Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies

David W. Scott, Anja Mottok, Daisuke Ennishi, George W. Wright, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Louis M. Staudt, Joseph M. Connors, Lisa M RimszaRandy D. Gascoyne

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Abstract

PURPOSE: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers).

PATIENTS AND METHODS: Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays.

RESULTS: The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P <.001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P <.001 for time to progression).

CONCLUSION: Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.

Original languageEnglish (US)
Pages (from-to)2848-2856
Number of pages9
JournalJournal of Clinical Oncology
Volume33
Issue number26
DOIs
StatePublished - Sep 10 2015

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Lymphoma, Large B-Cell, Diffuse
Paraffin
Formaldehyde
Biopsy
Gene Expression
B-Lymphocytes
Germinal Center
Proto-Oncogene Proteins c-bcl-2
Immunohistochemistry
Neoplasms
British Columbia
Survival
Vincristine
Prednisone
Doxorubicin
Cyclophosphamide
Disease-Free Survival

ASJC Scopus subject areas

  • Medicine(all)

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Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies. / Scott, David W.; Mottok, Anja; Ennishi, Daisuke; Wright, George W.; Farinha, Pedro; Ben-Neriah, Susana; Kridel, Robert; Barry, Garrett S.; Hother, Christoffer; Abrisqueta, Pau; Boyle, Merrill; Meissner, Barbara; Telenius, Adele; Savage, Kerry J.; Sehn, Laurie H.; Slack, Graham W.; Steidl, Christian; Staudt, Louis M.; Connors, Joseph M.; Rimsza, Lisa M; Gascoyne, Randy D.

In: Journal of Clinical Oncology, Vol. 33, No. 26, 10.09.2015, p. 2848-2856.

Research output: Contribution to journalArticle

Scott, DW, Mottok, A, Ennishi, D, Wright, GW, Farinha, P, Ben-Neriah, S, Kridel, R, Barry, GS, Hother, C, Abrisqueta, P, Boyle, M, Meissner, B, Telenius, A, Savage, KJ, Sehn, LH, Slack, GW, Steidl, C, Staudt, LM, Connors, JM, Rimsza, LM & Gascoyne, RD 2015, 'Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies', Journal of Clinical Oncology, vol. 33, no. 26, pp. 2848-2856. https://doi.org/10.1200/JCO.2014.60.2383
Scott, David W. ; Mottok, Anja ; Ennishi, Daisuke ; Wright, George W. ; Farinha, Pedro ; Ben-Neriah, Susana ; Kridel, Robert ; Barry, Garrett S. ; Hother, Christoffer ; Abrisqueta, Pau ; Boyle, Merrill ; Meissner, Barbara ; Telenius, Adele ; Savage, Kerry J. ; Sehn, Laurie H. ; Slack, Graham W. ; Steidl, Christian ; Staudt, Louis M. ; Connors, Joseph M. ; Rimsza, Lisa M ; Gascoyne, Randy D. / Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 26. pp. 2848-2856.
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abstract = "PURPOSE: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers).PATIENTS AND METHODS: Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays.RESULTS: The Lymph2Cx assay provided concordant COO calls in 96{\%} of 49 repeatedly sampled tumor biopsies and in 100{\%} of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P <.001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P <.001 for time to progression).CONCLUSION: Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.",
author = "Scott, {David W.} and Anja Mottok and Daisuke Ennishi and Wright, {George W.} and Pedro Farinha and Susana Ben-Neriah and Robert Kridel and Barry, {Garrett S.} and Christoffer Hother and Pau Abrisqueta and Merrill Boyle and Barbara Meissner and Adele Telenius and Savage, {Kerry J.} and Sehn, {Laurie H.} and Slack, {Graham W.} and Christian Steidl and Staudt, {Louis M.} and Connors, {Joseph M.} and Rimsza, {Lisa M} and Gascoyne, {Randy D.}",
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T1 - Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies

AU - Scott, David W.

AU - Mottok, Anja

AU - Ennishi, Daisuke

AU - Wright, George W.

AU - Farinha, Pedro

AU - Ben-Neriah, Susana

AU - Kridel, Robert

AU - Barry, Garrett S.

AU - Hother, Christoffer

AU - Abrisqueta, Pau

AU - Boyle, Merrill

AU - Meissner, Barbara

AU - Telenius, Adele

AU - Savage, Kerry J.

AU - Sehn, Laurie H.

AU - Slack, Graham W.

AU - Steidl, Christian

AU - Staudt, Louis M.

AU - Connors, Joseph M.

AU - Rimsza, Lisa M

AU - Gascoyne, Randy D.

PY - 2015/9/10

Y1 - 2015/9/10

N2 - PURPOSE: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers).PATIENTS AND METHODS: Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays.RESULTS: The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P <.001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P <.001 for time to progression).CONCLUSION: Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.

AB - PURPOSE: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers).PATIENTS AND METHODS: Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays.RESULTS: The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P <.001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P <.001 for time to progression).CONCLUSION: Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.

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