Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

Zaid, Mohammad Abu; Wu, Juan; Wu, Chenwei; Logan, Brent R.; Yu, Jeffrey; Cutler, Corey; Antin, Joseph H.; Paczesny, Sophie; Choi, Sung Won

doi:10.1182/blood-2016-08-735324

Cited by 74 publications

(59 citation statements)

References 31 publications

(63 reference statements)

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“…3,15–17,19,20 A study of cord blood recipients at day 28 after transplantation showed that ST2 was predictive of transplant-related mortality and grade 3–4 GVHD. 17 In another analysis of day 28 samples, ST2 and TIM3 were significantly associated with non-relapse mortality at 2 years.…”

Section: Discussionmentioning

confidence: 99%

“…17 In another analysis of day 28 samples, ST2 and TIM3 were significantly associated with non-relapse mortality at 2 years. 19 Analysis of plasma sTNFR1, Reg3α, and ST2 at GVHD diagnosis led to an algorithm that predicted NRM 6 months later. 3,32 In another study, serum levels of the inflammatory biomarkers B-cell activating factor, IL33, and C-X-C Motif Chemokine Ligands (CXCL) 10 and 11 were elevated in patients with acute GVHD, but were not compared to other cytokine/chemokine panels.…”

Section: Discussionmentioning

confidence: 99%

“…2,12 Several studies have tested the hypothesis that plasma biomarkers measured at GVHD onset or at a set time after transplant can predict whether GVHD is likely to respond to initial treatment or not. 3,15–19 We recently reported a study of plasma biomarkers measured before the clinical onset of acute GVHD. 20 A panel of IL6, TIM3, and sTNFR1 was associated with subsequent peak grade 3–4 GVHD and a panel of ST2 and sTNFR1 was associated with non-relapse mortality at one year.…”

Section: Introductionmentioning

confidence: 99%

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Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease

McDonald

Tabellini

Storer

et al. 2017

Biology of Blood and Marrow Transplantation

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We examined the hypothesis that plasma biomarkers and concomitant clinical findings after initial glucocorticoid therapy can accurately predict failure of graft-versus-host-disease treatment and mortality. We analyzed plasma samples and clinical data in 165 patients after 14 days of glucocorticoid therapy and used logistic regression and areas under receiver-operating characteristic curves (AUC) to evaluate associations with treatment failure and non-relapse mortality (NRM). Initial treatment of GVHD was unsuccessful in 49 patients (30%). For predicting GVHD treatment failure, the best clinical combination (total serum bilirubin and skin GVHD stage, AUC 0.70) was competitive with the best biomarker combination (TIM3 and ST2, AUC 0.73). The combination of clinical features and biomarker results offered only a slight improvement (AUC 0.75). For predicting NRM at 1 year, the best clinical predictor (total serum bilirubin, AUC 0.81) was competitive with the best biomarker combination (TIM3 and sTNFR1, AUC 0.85). The combination offered no improvement (AUC 0.85). Infection was the proximate cause of death in virtually all patients. We conclude that after 14 days of glucocorticoid therapy, clinical findings (serum bilirubin, skin GVHD) and plasma biomarkers (TIM3, ST2, sTNFR1) can predict failure of GVHD treatment and non-relapse mortality. These biomarkers reflect counter-regulatory mechanisms and provide insight into the pathophysiology of GVHD reactions following glucocorticoid treatment. The best predictive models, however, exhibit inadequate positive predictive values for identifying high-risk GVHD cohorts for investigational trials, as only a minority of patients with high-risk GVHD would be identified, and most patients would be falsely predicted to have adverse outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease

McDonald

Tabellini

Storer

et al. 2017

Biology of Blood and Marrow Transplantation

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“…In smaller studies, high serum concentrations of TIM3, an activation marker on CD4 + T cells that regu lates macrophage function, have been shown to predict the development of severe GVHD, and high levels of ST2 and TIM3 have been correlated with 2-year NRM and overall survival in patients with GVHD 52,53 .…”

Section: Diagnosismentioning

confidence: 99%

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

Naymagon

Wong

et al. 2017

Nat Rev Gastroenterol Hepatol

113

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Haematopoietic stem cell transplantation (HSCT) is central to the management of many haematological disorders. A frequent complication of HSCT is acute graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack healthy recipient tissues. The gastrointestinal system is among the most common sites affected by acute GVHD, and severe manifestations of acute GVHD of the gut portends a poor prognosis in patients after HSCT. Acute GVHD of the gastrointestinal tract presents both diagnostic and therapeutic challenges. Although the clinical manifestations are nonspecific and overlap with those of infection and drug toxicity, diagnosis is ultimately based on clinical criteria. As reliable serum biomarkers have not yet been validated outside of clinical trials, endoscopic and histopathological evaluation continue to be utilized in diagnosis. Once a diagnosis of gastrointestinal acute GVHD is established, therapy with systemic corticosteroids is typically initiated, and non-responders can be treated with a wide range of second-line therapies. In addition to treating the underlying disease, the management of complications including profuse diarrhoea, severe malnutrition and gastrointestinal bleeding is paramount. In this Review, we discuss strategies for the diagnosis and management of acute GVHD of the gastrointestinal tract as they pertain to the practising gastroenterologist.

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“…More specifically, increased CXCL9 levels correlated with increased cGVHD severity [23]. Elevated CXCL9 was associated with cGVHD in four other studies [41,45–47]. Using a quantitative proteomics approach, iTRAQ, in a cohort of 53 patients, CXCL9 along with 3 other biomarkers were found to be increased in cGVHD patient’s plasma compared to the non-GVHD.…”

Section: Useful Cgvhd Biomarkersmentioning

confidence: 99%

The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease

Ren

Adom

Paczesny

2018

Expert Review of Clinical Immunology

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Introduction Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an increasingly applied curative method for both benign and malignant hematologic disorders. Biomarker identification is crucial for the development of noninvasive and cost-effective cGVHD diagnostic, prognostic, and predictive test for use in clinic. Furthermore, biomarkers may help to gain a better insight on ongoing pathophysiological processes. The recent widespread application of omics technologies including genomics, transcriptomics, proteomics and cytomics provided opportunities to discover novel biomarkers. Areas covered This review focuses on biomarkers identified through omics that play a critical role in target identification for drug development, and that were verified in at least two independent cohorts. It also summarizes the current status on omics tools used to identify these useful cGVHD targets. We briefly list the biomarkers identified and verified so far. We further address challenges associated to their exploitation and application in the management of cGVHD patients. Finally, insights on biomarkers that are drug targetable and represent potential therapeutic targets are discussed. Expert commentary We focus on biomarkers that play an essential role in target identification.

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Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

Cited by 74 publications

References 31 publications

Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease

Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease

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