Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab
Bibliographic record
Abstract
BACKGROUND: The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximab-failure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes. METHODS: Genotypes for KIR/KIR-ligand were determined and assessed for associations with outcome [duration of response, TTRF and % tumor shrinkage] as a post-hoc analysis of this phase III trial. Our primary objective was to assess specific KIR/KIR-ligand genotype associations, followed by separate prespecified KIR/KIR-ligand genotype associations in follow-up analyses. Statistical analyses for association of genotype with clinical outcome included: Log-rank tests and Cox proportional hazards regression models to assess duration of response and TTRF; analysis of variance (ANOVA) was used for assessment of % tumor shrinkage. RESULTS: We found that patients inheriting KIR2DL2 and its ligand (HLA-C1) along with KIR3DL1 and its ligand (HLA-Bw4) had improved outcome over patients without this genotype. In addition, patients with KIR2DL2 and HLA-C1 along with KIR3DL1 and HLA-Bw4 also showed improved duration of response and tumor shrinkage if they received maintenance, while patients without this genotype showed no such improvement when receiving maintenance. CONCLUSIONS: The data presented here indicate that a subset of FL patients, identified by certain KIRs/KIR-ligands, have improved outcome and may benefit from additional rituximab treatment. Taken together, this suggests that the efficacy of tumor-reactive mAb treatment for some patients is influenced by KIRs on NK cells. However, prior to considering these genotypes in a clinically-actionable manner, these findings need independent validation in other studies.
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How this classification was reachedexpand
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) | 0.000 | 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) | 0.000 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".