Abstract PO-26: Prognostic significance of Fc gamma receptor IIB expression in the response of previously untreated diffuse large B-cell lymphomas to anti-CD20 monoclonal antibodies: Differing impact of rituximab and obinutuzumab
Why this work is in the frame
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Bibliographic record
Abstract
Abstract Background: The anti-CD20 monoclonal antibody (mAb), obinutuzumab (G), has shown improved outcomes versus rituximab (R) in indolent lymphomas; however, no improvement was seen in diffuse large B-cell lymphoma (DLBCL), and the molecular basis is unclear. The inhibitory Fc gamma receptor IIB (Fc γRIIB), expressed on lymphoma cells, can impair the effects of direct targeting mAbs, such as R, by binding and internalizing them, reducing opsonization and limiting FcγR-mediated killing. We hypothesized that FcγRIIB expression on cellular effectors and/or the lymphoma confers treatment resistance in some patients (pts) and evaluated if outcomes differ for therapies involving a non-internalized mAb (G). Methods: We evaluated correlates between FCGR2B mRNA and/or FcγRIIB protein expression and pt outcomes in two discovery cohorts of de novo DLBCL treated with R-CHOP (Arthur et al. 2018, n=372; Schmitz et al. 2018, n=234), and the phase III GOYA trial (NCT01287741; n=552), which compared R-CHOP with G-CHOP in pts with previously untreated DLBCL. FCGR2B mRNA expression was assessed by RNA-Seq, and protein expression was assessed in evaluable cohorts by immunohistochemistry, using tissue microarrays with macrophages identified by CD68. FCGR2B expression was also measured by a NanoString assay (Arthur cohort). Cox regression analyzed the impact of FcγRIIB/FCGR2B expression on progression-free survival (PFS), with univariate and multivariate models adjusted for International Prognostic Index (IPI), cell of origin (COO), and BCL2 protein expression. Results: In the discovery cohorts, a higher FCGR2B expression was significantly associated with shorter PFS (Arthur: HR 1.09 [95% CI: 1.01–1.19], P=0.036; Schmitz: HR 1.13 [95% CI: 1.02–1.26], P=0.0243). Expression by NanoString strongly correlated with RNA-Seq, confirming the association with shorter PFS (HR 1.13 [95% CI: 1.04–1.23], P=0.0048). In GOYA, a significant association between PFS and FCGR2B was observed in the R arm (HR 1.26 [95% CI: 1.00–1.58], P=0.0455), with no prognostic effect observed for G (HR 0.91 [95% CI: 0.69–1.20], P=0.5). Pts with high FCGR2B expression appeared to benefit more from G than R (HR 0.67 [95% CI: 0.44–1.02], P=0.0622), in contrast to pts with low FCGR2B expression (HR 1.58 [95% CI: 1.00–2.50], P=0.0503). In both Arthur and GOYA cohorts, FCGR2B expression by RNA-Seq was associated with FcγRIIB on the tumor, which correlated with a shorter PFS for R (HR 2.17 [95% CI: 1.04–4.50], P=0.03), but not G (HR 1.37 [95% CI: 0.66–2.87], P=0.4). This prognostic effect on PFS was independent of established prognostic biomarkers, IPI, COO and BCL2. Conclusion: High FcγRIIB/FCGR2B expression in pts with DLBCL has prognostic value in those treated with R and may confer differential responsiveness to R or G. Citation Format: Laura K. Hilton, Malgorzata Nowicka, Margaret Ashton-Key, Chantal E. Hargreaves, Chern Lee, Russell Foxall, Matthew J. Carter, Stephen A. Beers, Kathleen N. Potter, Christopher R. Bolen, Christian Klein, Andrea Knapp, Farheen Mir, Matthew Rose-Zerilli, Cathy Burton, Wolfram Klapper, David W. Scott, Laurie H. Sehn, Umberto Vitolo, Maurizio Martelli, Marek Trneny, Graham W. Slack, Pedro Farinha, Jonathan C. Strefford, Mikkel Z. Oestergaard, Ryan D. Morin, Mark S. Cragg. Prognostic significance of Fc gamma receptor IIB expression in the response of previously untreated diffuse large B-cell lymphomas to anti-CD20 monoclonal antibodies: Differing impact of rituximab and obinutuzumab [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-26.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it