
Prednisone
Pharmaceutical Preparations
Disease-Free Survival
Lymphoma
Pharmacokinetics
Germinal Center
Toxicity
Appointments and Schedules
Neutrophils
Survival Rate
Survival

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Wilson, W. H., Grossbard, M. L., Pittaluga, S., Cole, D., Pearson, D., Drbohlav, N., ... Balis, F. (2002). Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: A pharmacodynamic approach with high efficacy. Blood, 99(8), 2685-2693. https://doi.org/10.1182/blood.V99.8.2685

Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas : A pharmacodynamic approach with high efficacy. / Wilson, Wyndham H.; Grossbard, Michael L.; Pittaluga, Stefania; Cole, Diane; Pearson, Deborah; Drbohlav, Nicole; Steinberg, Seth M.; Little, Richard F.; Janik, John Edward; Gutierrez, Martin; Raffeld, Mark; Staudt, Louis; Cheson, Bruce D.; Longo, Dan L.; Harris, Nancy; Jaffe, Elaine S.; Chabner, Bruce A.; Wittes, Robert; Balis, Frank.

In: Blood, Vol. 99, No. 8, 15.04.2002, p. 2685-2693.

Research output: Contribution to journalArticle

Wilson, WH, Grossbard, ML, Pittaluga, S, Cole, D, Pearson, D, Drbohlav, N, Steinberg, SM, Little, RF, Janik, JE, Gutierrez, M, Raffeld, M, Staudt, L, Cheson, BD, Longo, DL, Harris, N, Jaffe, ES, Chabner, BA, Wittes, R & Balis, F 2002, 'Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: A pharmacodynamic approach with high efficacy', Blood, vol. 99, no. 8, pp. 2685-2693. https://doi.org/10.1182/blood.V99.8.2685
Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N et al. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: A pharmacodynamic approach with high efficacy. Blood. 2002 Apr 15;99(8):2685-2693. https://doi.org/10.1182/blood.V99.8.2685
Wilson, Wyndham H. ; Grossbard, Michael L. ; Pittaluga, Stefania ; Cole, Diane ; Pearson, Deborah ; Drbohlav, Nicole ; Steinberg, Seth M. ; Little, Richard F. ; Janik, John Edward ; Gutierrez, Martin ; Raffeld, Mark ; Staudt, Louis ; Cheson, Bruce D. ; Longo, Dan L. ; Harris, Nancy ; Jaffe, Elaine S. ; Chabner, Bruce A. ; Wittes, Robert ; Balis, Frank. / Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas : A pharmacodynamic approach with high efficacy. In: Blood. 2002 ; Vol. 99, No. 8. pp. 2685-2693.
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AU - Wilson, Wyndham H.

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AU - Cole, Diane

AU - Pearson, Deborah

AU - Drbohlav, Nicole

AU - Steinberg, Seth M.

AU - Little, Richard F.

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N2 - We hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug selection, schedule, and pharmacokinetics would improve outcome in patients with large B-cell lymphomas. A prospective multi-institutional study of administration of etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone (EPOCH therapy) was done in 50 patients with previously untreated large B-cell lymphomas. The doses of etoposide, doxorubicin, and cyclophosphamide were adjusted 20% each cycle to achieve a nadir absolute neutrophil count below 0.5 x 109/L. The median age of the patients was 46 years (range, 20-88 years); 24% were older than 60 years; and 44% were at high-intermediate or high risk according to International Prognostic Index (IPI) criteria. There was a complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and over-all survival (OS) rates were 70% and 73%, respectively. Neither IPI risk factors nor the index itself was associated with response, PFS, or OS. Doses were escalated in 58% of cycles, and toxicity levels were tolerable. Significant inverse correlations were observed between dose intensity and age for all adjusted agents, and drug clearance of doxorubicin and free etoposide was also inversely correlated with age (r = -0.54 and P2 = .08 and r = -0.45 and P2 = .034, respectively). Free-etoposide clearance increased significantly during successive cycles (P2 = .015). Lymphomas with proliferation of at least 80% had somewhat lower progression and those expressing bcl-2 had significantly higher progression (P2 = .04). Expression of bcl-2 may discriminate the recently described activated B-like from germinal-center B-like large-cell lymphomas and provide important pathobiologic and prognostic information. Dose-adjusted EPOCH may produce more cell kill than CHOP-based regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in younger patients, and compensate for increased drug clearance over time.

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