Discovery and validation of graft-versus-host disease biomarkers

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective tumor immunotherapy available. Although allo-HSCT provides beneficial graft-versus-tumor effects, acute GVHD (aGVHD) is the primary source of morbidity and mortality after HSCT. Diagnosis of aGVHD is typically based on clinical symptoms in one or more of the main target organs (skin, liver, gastrointestinal tract) and confirmed by biopsy. However, currently available diagnostic and staging tools often fail to identify patients at higher risk of GVHD progression, unresponsiveness to therapy, or death. In addition, there are shortcomings in the prediction of GVHD before clinical signs develop, indicating the urgent need for noninvasive and reliable laboratory tests. Through the continuing evolution of proteomics technologies seen in recent years, plasma biomarkers have been identified and validated as promising diagnostic tools for GVHD and prognostic tools for nonrelapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention but should be more widely validated and incorporated into a new grading system for risk stratification of patients and better-customized treatment. This review identifies biomarkers for detecting GVHD, summarizes current information on aGVHD biomarkers, proposes future prospects for the blinded evaluation of these biomarkers, and discusses the need for biomarkers of chronic GVHD. (Blood. 2013;121(4):585-594) IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a widely used therapy for a variety of malignant and nonmalignant hematologic diseases. In malignant disease, the donor immune system recognizes residual tumor cells as foreign and eradicates them by immunologic means, known as the graft-versustumor (GVT) effect. Unfortunately, donor immune cells may also attack normal host tissue, particularly the skin, liver, and gastrointestinal (GI) tract, resulting in acute GVHD (aGVHD). GVHD remains one of the major barriers to a more widespread and successful application of allo-HSCT. Known risk factors that increase the incidence and severity of aGVHD include the use of HLA-mismatched unrelated donors rather than HLA-matched sibling donors. 1 A major barrier to GVHD research and treatment is that diagnosis and prognosis rely almost entirely on the presence of clinical symptoms and should be confirmed by biopsy of the involved target organs. No currently used laboratory tests can predict the risk of developing GVHD, responsiveness to treatment, or patient survival. The importance of biomarkers in HSCT settings is crucial because the ability to identify patients at high risk for GVHD early in their transplantation and treatment course has important therapeutic consequences, including more stringent monitoring and/or preventive care. The ability to identify patients who will not respond to traditional treatment and are at particularly high risk for subsequent morbidity and mortality could enable tailored treatment plans, such as additional immunosuppressive...

Circulating endothelial cell count: a reliable marker of endothelial damage in patients undergoing hematopoietic stem cell transplantation

“…12,[16][17][18][19]28 The commercial availability of the CellSearch system for CEC identification and count allows to easily monitor CEC changes as a function of endothelial damage in allo-HSCT patients. 19 Since validated noninvasive biomarkers for GvHD diagnosis have not yet routinely been implemented in clinical practice, 14 we propose the CellSearch system as a valid and reliable approach to help/support clinicians in their diagnosis of acute GvHD. Since vascular complications have a strong impact on the outcome of allo-HSCT, CEC changes have been correlated with the occurrence of endothelial complications.…”

“…Moreover, laboratory tests can hardly predict the risk of developing GvHD or its response to treatment. [11][12][13][14] Thus, the identification of specific biomarkers from peripheral blood (PB) samples would represent a valuable tool to avoid invasive diagnostic procedures and help personalize treatments after allo-HSCT. 15 In recent years, the direct count of circulating endothelial cells (CEC) has emerged as a valuable biomarker of endothelial damage in a variety of disorders.…”

Plasma biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements before GVHD onset and treatment

“…5,6 If it were possible to predict the ultimate severity of GVHD before or at the onset of symptoms, preemptive immune suppressive therapy could be administered in an effort to blunt the intensity of tissue damage, especially in the gastrointestinal tract. 2,7 Research on the predictive value of plasma biomarkers has yielded several candidate analytes that have been measured at higher levels in patients with GVHD than in allografted controls with no GVHD or less severe GVHD. 2,[7][8][9][10][11][12][13] In the study reported here, 2 cohorts of patients provided frequent blood samples after allogeneic transplantation, and we measured plasma levels of 23 analytes previously reported to be elevated in patients with GVHD.…”

“…2,7 Research on the predictive value of plasma biomarkers has yielded several candidate analytes that have been measured at higher levels in patients with GVHD than in allografted controls with no GVHD or less severe GVHD. 2,[7][8][9][10][11][12][13] In the study reported here, 2 cohorts of patients provided frequent blood samples after allogeneic transplantation, and we measured plasma levels of 23 analytes previously reported to be elevated in patients with GVHD. In plasma samples from patients in the first cohort, we identified 6 analytes with the greatest accuracy in predicting more severe GVHD.…”

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…[134]) Hence, it is possible to envision the future development of algorithms that would predict risk of aGVHD for individual patients and would further guide risk-adapted aGVHD prophylaxis.…”