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Prognostic Impact of Germinal Center–Associated Proteins and Chromosomal Breakpoints in Poor-Risk Diffuse Large B-Cell Lymphoma

Gustaaf W. van Imhoff, Evert-Jan G. Boerma, Bronno van der Holt, Ed Schuuring, Leo F. Verdonck, Hanneke C. Kluin-Nelemans, Philip M. Kluin

From the Departments of Hematology and Pathology, University Medical Center Groningen, University of Groningen, Groningen; Department of Trials and Statistics–HOVON Data Center, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam; and the Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands

Address reprint requests to Gustaaf W. van Imhoff, MD, Department of Hematology, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands; e-mail: g.w.van.imhoff{at}int.umcg.nl

Purpose: Outcome of diffuse large B-cell lymphoma (DLBCL) with a germinal center B-cell (GCB) expression profile is superior to that of non-GCB DLBCL. This conclusion is mainly derived from patients with mixed international prognostic index (IPI) risk profiles treated with CHOP-like therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). We wondered whether the prognostic impact of the expression profile would hold out in a homogeneous cohort of poor-risk DLBCL patients treated with high-dose sequential therapy (HDT) and autologous stem-cell transplantation (ASCT) as first-line therapy.

Patients and Methods: DLBCL from 66 newly diagnosed poor-risk patients, treated in two sequential prospective Dutch Hemato-Oncology Association (HOVON) trials, were studied retrospectively for expression of CD10, bcl6, MUM1/IRF4, bcl2, Ki67, and CD21⁺ follicular dendritic cells (FDC) by immunohistochemistry, and for the breakpoints of BCL2, BCL6, and MYC by fluorescent in situ hybridization (FISH). Lymphomas with any follicular component were excluded.

Results: A GCB immunophenotype profile was found in 58% and non-GCB immunophenotype profile in 42% of the tumors. Clinical characteristics of both groups were similar. Complete response (CR) rate was higher in patients with CD10⁺ tumors (58% v 30%; P = .03). A GCB immunophenotype profile, its constituting markers CD10 more than 30% and MUM1 less than 70%, and bcl2 less than 10% were each associated with a better overall survival (OS). FDC networks, equally present in GCB and non-GCB tumors, had superior CR (73% v 31%; P = .01), but disease-free survival rates were lower and there was no difference in OS rates. None of the breakpoints had a prognostic impact on outcome.

Conclusion: Also in patients with poor-risk DLBCL treated with HDT and ASCT, the GCB immunophenotype and bcl2 expression retained a major impact on survival.

Presented in part at the 9th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 9-11, 2005.

G.W.v.I. and E.G.B. contributed equally to this study.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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