Janus Kinase (JAK) 1 Inhibition Results in Significant Changes in Serum Proteins and Peripheral T-Cell Populations That Correlated with Clinical Scores in Chronic Graft Versus Host Disease (GVHD) Patients (an Analysis from GRAVITAS-309)
Bibliographic record
Abstract
Background: Chronic GVHD (cGVHD) occurs in 30-70% of allogeneic hematopoietic cell transplantation patients, and the rate has increased over the past 2 decades. Based on the degree of organ involvement, cGVHD is classified as mild, moderate, or severe. Standard treatment includes systemic corticosteroids (CS), together with immunosuppressive agents. GRAVITAS-309 (NCT03584516) was designed as a 2-part, multicenter, randomized trial to assess efficacy and safety of itacitinib, an orally bioavailable, selective JAK1 inhibitor, in combination with CS as first-line treatment for moderate to severe cGVHD. The dose-finding, open-label, randomized portion of the study initially investigated itacitinib at 200 mg once daily (qd) and 300 mg qd in combination with CS (methylprednisolone or prednisone); both doses were well tolerated. The trial was expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300 mg qd cohort was expanded and a CS monotherapy cohort was added. Results from the expanded portion of the study (n=139 patients) showed improved overall response rate (ORR) at 6 months in patients treated with itacitinib + CS vs CS alone (Im, et al. Blood 2022;140[Suppl 1]:1870). Here, we analyzed samples collected from patients in 4 cohorts (cohort A [300 mg qd], cohort B [400 mg qd], cohort C [300 mg bid], and cohort D [CS alone]) for systemic proteins and immune cell populations, to support investigation into the itacitinib mechanism of action and to correlate with clinical outcomes. Methods: Peripheral blood mononuclear cells (PBMCs) and serum were collected before treatment (baseline, day 1), and day 7, day 14 (PBMCs only), and day 28 following treatment initiation. Serum proteins were analyzed using the OLINK Target 96 platform, and circulating T-cell subsets were measured using flow cytometry of PBMCs and presented as a percentage of parent population. Samples were assessed irrespective of patients' response. Most of the patients (70-100% per cohort) with samples available for analysis were responders (achieved complete or partial responses). Results: Serum levels of proteins, including several proposed as potential prognostic cGVHD biomarkers, changed significantly at day 28 relative to baseline following treatment with itacitinib (Table 1). Levels of elafin, a marker of acute GVHD of the skin, were significantly reduced and levels of dickkopf-3 (DKK3), a marker of sclerotic and nonsclerotic cGVHD, were significantly increased in itacitinib cohorts only. Based on a repeated measures correlation analysis, both markers significantly correlated with overall clinical skin scores (elafin: r=+0.43; DKK3: r=-0.53; both P<0.001). Serum levels of other reported markers of cGVHD, including osteopontin, C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, were significantly decreased exclusively in itacitinib-treated cohorts, and not in the CS only cohort. Some proteins, including matrix metalloproteinase (MMP) 3, increased in all cohorts, suggesting that changes in these proteins cannot be attributed to itacitinib alone, but may reflect response to CS; other proteins, such as suppression of tumorigenicity (ST2), remained unchanged in response to treatment in all cohorts. CS treatment alone resulted in an increase in naive CD4 T cells (CD4 +CD8 ->CD45RA +CCR7 -) and a corresponding reduction of CD4 effector memory T cells (CD4 +CD8 ->CD45RA -CCR7 +) within 28 days (Figure 1, cohort D). Changes in naive CD4 T cells following CS monotherapy were significantly attenuated by itacitinib ( P<0.05 vs CS at day 28), particularly at the 400 mg qd dose (Figure 1, cohort B), which demonstrated the best ORR at 6 months (53% with 400 mg qd vs 36% with CS). Conclusions: Analysis of patient samples from GRAVITAS-309 revealed that serum elafin and DKK3 levels significantly correlated with skin GVHD scores, possibly reflecting the systemic origin of observed skin manifestations. Serum levels of osteopontin, CXCL9, and CXCL10 were specifically reduced by itacitinib in patients with cGVHD and may represent potential pharmacodynamic markers. Observed changes in different peripheral T-cell populations in patients' samples following itacitinib treatment were consistent with those reported in murine GVHD models, suggesting a potential role of naive CD4 + T cells in driving this disease. Planned future analyses will include identification of novel biomarkers that correlate with organ involvement.
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".