Dataset Information

Elevated REG3α predicts refractory aGVHD in patients who received steroids-ruxolitinib as first-line therapy.

ABSTRACT: We started a single-arm, phase II, open-label, prospective clinical trial using steroids-ruxolitinib as the first-line therapy for intermediate- to high-risk aGVHD (NCT04397367). Here, we report the association of a biomarker panel (sST2, REG3α, sTNFR1, IL-6 and IL-8) with responses to GVHD therapy. The novel first-line therapy for 39 patients with newly diagnosed aGVHD consisted of 1 mg/kg methylprednisolone and 5 mg/day ruxolitinib. The serum concentrations of the biomarkers were prospectively detected at planned time points. Of the 39 patients, the complete response rate at day 28 was 82.05%. In patients who achieved CR, the concentrations of REG3α (P₁₄ = 0.01; P₂₈ = 0.10) and sTNFR1 (P₁₄ = 0.42; P₂₈ = 0.04) declined at day 14 and day 28 compared with the pre-enrolment levels. In refractory patients, the levels of REG3α at day 14 were higher than those pre-enrolment (P = 0.04). REG3α (P = 0.02) was elevated in the refractory patients compared with the patients achieving CR at day 14 after enrolment, while there was no significant difference in the levels of sST2, sTNFR1 or IL-6. Elevated REG3α levels may predict refractory aGVHD after novel first-line therapy with steroids-ruxolitinib.

SUBMITTER: Yang J

PROVIDER: S-EPMC8610441 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Elevated REG3α predicts refractory aGVHD in patients who received steroids-ruxolitinib as first-line therapy.

Yang Jingjing J Peng Bo B Wang Lu L Li Xin X Li Fei F Jin Xiangshu X Jia Mingyu M Xu Lingmin L Dou Liping L Liu Daihong D

Annals of hematology 20211123 3

We started a single-arm, phase II, open-label, prospective clinical trial using steroids-ruxolitinib as the first-line therapy for intermediate- to high-risk aGVHD (NCT04397367). Here, we report the association of a biomarker panel (sST2, REG3α, sTNFR1, IL-6 and IL-8) with responses to GVHD therapy. The novel first-line therapy for 39 patients with newly diagnosed aGVHD consisted of 1 mg/kg methylprednisolone and 5 mg/day ruxolitinib. The serum concentrations of the biomarkers were prospectively ...[more]

PMID: 34816294

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Project description:ObjectiveSteroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens.MethodsLiterature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method.ResultsEight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01-1.32, P = 0.04), especially in patients with severe (grade III-IV or grade C-D) aGVHD (RR = 1.26, 95% CI = 1.04-1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05-1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy.ConclusionsAdding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487.

Project description:BackgroundGraft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation. Donor T-cells cause inflammation and tissue damage in GvHD target organs such as liver, gut and skin. Cytokine receptor associated kinases JAK1 and JAK2 are critical for inflammatory cytokine response in GvHD. Ruxolitinib is a small molecule inhibitor of JAK1 and JAK2. Preliminary data indicated substantial clinical activity in patients with steroid-refractory (SR) acute and chronic GvHD.MethodsThe RIG-study is an investigator-initiated open-label, multicenter, prospective randomized controlled two-arm phase 2 study, comparing the efficacy of ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute GvHD (SR-aGvHD). Patients with acute skin, intestinal or liver GvHD > grade 1 and failure of previous treatment are eligible. The trial aims to include 160 patients who will be randomized in a 1:1 ratio and stratified by GvHD grade (≤ grade 3 versus grade 4) and number of previous immunosuppressive treatments (≤ 3 versus ≥4). The primary endpoint is the overall response rate at day 28, defined as: Improvement of at least one stage in the severity of acute GvHD in one organ without deterioration in any other organ, or disappearance of any GvHD signs from all organs without requirement for new systemic immunosuppressive treatment. Secondary objectives include time to response, overall survival, event-free survival, non-relapse mortality (NRM), failure-free survival, graft failure rates, quality of life and changes in serum levels of pro-inflammatory cytokines and GvHD-related biomarkers.DiscussionThis randomized prospective trial will provide further evidence if the retrospectively collected data demonstrating activity of ruxolitinib for SR-aGvHD can be reproduced. A major advantage of ruxolitinib might be the limited and predictable toxicity profile compared to other immunosuppressive therapies that mainly includes viral reactivation and cytopenias. This trial will establish candidate biomarkers to predict and monitor responses to ruxolitinib. As a next step ruxolitinib might be tested upfront against steroids or in a preemptive manner to prevent GvHD to occur.Trial registrationNCT02396628 (registration date 17.07.2015); DRKS00007939 (registration date 26.03.2015).

Project description:BackgroundThe therapeutic landscape for advanced urothelial carcinoma (mUC) has changed significantly since studies establishing superiority of cisplatin as first-line therapy were conducted. Most patients who are eligible now receive either maintenance or second-line immune checkpoint inhibitors (ICI) and data comparing first-line platinum chemotherapy agents in this setting is limited.Patients and methodsThe objective of this study was to determine the impact of first-line platinum chemotherapy agent on survival for patients who receive second-line ICI. This is a retrospective cohort study of real-world data, performed from January 1, 2015, to March 21, 2021, included patients with a diagnosis of metastatic or locally advanced urothelial carcinoma. Exposure of interest was first-line platinum-doublet chemotherapy (gemcitabine and/or cisplatin or gemcitabine and/or carboplatin) followed by single-agent second-line ICI. The primary endpoint was overall survival from start of second-line therapy.Results2,042 patients received either gemcitabine and cisplatin (gem/cis) or gemcitabine and carboplatin (gem/carbo) as first-line therapy. The primary analysis of 890 patients who received second-line single-agent ICI had a median follow-up was 24.2 months from initiation of second-line therapy. Important differences in baseline demographics and/or clinical factors between groups were age, performance status, incidence of upper tract disease, and cisplatin eligibility. Unadjusted overall survival (OS) calculated from start of second-line therapy was longer in patients who received gem/cis compared to gem/carbo followed by ICI (median 9.3 vs. 8.8 months, P = 0.0009). However, OS adjusted for covariates was not significantly different with a hazard ratio (HR) of 0.94 (95% CI, 0.79-1.13; P = 0.50). A separate time-varying covariate model also showed no association between OS and first-line gem/cis (HR 1.00 [95% CI, 0.84-1.19]) while receiving second-line ICI.ConclusionsSurvival time on ICI in the second-line setting is the same regardless of choice of prior platinum agent (cisplatin vs. carboplatin) suggesting against specific synergy for one of these agents with ICI. However, a significantly greater proportion of patients in a landmark analysis had long-term benefit with cisplatin strongly supporting it is as the preferred first-line platinum agent.

Dataset Information

Elevated REG3α predicts refractory aGVHD in patients who received steroids-ruxolitinib as first-line therapy.

Publications

Elevated REG3α predicts refractory aGVHD in patients who received steroids-ruxolitinib as first-line therapy.

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