Biomarker analysis of patients with follicular lymphoma treated with ibrutinib in the phase 2 <scp>DAWN</scp> study
Bibliographic record
Abstract
Background: Ibrutinib (ibr), a first-in-class, oral, covalent Bruton's tyrosine kinase inhibitor, is approved for and has demonstrated robust activity in various B-cell non-Hodgkin lymphomas. The DAWN study (FLR2002, NCT01779791) investigated the efficacy and safety of single-agent ibr in chemoimmunotherapy (CIT)-refractory follicular lymphoma (FL) patients (pts). Ibr may modulate T-cell activity via inhibition of interleukin-2-inducible T-cell kinase by activating T-helper 1 (Th1) cells (Dubovsky, et al. Blood 2013). We describe the effect of ibr treatment on T-cells and cytokines in pts in the DAWN study. Methods: This was a multicenter, single-arm, phase 2 study of ibr in FL pts with ≥2 prior lines of therapy and progressive disease (PD) ≤ 12 months after CIT regimen. Pts received ibr (560 mg QD) on a 21-day cycle until PD or toxicity. A protocol amendment allowed continued ibr treatment in clinically stable/improving pts with radiological evidence of PD (new lesion/increase ≥50%) to account for “pseudo-PD”. The primary end point was the overall response rate (ORR) (complete response [CR] + partial response). Flow cytometry assessed T-cell subsets in peripheral blood at baseline (C1D1) and at cycle 3 (C3D1) for 57 pts (14 responders, 43 nonresponders); cytokine and chemokine analyses were performed at C1D1 and at cycle 2 (C2D1) for 50 pts (21 responders, 29 nonresponders). Results: The DAWN study results have been presented (Gopal A, et al. ASH 2016); ibr achieved an ORR of 20.9% (CR rate, 10.9%). Flow cytometry analysis revealed CD4 + CD25 + CD127− Tregs were downregulated at C3D1 in responders (CR + PR, mean decrease 17 to 12.9% CD4, p = 0.02) but not in nonresponders (11.5 to 10.4% CD4, p = 0.17). There were no differences between responders and nonresponders in a large panel of inflammation-related cytokines and chemokines at C1D1, confirmed by gene expression profiling in the tumor. After 21 days, Th1 cytokines interferon (IFN)-γ and interleukin (IL)-12 were increased in responders but decreased in nonresponders (p = 0.0025 and p = 0.035, respectively; Figure). The chemokines IFN-γ-induced protein 10 and monocyte-chemotactic protein 3 were decreased in responders but increased in nonresponders (p = 0.022 and 0.016, respectively). Available data in pseudo-PD pts showed a similar trend of decreased Tregs at C3D1 as responders, but the cytokines showed a similar trend as nonresponders. Keywords: follicular lymphoma (FL); ibrutinib; immunomodulators (IMIDs)
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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 | 0.001 | 0.001 |
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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".