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

Abstract

SUMMARY Background Graft-versus-host disease (GVHD) is the major cause of non-relapse mortality (NRM) after allogeneic hematopoietic stem-cell transplantation (HCT). 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 We prospectively collected plasma from 492 HCT patients with newly diagnosed acute GVHD and randomly divided them 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 NRM six months after GVHD onset for individual patients in the training set alone. We rank ordered the probabilities and identified thresholds that created three distinct NRM scores. We evaluated the algorithm in the testset, and again in an independent validation set of 300 additional HCT patients enrolled on multicenter clinical trials of primary therapy for acute GVHD. Findings In all three datasets, the cumulative incidence of twelve month NRM significantly increased as the GVHD score increased (8% [95% confidence interval (CI); 3%, 16%], 27% [95% CI; 20%%, 34%], and 46% [95% CI; 33%, 58%], for scores 1, 2 and 3 respectively in the multicenter validation set, p<0 · 0001). Conversely, the response rates to primary GVHD treatment decreased as the GVHD score increased (86%, 67%, and 46%, for scores 1, 2 and 3 respectively in the multicenter validation set, p<0 · 0001). Interpretation Biomarker-based scores can be used to guide risk-adapted therapy at the onset of acute GVHD.

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

“…1 Although the overall frequency of GVHD has remained stable during the past decade, its presentation has shifted toward gastrointestinal involvement as the major cause of morbidity and away from severe damage to the skin and liver. 1,2 The result of these clinical trends has been a reduction in the frequency of grade 3-4 GVHD to ,10% in most centers, along with a 50% reduction in nonrelapse mortality (NRM). 1 Retrospective analyses demonstrate that patients with more severe peak symptoms and especially more prolonged acute GVHD have substantially higher mortality rates than those with less severe and shorter-duration GVHD.…”

“…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.…”

A risk-adapted approach to acute GVHD treatment: are we there yet?

“…The Ann Arbor grade is based upon serum or plasma levels of TNF receptor-1 (TNFR1), regenerating islet-derived 3-alpha (REG3α) and suppression of tumorigenicity 2 (ST2), and has been validated from independent cohorts of patients with aGVHD from the University of Michigan, the University of Regensberg and from multicenter Blood and Marrow Transplant Clinical Trials Network aGVHD treatment trials 0302 and 0802. 28 In these cohorts, non-relapse mortality could be stratified by AA1 versus AA2 versus AA3, although day 28 CR/PR was not significantly different in patients with mild, Glucksberg grade I-II aGVHD and AA1-2 biomarker grades. CR/PR was also not significantly different between AA2 and AA3 biomarker grades in severe, Glucksberg grade III-IV aGVHD, 28 leaving room for future refinement of the algorithm.…”

“…28 In these cohorts, non-relapse mortality could be stratified by AA1 versus AA2 versus AA3, although day 28 CR/PR was not significantly different in patients with mild, Glucksberg grade I-II aGVHD and AA1-2 biomarker grades. CR/PR was also not significantly different between AA2 and AA3 biomarker grades in severe, Glucksberg grade III-IV aGVHD, 28 leaving room for future refinement of the algorithm. As with the Minnesota (MN) clinical Risk Score, proteomics-based risk stratification of aGVHD has yet to be tested prospectively.…”

“…28 This Ann Arbor risk stratification system will be applied to an upcoming University of Michigan clinical trial of natalizumab plus steroids for the initial treatment of HR AA3 aGVHD (ClinicalTrials. gov identifier NCT02133924).…”