Elsevier

The Lancet Haematology

Volume 2, Issue 1, January 2015, Pages e21-e29
The Lancet Haematology

Articles
A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study

https://doi.org/10.1016/S2352-3026(14)00035-0Get rights and content

Summary

Background

Graft-versus-host disease (GVHD) is the major cause of non-relapse mortality after allogeneic haemopoietic stem-cell transplantation (SCT). The severity of symptoms at the onset of GVHD does not accurately define risk, and thus most patients are treated alike with high dose systemic corticosteroids. We aimed to define clinically meaningful risk strata for patients with newly diagnosed acute GVHD using plasma biomarkers.

Methods

Between April 13, 2000, and May 7, 2013, we prospectively collected plasma from 492 SCT patients with newly diagnosed acute GVHD and randomly assigned (2:1) using a random number generator, conditional on the final two datasets having the same median day of onset, into training (n=328) and test (n=164) sets. We used the concentrations of three recently validated biomarkers (TNFR1, ST2, and Reg3α) to create an algorithm that computed the probability of non-relapse mortality 6 months after GVHD onset for individual patients in the training set alone. We rank ordered the probabilities and identified thresholds that created three distinct non-relapse mortality scores. We evaluated the algorithm in the test set, and again in an independent validation set of an additional 300 patients who underwent stem cell transplant and were enrolled on multicentre clinical trials of primary therapy for acute GVHD.

Findings

In all three datasets (training, test, and validation), the cumulative incidence of 6-month non-relapse mortality significantly increased as the Ann Arbor GVHD score increased. In the multicentre validation set, scores were 8% (95% CI 3–16) for score 1, 27% (20–34) for score 2, and 46% (33–58) for score 3 (p<0·0001). Conversely, the response to primary GVHD treatment within 28 days decreased as the GVHD score increased 86% for score 1, 67% for score 2, and 46% for score 3 in the multicentre validation set, p<0·0001).

Interpretation

Biomarker-based scores can be used to guide risk-adapted therapy at the onset of acute GVHD. High risk patients with a score of 3 are candidates for intensive primary therapy, while low risk patients with a score of 1 are candidates for rapid tapers of systemic steroid therapy.

Funding

The National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Doris Duke Charitable Fund, the American Cancer Society, and the Judith Devries Fund.

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

References (37)

Cited by (0)

View full text