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. Rimsza; Randy D. Gascoyne

doi:10.1200/JCO.2014.60.2383

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

Research output: Contribution to journal › Article › peer-review

264 Citations (Scopus)

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 language	English
Pages (from-to)	2848-2856
Number of pages	9
Journal	Journal of Clinical Oncology
Volume	33
Issue number	26
DOIs	https://doi.org/10.1200/JCO.2014.60.2383
Publication status	Published - 2015
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1200/JCO.2014.60.2383

Cite this

Scott, D. W., Mottok, A., Ennishi, D., Wright, G. W., Farinha, P., Ben-Neriah, S., Kridel, R., Barry, G. S., Hother, C., Abrisqueta, P., Boyle, M., Meissner, B., Telenius, A., Savage, K. J., Sehn, L. H., Slack, G. W., Steidl, C., Staudt, L. M., Connors, J. M., ... Gascoyne, R. D. (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, 33(26), 2848-2856. https://doi.org/10.1200/JCO.2014.60.2383

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

@article{c9ab0391ca984accaa28a09eb05aab7c,

title = "Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies",

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.}",

note = "Funding Information: Supported by the Terry Fox Foundation and by the British Columbia Cancer Foundation (D.W.S.); A.M. holds fellow ship awarded by the Mildred Scheel Cancer Foundation. Funding Information: Supported by the Terry Fox Foundation and by the British Columbia Cancer Foundation (D.W.S.); A.M. holds fellowship awarded by the Mildred Scheel Cancer Foundation. Publisher Copyright: {\textcopyright} 2015 American Society of Clinical Oncology. All rights reserved.",

year = "2015",

doi = "10.1200/JCO.2014.60.2383",

language = "English",

volume = "33",

pages = "2848--2856",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "26",

}

TY - JOUR

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.

N1 - Funding Information: Supported by the Terry Fox Foundation and by the British Columbia Cancer Foundation (D.W.S.); A.M. holds fellow ship awarded by the Mildred Scheel Cancer Foundation. Funding Information: Supported by the Terry Fox Foundation and by the British Columbia Cancer Foundation (D.W.S.); A.M. holds fellowship awarded by the Mildred Scheel Cancer Foundation. Publisher Copyright: © 2015 American Society of Clinical Oncology. All rights reserved.

PY - 2015

Y1 - 2015

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.

UR - http://www.scopus.com/inward/record.url?scp=84964994916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964994916&partnerID=8YFLogxK

U2 - 10.1200/JCO.2014.60.2383

DO - 10.1200/JCO.2014.60.2383

M3 - Article

C2 - 26240231

AN - SCOPUS:84964994916

SN - 0732-183X

VL - 33

SP - 2848

EP - 2856

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 26

ER -

Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this