The MAGIC algorithm probability is a validated response biomarker of treatment of acute graft-versus-host disease

Srinagesh, Hrishikesh K.; Özbek, Umut; Kapoor, Urvi; Ayuk, Francis; Aziz, Mina; Ben-David, Kaitlyn; Choe, Hannah; DeFilipp, Zachariah; Etra, Aaron; Grupp, Stephan A.; Hartwell, Matthew J.; Hexner, Elizabeth O.; Hogan, William J.; Karol, Alexander B.; Kasikis, Stelios; Kitko, Carrie L.; Kowalyk, Steven; Lin, Jung Yi; Major-Monfried, Hannah; Mielke, Stephan; Merli, Pietro; Morales, George; Ordemann, Rainer; Pulsipher, Michael A.; Qayed, Muna; Reddy, Pavan; Reshef, Ran; Rösler, Wolf; Sandhu, Karamjeet S.; Schechter, Tal; Shah, Jay; Sigel, Keith; Weber, Daniela; Wölfl, Matthias; Wudhikarn, Kitsada; Young, Rachel; Levine, John E.; Ferrara, James L.M.

doi:10.1182/bloodadvances.2019000791

Cited by 71 publications

(56 citation statements)

References 27 publications

(49 reference statements)

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“…Because of the number of variables impacting the development of GVHD in clinical settings, there is a significant need to identify prognostic indicators of GVHD risk before the onset of pathology. Studies to date have predominantly focused on plasma biomarkers, with ST2 and REG3a both rigorously validated as indicators of GVHD severity, probability of nonrelapse mortality, and steroid-refractory GVHD (34,35). Additionally, the recovery of microbial diversity or lack thereof after transplant is a biomarker of GVHD development that is currently gaining traction (36).…”

Section: Discussionmentioning

confidence: 99%

Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation

Hess

Hudson

Hematti

et al. 2020

The Journal of Immunology

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Acute graft-versus-host disease (GVHD) is a frequent complication of hematopoietic transplantation, yet patient risk stratification remains difficult, and prognostic biomarkers to guide early clinical interventions are lacking. We developed an approach to evaluate the potential of human T cells from hematopoietic grafts to produce GVHD. Nonconditioned NBSGW mice transplanted with titrated doses of human bone marrow developed GVHD that was characterized by widespread lymphocyte infiltration and organ pathology. Interestingly, GVHD was not an inevitable outcome in our system and was influenced by transplant dose, inflammatory status of the host, and type of graft. Mice that went on to develop GVHD showed signs of rapid proliferation in the human T cell population during the first 1-3 wk posttransplant and had elevated human IFN-g in plasma that correlated negatively with the expansion of the human hematopoietic compartment. Furthermore, these early T cell activation metrics were predictive of GVHD onset 3-6 wk before phenotypic pathology. These results reveal an early window of susceptibility for pathological T cell activation following hematopoietic transplantation that is not simply determined by transient inflammation resulting from conditioning-associated damage and show that T cell parameters during this window can serve as prognostic biomarkers for risk of later GVHD development.

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Section: Discussionmentioning

confidence: 99%

Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation

Hess

Hudson

Hematti

et al. 2020

The Journal of Immunology

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“…The second is the degree of host damage which is also associated with a more myeloablative conditioning ( 12 ). This is highlighted by the MAGIC consortium that have used the serum biomarkers sST2 and REG3α, both released by damage host cells, as predictors of non-relapse mortality (NRM) and SR-GVHD ( 73 , 74 ). In addition to sST2 and REG3α, necrotic and pyroptotic (two inflammatory forms of cell death) host cells release a variety of damage-associated-molecular-patterns (DAMPs) that activate the innate immune response (e.g.…”

Section: Extracellular Messengers: Signalmentioning

confidence: 99%

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

2021

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Graft-vs-host disease (GVHD) is the most common cause of non-relapse mortality following allogeneic hematopoietic stem cell transplantation (HSCT) despite advances in conditioning regimens, HLA genotyping and immune suppression. While murine studies have yielded important insights into the cellular responses of GVHD, differences between murine and human biology has hindered the translation of novel therapies into the clinic. Recently, the field has expanded the ability to investigate primary human T cell responses through the transplantation of human T cells into immunodeficient mice. These xenogeneic HSCT models benefit from the human T cell receptors, CD4 and CD8 proteins having cross-reactivity to murine MHC in addition to several cytokines and co-stimulatory proteins. This has allowed for the direct assessment of key factors in GVHD pathogenesis to be investigated prior to entering clinical trials. In this review, we will summarize the current state of clinical GVHD research and discuss how xenogeneic HSCT models will aid in advancing the current pipeline of novel GVHD prophylaxis therapies into the clinic.

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“…Recent studies suggest that the measurement of REG3α and ST2 in haplo HCT may be associated with a higher incidence of GVHD and NRM ( 99 , 100 ). Moreover, MAGIC predictive algorithm not only is prognostic for NMR and overall survival, but it can be used as response biomarker for acute GVHD treatment ( 108 ).…”

Section: Biomarkers Of Endothelial Activation and Damagementioning

confidence: 99%

Biomarkers for Early Complications of Endothelial Origin After Allogeneic Hematopoietic Stem Cell Transplantation: Do They Have a Potential Clinical Role?

et al. 2021

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Endothelial cell (EC) dysfunction causes a number of early and life-threatening post hematopoietic stem cell transplant (HCT) complications that result in a rapid clinical decline. The main early complications are graft-vs.-host disease (GVHD), transplant associated thrombotic microangiopathy (TA-TMA), and sinusoidal obstruction syndrome (SOS). Post-HCT endothelial dysfunction occurs as a result of chemotherapy, infections, and allogeneic reactivity. Despite major advances in transplant immunology and improvements in supportive care medicine, these complications represent a major obstacle for successful HCT. In recent years, different biomarkers have been investigated for early detection of post-transplant endothelial cell dysfunction, but few have been validated. In this review we will define GVHD, TA-TMA and SOS, summarize the current data available in HCT biomarker research and identify promising biomarkers for detection and diagnosis of early HCT complications.

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The MAGIC algorithm probability is a validated response biomarker of treatment of acute graft-versus-host disease

Abstract: Key Points The MAGIC algorithm probability, computed from 2 serum biomarkers, predicts mortality in all GVHD grades after 4 weeks of treatment. Dynamic changes in the MAGIC algorithm probability occur within all biomarker risk groups and can guide therapy.

Cited by 71 publications

References 27 publications

Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation

Early T Cell Activation Metrics Predict Graft-versus-Host Disease in a Humanized Mouse Model of Hematopoietic Stem Cell Transplantation

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

Biomarkers for Early Complications of Endothelial Origin After Allogeneic Hematopoietic Stem Cell Transplantation: Do They Have a Potential Clinical Role?

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