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. 2015 Sep 10;33(26):2848-56.
doi: 10.1200/JCO.2014.60.2383. Epub 2015 Aug 3.

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  1 , Anja Mottok  2 , Daisuke Ennishi  2 , George W Wright  2 , Pedro Farinha  2 , Susana Ben-Neriah  2 , Robert Kridel  2 , Garrett S Barry  2 , Christoffer Hother  2 , Pau Abrisqueta  2 , Merrill Boyle  2 , Barbara Meissner  2 , Adele Telenius  2 , Kerry J Savage  2 , Laurie H Sehn  2 , Graham W Slack  2 , Christian Steidl  2 , Louis M Staudt  2 , Joseph M Connors  2 , Lisa M Rimsza  2 , Randy D Gascoyne  2
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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

David W Scott et al. J Clin Oncol. .

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.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Outcomes in patients with diffuse large B-cell lymphoma (DLBCL) after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone according to cell of origin. Curves shown for (A) time to progression, (B) progression-free survival, (C) disease-specific survival, and (D) overall survival. ABC, activated B-cell–like DLBCL; GCB, germinal center B-cell–like DLBCL; HR, hazard ratio; U, unclassified DLBCL.
Fig 2.
Fig 2.
Outcomes in patients with diffuse large B-cell lymphoma after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone according to groups defined by immunohistochemistry for MYC and BCL2. Curves shown for (A) time to progression, (B) progression-free survival, (C) disease-specific survival, and (D) overall survival. Positivity for MYC was defined as ≥ 40% of tumor cells stained and for BCL2 as ≥ 50% of tumor cells stained. HR, hazard ratio.
Fig 3.
Fig 3.
Time to progression for patients with diffuse large B-cell lymphoma (DLBCL) after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone according to cell of origin and immunohistochemistry for MYC and BCL2. Curves shown for patients with (A) non–MYC-positive/BCL2-positive status, (B) MYC-positive/BCL2-positive status, (C) germinal center B-cell–like (GCB) subtype, and (D) activated B-cell–like (ABC) subtype. HR, hazard ratio; U, unclassified DLBCL.
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References

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