CD20 Is an Unstable Target in Primary-Refractory High-Grade Lymphomas
Bibliographic record
Abstract
Introduction: A third of patients with diffuse large B cell lymphoma (DLBCL) are not cured with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP). Approximately 20% of DLBCLs will lose CD20-protein expression (CD20-neg) at the time of relapse. The incidence of CD20-neg relapses in other aggressive B cell lymphomas is unknown. CD20 is not only targeted by rituximab but other antibody-based therapies that are being investigated in salvage regimens. We hypothesized that prolonged exposure to anti-CD20 containing regimens may lead a CD20-neg relapse. Our goal was to determine the clinical and genetic factors associated with loss of CD20 expression in high-grade lymphomas treated with curative intent. Method: We consented 374 patients with B cell high-grade lymphomas that were treated with RCHOP or more intensive regimens at the time of diagnosis or had a histological transformation from a prior indolent lymphoma (TLy). We recorded the baseline clinical characteristics, histological diagnosis, date of first relapse and the number of treatment regimens prior to their second biopsy. CD20 expression and cell of origin (COO) were determined by immunohistochemistry and, in the latter, using Hans criteria. We performed targeted sequencing of 63 lymphoma-related genes, including MS4A1, the gene that encodes CD20. Sequencing was performed using circulating tumor DNA in the plasma or DNA from the tumor biopsy, both obtained at the time of relapse. Results: Relapse occurred in 170/374 (45%) of patients: 102/253 DLBCL, 55/96 TLy, 6/16 primary mediastinal B cell lymphoma (PMBCL) and 7/9 high grade B cell lymphomas (HGBL) with or without translocations in MYC and BCL2 or BCL6. The median age at diagnosis was 62 years old, 54% were male and 85% had an elevated international prognostic index of ≥ 2. Of these, 104 had a biopsy taken at first (47%) or subsequent relapse (53%) to confirm the diagnosis or performed in the context of a clinical trial. CD20 could be assessed in 100 cases, of which 26 had CD20-neg lymphoma cells: 15/56 (27%) of DLBCL, 7/38 (18%) of TLy, 2/3 (66%) PMBCL and 2/3 (66%) HGBL. Relapsed PMBCL and HGBL combined, appeared to have an increased risk of CD20 negativity at relapse compared to DLBCL and TLy (p=0.043). A GCB phenotype in DLBCL was present in 35% of cases and was not associated with CD20 status. The mean number of therapies given before the second biopsy was similar in both groups (CD20+ = 2.2 and CD20-neg = 2.7, p=0.2). In fact, 11/26 (44%) of CD20-neg cases had biopsies taken after RCHOP alone. Additional chemo-immunotherapy (range 2 to 8) did not increase the risk of having a CD20-neg relapse (p=0.5), suggesting that unlike follicular lymphoma, the emergence of CD20-neg cells occurs early after rituximab exposure in high-grade lymphomas. Supporting this hypothesis, patients with a CD20-neg relapse had a shorter progressive free survival (PFS) after RCHOP (1,7 vs 3,2 years, p=0.025). Patients with primary treatment failure, defined here as a PFS of < 1 year, had a significantly increased risk of having a CD20-neg relapse (hazard ratio 7.9, p= 0.005). Sequencing was performed in 75/100 patients. MS4A1 mutations were present in 16% of CD20-neg cases, while none were present in the CD20+ cases (p=0.003). There was no significant difference in the mutation rate of TP53 (47%) or histone-modifying genes based on CD20 expression status. Conclusion: Decreased CD20 expression occurs early in high-grade lymphomas under the selective pressure of RCHOP, 16% of which are a consequence of MS4A1 mutations, suggesting that other mechanisms also modulate CD20 expression. In patients with a PFS of < 1 year, a repeat biopsy would be recommended if primary anti-CD20-targeted therapy is considered. Disclosures Assouline: F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Johnson:Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; BMS: Consultancy, Honoraria; Merck: Consultancy, Honoraria; BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Seattle Genetics: Honoraria; Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.002 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".