ArticlesA prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study
Introduction
The ability of allogeneic haemopoietic stem cell transplantation (SCT) to cure haematological malignancies is due, in part, to the graft-versus-leukaemia (GVL) effect mediated by alloreactive T cells in the donor graft. But GVL effects remain closely associated with graft-versus-host disease (GVHD), which is mediated by those same T cells and natural killer cells.1 GVHD, which occurs in both acute and chronic forms, remains the major cause of death without relapse of primary disease or non-relapse mortality.2, 3, 4 The primary treatment of acute GVHD, high dose systemic glucocorticoids, has not changed in 40 years.5 Only a third of patients achieve durable responses to initial corticosteroid therapy and survival among the remaining patients is poor.6
An important obstacle to the development of new therapies of acute GVHD is the inability to determine risk for an individual patient at the onset of symptoms. Risk of mortality correlates with maximum clinical severity in current grading systems, which can only be assigned retrospectively after the response to treatment is known.7, 8, 9 Thus, at disease onset, most patients are treated alike with high dose corticosteroids resulting in substantial numbers of patients who are both undertreated and overtreated. Overtreated patients who are likely to respond to low doses of glucocorticoids have additional infectious risks associated with profound immunosuppression and morbidities such as avascular necrosis of bone and diabetes mellitus.10, 11, 12, 13 An excess of 70–90% of undertreated patients who develop steroid resistant acute GVHD die.14, 15, 16
We aimed to define clinically meaningful risk strata for patients with newly diagnosed acute GVHD using plasma biomarkers.
Section snippets
Clinical specimens and study design
The study population for the training and test sets consisted of patients with new onset acute GVHD grade I–IV from the University of Michigan, Ann Arbor, MI, USA (n=360) and the University of Regensburg, Germany (n=132), who provided blood samples at the onset of acute GVHD on institutional review board-approved protocols at each centre. Both centres used standardised guidance that was developed through a long-standing collaboration to minimise variability in the diagnosis and estimation of
Results
The clinical characteristics of the two-centre training and test sets and the multicentre BMT CTN validation set are shown in appendix p 8. The multicentre validation set differed significantly from the test and training sets in their overall distributions of age, stem-cell source, indication for SCT, day of onset and severity of GVHD, and GVHD prophylaxis (appendix p 8). Patients in the multicentre validation set were older than those in the other sets (median age 52 years [IQR 41–60] vs 48
Discussion
Maximum clinical severity of GVHD in symptom-based grading systems correlates with survival, but these systems are not often able to guide treatment at symptom onset. As a result, clinicians do not intensify immunosuppressive treatment of GVHD until primary therapy has failed. In our study, we have developed and validated an algorithm using biomarkers that define three GVHD severity scores, each with a distinct risk of non-relapse mortality. We observed that our Ann Arbor GVHD scores defined
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