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Biomarkers predicted severity of GVHD after allogeneic HSCT
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A prognostic score based on the concentration of biomarkers guided risk-adapted therapy at the onset of graft-versus-host disease following allogeneic hematopoietic stem cell transplantation, according to study results.
The symptoms at the presentation of graft-versus-host disease (GVHD) often do not provide enough indication to guide therapy, James L. M. Ferrara, MD, DSc, Ward-Coleman chair in cancer medicine at Icahn School of Medicine at Mount Sinai and Ruth Heyn professor of pediatric oncology at the University of Michigan Medical School, and colleagues wrote.
“High-dose steroids is the only proven treatment for GVHD,” Ferrara said in a press release. “Those with low-risk GVHD are often over-treated and face significant side effects from treatment. Patients with high-risk GVHD are undertreated and the GVHD progresses, often with fatal consequences. Our goal is to provide the right treatment for each patient. We hope to identify those patients at higher risk and design an aggressive intervention while tailoring a less-aggressive approach for those with low risk.”
Ferrara and colleagues developed an Ann Arbor GVHD score based on the concentration of the biomarkers TNFR1, ST2 and Reg3-alpha.
Researchers collected plasma from 492 patients who had newly diagnosed acute GVHD after undergoing allogeneic hematopoietic stem cell transplantation (HSCT).
Ferrara and colleagues randomly assigned patients to the training (n=328) and test (n=164) cohorts. An additional 300 patients enrolled on trials evaluating primary therapy for GVHD were included in the validation cohort.
Overall, the cumulative incidence of non-relapse mortality in each the cohorts significantly increased as the Ann Arbor score increased (P˂.0001).
In the validation cohort, researchers defined 74 patients as having an Ann Arbor score 1, 165 as score 2 and 61 as score 3. The incidence of non-relapse mortality at 12 months was 8% (95% CI, 3-16) among those with score 1, 27% (95% CI, 20-34) among those with a score 2, and 46% (95% CI, 33-58) among those with score 3 (P˂.0001).
More patients in the validation cohort with score 1 responded to primary GVHD treatment within 28 days (86%) than patients with score 2 (67%) or score 3 (46%; P˂.0001).
“This new scoring system will help identify patients who may not respond to standard treatments, and may require an experimental and more aggressive approach,” Ferrara said. “And it will also help guide treatment for patients with lower-risk GVHD who may be over-treated. This will allow us to personalize treatment at the onset of the disease. Future algorithms will prove increasingly useful to develop precision medicine for all HSCT patients.”
Evaluating plasma biomarkers will further help target agents in this setting, Brian Betts, MD, Claudio Anasetti, MD and Joseph Pidala, MD, PhD, all from the department of blood and marrow transplantation at the Moffitt Cancer Center, wrote in an invited commentary.
“GVHD biomarker discovery is rapidly evolving,” Betts, Anasetti and Pidala wrote. “As a field, we must focus on functional and druggable targets, and ensure that the correct patient population is selected for clinical trials based on relevant biomarker expression. Levine and colleagues should be commended for their efforts in advancing these concepts.”
For more information:
Betts B. Lancet Haematol. 2014;doi:10.1016/S2352-3026(14)00040-4.
Levine JE. Lancet Haematol. 2014;doi:10.1016/S2352-3026(14)00035-0.
Disclosure: The researchers report royalties from patents on GVHD biomarkers. Betts, Anasetti and Pidala report no relevant financial disclosures.
Perspective
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Sergio A. Giralt, MD
For all of us who round on allogeneic hematopoietic cell transplant (HCT) patients every day, few things are more frustrating than the differential diagnosis of graft-versus-host disease. The reality on the wards is that practitioners fall into two categories — those who, in the context of an un-manipulated HCT, think anybody with a rash, diarrhea or protracted nausea who has engrafted has acute GVHD and should be treated, and those who will avoid using systemic steroids at all costs until other causes have been ruled out.
Moreover, after a diagnosis has been made and steroids have been started, the decisions of how to taper and when to use second-line treatment are hampered by the fact that — until recently — we could not tell who was going to do very well or very poorly.
The paper by Levine and colleagues hopefully will be the beginning of a new era in GVHD treatment. Samples from 492 HCT patients with newly diagnosed acute GVHD had samples prospectively collected and analyzed for three recently validated biomarkers (TNFR1, ST2 and Reg3α). These measurements were used to create an algorithm that computed the probability of nonrelapse mortality at 6 months after GVHD onset that were developed in a training set and validated in two other datasets. The “score” that was derived from this calculation was appropriately named the Ann Arbor GVHD Score, in honor of the place where — based on pioneering work by James L.M. Ferrara, MD, DSc — this concept was developed.
In the multicenter validation set, 6-month nonrelapse mortality rates were 8% among those with an Ann Arbor Score of 1, 27% for those with a score of 2, and 46% for those with a score of 3. Likewise, response to primary GVHD treatment decreased as the GVHD score increased, peaking at 86% for those with a score of 1, 67% for those with a score of 2, and 46% for those with a score of 3.
If the algorithm is true to form, we could risk-stratify patients in a much better way at the moment of initiation of therapy, focusing on novel combinations for patients with scores of 3 and minimizing steroids use for patients with a score of 1. This truly may be a game changer, and we look forward to seeing the future trials that will be made possible by this observation.
Finally, this study once again demonstrates the enormous value that the Blood and Marrow Transplant Clinical Trials Network brings to the HCT community. The value of the multicenter validation with prospectively collected samples on curated clinical data is priceless. It allowed the investigators to confirm their findings and advance the field less than 5 years from their original observation, which now can begin to be tested in clinical practice — truly a great investment of the “people’s money.”
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