NEW YORK (GenomeWeb) – Scientists at the Mount Sinai Acute GVHD International Consortium (MAGIC) have developed an algorithm to predict whether blood cancer patients who received a bone marrow transplant will develop severe cases of graft-versus-host disease (GVHD) following their treatment.
According to a paper published yesterday in the Journal of Clinical Investigation Insight, the researchers examined around 1,300 blood samples from bone marrow transplant patients treated at 11 cancer centers across the country. They identified two proteins — ST2 and REG3 — that are present in blood samples drawn a week following transplant that predict whether a patient will develop GVHD weeks before the disease's symptoms normally occur. The so-called MAGIC algorithm determines patients' risk of developing the disease by measuring the concentrations of these proteins.
The algorithm will let physicians use a simple blood test to determine which patients are at high risk for lethal complications before they occur, James Ferrara, a professor at the Icahn School of Medicine at Mount Sinai and co-director of MAGIC, said in a statement.
GVHD occurs when a bone marrow donor's immune cells see the recipient's body as foreign and attacks the recipient's tissue targeting primarily the skin, liver, and gastrointestinal tract. Forty to 60 percent of patients who receive bone marrow transplants later develop severe GVHD, and about 40 percent of these patients die. Currently, there are no laboratory tests that can predict patients risk of developing severe GVHD following a stem cell transplant. Testing with MAGIC will "allow early intervention and potentially save many lives," Ferrara said.
Early testing will also make bone marrow transplants safer and more effective for patients because physicians will be able to adjust patients' treatment regimens to protect against GVHD, according to John Levine, MAGIC co-director and also a professor at Mount Sinai. "If successful, the early use of the drugs would become a standard of care for bone marrow transplant patients," he said.
To develop the algorithm, the researchers used an ELISA-based method to measure the concentrations of four GVHD biomarkers — ST2, REG3α, TNFR1, and IL-2Rα — in blood samples from 1,287 patients. They used 75 different biomarker combinations to model six-month non-relapse mortality for patients in the test dataset. They also used cross-validation strategies to identify the best algorithm that defined two distinct risk groups independent of factors such as the degree of HLA match between donor and recipient and the genetic relationship between the donor and the recipient.
They then tested the chosen algorithm on two datasets from an independent test cohort of 309 patients and a multicenter validation cohort of 358 patients. Their results showed that the algorithm performed equally well in both the training and validation datasets, identifying 17 percent and 20 percent, respectively, of patients as high risk based on the two protein biomarkers. GVHD-related mortality was greatest in these high-risk patients as well as severe gastrointestinal GVHD, according to the researchers. In fact, patients classified as high-risk were three times more likely to die from GVHD than low-risk patients when all 1,287 patients were considered, the paper states.
Investigators at Mount Sinai are now designing clinical trials that will test whether immunotherapy drugs that are normally used during the onset of GVHD would benefit patients whose tests confirm that they would be at high risk for severe onset of the disease. They hypothesize that if patients who are treated immediately after testing before symptoms develop would be spared from more severe forms of the disease, resulting in fewer fatal cases.
"The primary cause of death from GVHD is the GVHD that affects the GI tract so we are specifically designing trials that block the traffic of the pathogenic T cells to the GI tract with monoclonal antibodies," Ferrara said in an interview. The therapies that will be assessed as part of the trial are vedolizumab and natalizumab, which block activated T cells from attacking the GI tract tissue. The researchers plan to enroll between 60 and 100 patients in the trial, according to Ferrara. Also GVHD-linked liver disease is almost always related to gut disease so "if we can prevent the gut disease, we think we can prevent the liver disease."
Furthermore, the developers plan to make improvements to the algorithm including repeating the test to increase sensitivity, Ferrara said. "This test is from a one-time snapshot at day seven after transplant before any of the GVHD develops [but] most GVHD develops after the third week," he explained. "So we are going to repeat the test basically every week … and by this repeat testing, we can increase the sensitivity significantly."
Ferrara expects it will take some years before MAGIC can be ready for clinical use. "We need to have at least one clinical trial where we can show that acting on this test makes a difference to be ready for prime time," he said. Equally important is ensuring that there are no harmful side effects to the patients following treatment, he added.