Current Definitions and Clinical Implications of Biomarkers in Graft-versus-Host Disease

Bidgoli, Alan; DePriest, Brittany Paige; Saatloo, Maedeh Vakili; Jiang, Hua; Fu, Denggang; Paczesny, Sophie

doi:10.1016/j.jtct.2022.07.008

Cited by 16 publications

(13 citation statements)

References 72 publications

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“…General markers of inflammation such as CRP and ferritin could be used, although would in general reflect unspecified inflammatory conditions [ 44 , 45 ]. New biomarkers are entering the research fields of cGVHD [ 46 , 47 ], although if they have a diagnostic or prognostic impact in musculoskeletal cGVHD remains unanswered.…”

Section: Discussionmentioning

confidence: 99%

Musculoskeletal Chronic Graft versus Host Disease—A Rare Complication to Allogeneic Hematopoietic Stem Cell Transplant: A Case-Based Report and Review of the Literature

et al. 2022

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Musculoskeletal graft versus host disease (GVHD) is a rare manifestation of chronic GVHD (cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Left untreated, the disease can cause extensive damage to muscle tissue and joints. We describe a 62-year-old male with musculoskeletal GVHD and generalized muscle pain and stiffness. In addition, we performed a systemic literature review based on published cases of musculoskeletal GVHD between 1983 and 2019. We identified 85 cases, 62% male and 38% female with an age of 4–69 years and median age of 39 years at diagnosis. The majority of patients (72%) also had manifestations of cGVHD in at least one other organ system, most frequently the skin (52%), followed by oropharyngeal mucosa (37%), and pulmonary and gastrointestinal tract (GI tract) (21%). We conclude that, while musculoskeletal cGVHD is a rare complication of allo-HSCT, it remains a serious and debilitating risk that must be considered in patients with muscle pain, muscle weakness, joint stiffness, and tissue inflammation. Early intervention is critical for the patient’s prognosis.

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Section: Discussionmentioning

confidence: 99%

Musculoskeletal Chronic Graft versus Host Disease—A Rare Complication to Allogeneic Hematopoietic Stem Cell Transplant: A Case-Based Report and Review of the Literature

et al. 2022

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“…Risk biomarkers detect the potential for disease in patients without a clinically evident disease. Prognostic biomarkers determine the anticipated disease course in patients with clinically evident disease ( 27 ).…”

Section: Methodsmentioning

confidence: 99%

A systematic review of diagnostic, prognostic, and risk blood and urine biomarkers of transplant-associated thrombotic microangiopathy

2023

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Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of allogeneic and autologous hematopoietic cellular therapy (HCT), associated with significant morbidity and mortality. Although the central drivers of the disease are thought to be endothelial damage and complement activation, no specific diagnostic biomarkers have been identified. TA-TMA is typically diagnosed using criteria comprised of non-specific clinical and laboratory features. Some patients will have a self-remitting course, but more than half develop multi-organ dysfunction or die, making prognostic biomarkers critical. Prevention of TA-TMA, an approach central to other HCT complications such as graft-versus-host disease, is largely untested in part due to a lack of identified early high-risk biomarkers. We conducted a systematic review to summarize the diagnostic, early risk, and prognostic biomarkers of TA-TMA. We screened the titles and abstracts of 1524 citations. After screening out duplications, we read the abstracts of 979 papers and fully reviewed 132 full-text publications. Thirty-one publications fulfilled the inclusion criteria of more than five patients with TA-TMA and a reported measure of association with diagnosis, prognosis, or risk of later development of the disease. Fourteen studies (45%) were with adults, 12 (39%) were with children <18 years old, three included both children and adults, and two did not report age. There were 53 biomarker or biomarker signature entries, and a total of 27 unique biomarkers. Only four biomarkers reported sensitivity and specificity. The single biomarker with the most robust data was sC5b-9, which conferred diagnostic, prognostic, and risk implications. Studies of combinations of biomarkers were rare. No meta-analyses were performed because of significant heterogeneity between studies. The limitations of studies included small sample size, study designs with a high risk of bias (i.e., case–control), the timing of sample collection, and the selection of controls. Furthermore, only two (6%) studies included a training and validation cohort. Cut-off points are needed to stratify groups, as most biomarkers do not have normal values, or normal values cannot be assumed in the HCT setting. In the future, multi-institutional, collaborative efforts are needed to perform rigorously designed, prospective studies with serially enrolled patients, with samples collected at the time of TA-TMA diagnosis, careful selection of controls, and validation of selected biomarkers and cut-off points in a separate cohort.

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“…In combination with tacrolimus, sirolimus can be used to prevent GVHD in recipients of an allogeneic hematopoietic cell transplant (HCT) ( Khaled et al, 2016 ; McCune and Bemer, 2016 ; McCune et al, 2016 ). Because GVHD persists as a significant source of non-relapse mortality ( Bidgoli et al, 2022 ), we are describing preliminary data from two pilot studies seeking to improve the dosing of sirolimus and tacrolimus in HCT recipients.…”

Section: Ongoing Pilot Studiesmentioning

confidence: 99%

Precision sirolimus dosing in children: The potential for model-informed dosing and novel drug monitoring

et al. 2023

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The mTOR inhibitor sirolimus is prescribed to treat children with varying diseases, ranging from vascular anomalies to sporadic lymphangioleiomyomatosis to transplantation (solid organ or hematopoietic cell). Precision dosing of sirolimus using therapeutic drug monitoring (TDM) of sirolimus concentrations in whole blood drawn at the trough (before the next dose) time-point is the current standard of care. For sirolimus, trough concentrations are only modestly correlated with the area under the curve, with R2 values ranging from 0.52 to 0.84. Thus, it should not be surprising, even with the use of sirolimus TDM, that patients treated with sirolimus have variable pharmacokinetics, toxicity, and effectiveness. Model-informed precision dosing (MIPD) will be beneficial and should be implemented. The data do not suggest dried blood spots point-of-care sampling of sirolimus concentrations for precision dosing of sirolimus. Future research on precision dosing of sirolimus should focus on pharmacogenomic and pharmacometabolomic tools to predict sirolimus pharmacokinetics and wearables for point-of-care quantitation and MIPD.

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Current Definitions and Clinical Implications of Biomarkers in Graft-versus-Host Disease

Cited by 16 publications

References 72 publications

Musculoskeletal Chronic Graft versus Host Disease—A Rare Complication to Allogeneic Hematopoietic Stem Cell Transplant: A Case-Based Report and Review of the Literature

Musculoskeletal Chronic Graft versus Host Disease—A Rare Complication to Allogeneic Hematopoietic Stem Cell Transplant: A Case-Based Report and Review of the Literature

A systematic review of diagnostic, prognostic, and risk blood and urine biomarkers of transplant-associated thrombotic microangiopathy

Precision sirolimus dosing in children: The potential for model-informed dosing and novel drug monitoring

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