New Test Could Guide More Precise Treatment of GVHD

James L. M. Ferrara MD, DSc
Published: Monday, Aug 17, 2015
The Tisch Cancer Institute James L. M. Ferrara MD, DSc
James L. M. Ferrara, MD, DSc

Ward-Coleman Chair in Cancer Medicine
Professor and Director
Hematologic Malignancies Translational Research Center
The Tisch Cancer Institute & Division of Hematology/Medical Oncology
Dr. Yixuan Gong
A new test reveals which patients with leukemia and other blood disorders are likely to respond to treatment for graft-versus-host disease (GVHD) that develops after a stem cell transplant (SCT), according to a study led by researchers at the Icahn School of Medicine at Mount Sinai and published in Lancet Haematology.

Patients with fatal blood cancers like leukemia often require allogenic SCT to survive. Donor lymphocytes, which are transplanted along with donor stem cells into a recipient, can seek out and eliminate malignant cells that survived intensive chemoradiotherapy, causing a complete remission of the malignancy. But these lymphocytes cause GVHD, a life-threatening complication and major cause of death after SCT.

The disease, which can be mild to severe, occurs when the transplanted donor cells attack the GI tract, liver, and skin of the patient. Symptom severity, however, does not accurately define how patients will respond to treatment and patients are often treated alike with high-dose steroids. Although SCT cures cancer in approximately 50% of the patients, 25% die from relapsed cancer, and the remaining go into remission but later succumb to the effects of GVHD.

High-dose steroids are the only proven treatment for GVHD. Those with low-risk GVHD are often overtreated and face significant side effects from treatment, such as diabetes or bone disease. Patients with high-risk GVHD are undertreated and the GVHD progresses, often with fatal consequences. The goal is to provide the right treatment for each patient at the right time. This test identifies those patients at higher risk at the onset of their symptoms, allowing clinicians to design an aggressive intervention early on. Equally important is the ability to tailor a less-aggressive approach for those with low-risk disease who may not need a long course of high-dose, systemic steroids.

Along with a multicenter team of researchers, we first developed and tested a new scoring system using almost 500 blood samples from patients with newly diagnosed GVHD in varying grades from two different centers. We created an algorithm using concentrations of three biomarkers previously discovered by our team: The Tisch Cancer Institute at The Mount Sinai Medical Center tumor necrosis factor receptor Type 1 [TNFR1], soluble IL-33 receptor [ST2], and regenerative 3 alpha [Reg3α].

We were able to calculate the probability of nonrelapse mortality (usually caused by GVHD that does not respond to therapy) and divided the patients into three distinct groups to predict the patient’s response to GVHD treatment. The low-risk group had complete responses to treatment 75% of the time, whereas only 25% of the high-risk group showed complete responses.

The acid test was to evaluate the algorithm in a validation set of 300 additional patients from 20 different SCT centers throughout the United States. The algorithm worked perfectly, and the cumulative incidence of nonrelapse mortality significantly increased as the GVHD score increased, and conversely, the response rate to primary GVHD treatment decreased.

This new scoring system will help identify patients who may not respond to standard treatments, and may require an experimental and more aggressive approach, and it will also help guide treatment for patients with lower-risk GVHD who may be overtreated. This test will allow us to personalize treatment at the onset of the disease, where small differences in treatment may make big differences in outcomes. Also, future algorithms may incorporate additional biomarkers or clinical characteristics, proving increasingly useful to develop precision medicine for all SCT patients.

In order to capitalize on this discovery, we’ve created the Mount Sinai Acute GVHD International Consortium (MAGIC), which consists of a group of 10 SCT centers in the United States and Europe who will collaborate to use this new scoring system to test new treatments for acute GVHD. This group will use the biomarker algorithm to direct treatment in patients who volunteer to participate in clinical trials based on their risk assigned by the algorithm.

Preparations are underway to offer this test under the Clinical Laboratory Improvement Amendments (CLIA) certification of the Mount Sinai Clinical Laboratories for these clinical trials. My colleagues and I have also written a protocol to treat high-risk GVHD that has been approved by the FDA. In the future, other SCT centers may be able to send blood samples directly to Mount Sinai for this analysis.

Co-collaborators on the research included the University of Michigan, the University of Regensburg, and the Blood and Marrow Clinical Trials Network.


Levine JE, Braun TM, Harris AC, et al. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicenter study. Lancet Haematol. 2015;2(1):e21-e29

The study was supported by grants from 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.




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