Previous presentation: part of the study results were presented as an oral presentation at the 2019 International Conference on Malignant Lymphoma, Lugano, Switzerland.

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Summary

We assessed the concordance between immunohistochemistry (IHC) and gene expression profiling (GEP) for determining diffuse large B-cell lymphoma (DLBCL) cell of origin (COO) in the phase III PHOENIX trial of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with or without ibrutinib. Among 910 of 1114 screened patients with non-germinal centre B cell-like (non-GCB) DLBCL by IHC, the concordance with GEP for non-GCB calls was 82·7%, with 691 (75·9%) identified as activated B cell-like (ABC), and 62 (6·8%) as unclassified. Among 746 of 837 enrolled patients with verified non-GCB DLBCL by IHC, the concordance with GEP was 82·8%, with 567 (76·0%) identified as ABC and 51 (6·8%) unclassified; survival outcomes were similar regardless of COO or treatment, whereas among patients with ABC DLBCL aged <60 years, the overall and event-free survival were substantially better with ibrutinib versus placebo plus R-CHOP [hazard ratio (HR) 0·365, 95% confidence interval (CI) 0·147–0·909, P = 0·0305; HR 0·561, 95% CI 0·326–0·967, P = 0·0348, respectively]. IHC and GEP showed high concordance and consistent survival outcomes among tested patients, indicating centralised IHC may be used to enrich populations for response to ibrutinib plus R-CHOP.

Conflict of interest

Sriram Balasubramanian: Janssen employment and stock ownership from Johnson & Johnson, Gilead Sciences, Celgene, Vertex and AbbVie; Songbai Wang, Christopher Major, Michael Schaffer, Jodi Carey, S. Martin Shreeve, Steven Sun and Jessica Vermeulen: Janssen employment and stock ownership from Johnson & Johnson; Brendan Hodkinson and John Gerecitano: Janssen employment; Laurie H. Sehn: honoraria from Amgen, Apobiologix, AbbVie, Celgene, Gilead Sciences, Janssen-Ortho, Karyopharm Therapeutics, Kite Pharma, Lundbeck, Merck, Roche/Genentech, Seattle Genetics, Takeda Pharmaceuticals, TEVA Pharmaceuticals Industries and TG Therapeutics, research funding from Roche/Genentech, consulting or an advisory role with Karyopharm Therapeutics, Kite Pharma, Merck, Takeda Pharmaceuticals, TEVA Pharmaceuticals Industries and TG Therapeutics; Peter Johnson: honoraria from Bristol Myers Squibb, Takeda, Novartis, Celgene, Janssen, Epizyme, Boehringer Ingelheim, Kite, Genmab and Incyte, research funding from Epizyme and Janssen, and consulting or advisory role with Janssen; Pier Luigi Zinzani: advisory roles for Verastem, Janssen, Takeda, TG Therapeutics, Bristol Myers Squibb, Roche, Gilead, Novartis and Celltrion; Wyndham Wilson and Louis M. Staudt: have no competing interests.

Supporting Information

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bjh17450-sup-0001-Supinfo.docxWord document, 1.3 MB

Table SI. Summary of predicted probability score. ABC, activated B-cell–like; GCB, germinal centre B-cell–like; GEP, gene expression profiling; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; SD, standard deviation.

Table SII. Hazard ratios in all patients treated with ibrutinib plus R-CHOP versus R-CHOP by probability score. CI, confidence interval; EFS, event-free survival; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Fig S1. Percentage and concordance of screened and enrolled IHC-selected patients in each GEP subpopulation. CI, confidence interval; COO, cell of origin; GCB, germinal centre B cell-like; GEP, gene expression profiling; IHC, immunohistochemistry; UNC, unclassified.

Fig S2. Percentage of enrolled immunohistochemistry-selected patients in each GEP subpopulation by those patients aged (A) aged <60 years and (B) aged ≥60 years. ABC, activated B cell-like; CD10- GCB, CD10-negative GCB; GCB, germinal centre B cell-like; GEP, gene expression profiling; UNC, unclassified.

Fig S3. EFS by GEP subpopulation in both treatment arms in the ITT population by (A) ABC and (B) CD10-negative GCB subpopulations. *P values are from an exploratory analysis. ABC, activated B cell-like; CD10- GCB, CD10-negative GCB; CI, confidence interval; EFS, event-free survival; GCB, germinal centre B cell-like; GEP, gene expression profiling; HR, hazard ratio; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone.

Fig S4. EFS by GEP subpopulations in both treatment arms in patients aged <60 years by (A) ABC and (B) CD10-negative GCB subpopulations. *P values are from exploratory analysis. ABC, activated B cell-like; CD10- GCB, CD10-negative GCB; CI, confidence interval; EFS, event-free survival; GCB, germinal centre B cell-like; GEP, gene expression profiling; HR, hazard ratio; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone.

Fig S5. EFS by GEP subpopulations in both treatment arms in patients aged ≥60 years by (A) ABC and (B) CD10-negative GCB subpopulations. *P values are from an exploratory analysis. ABC, activated B cell-like; CD10- GCB, CD10-negative GCB; CI, confidence interval; EFS, event-free survival; GCB, germinal centre B cell-like; GEP, gene expression profiling; HR, hazard ratio; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone.

Fig S6. EFS probability score by quartile and treatment. EFS, event-free survival; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone.

Fig S7. OS probability score by quartile and treatment. OS, overall survival; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone.

Fig S8. PFS probability score by quartile and treatment. PFS, progression-free survival; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone.

Fig S9. HR by different HTG COO assay-derived GCB probability score cut-off. CI, confidence interval; COO, cell of origin; EFS, event-free survival; GCB, germinal centre B cell-like; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

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Volume194, Issue1

July 2021

Pages 83-91

Comparison of immunohistochemistry and gene expression profiling subtyping for diffuse large B-cell lymphoma in the phase III clinical trial of R-CHOP ± ibrutinib

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Comparison of immunohistochemistry and gene expression profiling subtyping for diffuse large B-cell lymphoma in the phase III clinical trial of R-CHOP ± ibrutinib

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