ST2 as a Marker for Risk of Therapy-Resistant Graft-versus-Host Disease and Death
ABSTRACT No plasma biomarkers are associated with the response of acute graft-versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation.
We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation.
Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen.
ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation. (Funded by the National Institutes of Health.)
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ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective form of tumor immunotherapy available to date and the frequency of transplants continues to increase worldwide. However, while allo-HSCT usually induces a beneficial graft-versus-leukemia effect, a major source of morbidity and mortality following allo-HSCT is graft-versus-host disease (GVHD). Currently available diagnostic and staging tools frequently fail to identify those at higher risk for GVHD morbidity, treatment unresponsiveness, and death. Furthermore, there are shortcomings in the risk stratification of patients before GVHD clinical signs develop. In parallel, recent years have been characterized by an explosive evolution of omics technologies, largely due to technological advancements in chemistry, engineering, and bioinformatics. Building on these opportunities, plasma biomarkers have been identified and validated as promising diagnostic and prognostic tools for acute GVHD. This review summarizes current information on the types of GVHD biomarkers, the omics tools used to identify them, the biomarkers currently validated as acute GVHD markers, and future recommendations for incorporating biomarkers into new grading algorithms for risk-stratifying patients and creating more personalized treatment courses. Future directions will include randomized evaluations of these biomarkers in multicenter prospective studies while extending on the need for biomarkers of chronic GVHD.International journal of hematology 08/2013; 98(3). DOI:10.1007/s12185-013-1406-9
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ABSTRACT: Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 family includes seven ligands with agonist activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38), and an anti-inflammatory cytokine (IL-37). Members of the IL-1 Receptor (IL-1R) family include six receptor chains forming four signaling receptor complexes, two decoy receptors (IL-1R2, IL-18BP), and two negative regulators (TIR8 or SIGIRR, IL-1RAcPb). A tight regulation via receptor antagonists, decoy receptors, and signaling inhibitors ensures a balance between amplification of innate immunity and uncontrolled inflammation. All cells of the innate immune system express and/or are affected by IL-1 family members. Moreover, IL-1 family members play a key role in the differentiation and function of polarized innate and adaptive lymphoid cells. Here we will review the key properties of IL-1 family members, with emphasis on pathways of negative regulation and orchestration of innate and adaptive immunity.Immunity 12/2013; 39(6):1003-1018. DOI:10.1016/j.immuni.2013.11.010
- Biomarkers in Medicine 01/2014; 8(1):65-8. DOI:10.2217/bmm.13.113