MADRID — A blood test that measures the activity of genes that help control immune response to a transplanted heart was able to reliably rule out future organ rejection in a study with 192 patients.
“We believe that these findings may pave the way to a reduced need for protocol-mandated cardiac biopsies” in patients who have received a heart transplant, Dr. Mandeep R. Mehra said at the annual meeting of the International Society for Heart and Lung Transplantation. The results also may point to a new approach for assessing the adequacy of steroid treatment for a variety of diseases and conditions.
A new analysis of data collected in a previously reported study showed that about one-third of the heart-transplant patients involved had low scores on a specially designed gene expression test performed 30 or more days following transplantation. These low-score patients showed no sign of rejection in biopsies taken during the next 3 months, whereas patients with higher scores had an incidence of biopsy-proven rejections of about 60% over the subsequent 3 months.
On the basis of these results, Dr. Mehra said that he would be comfortable skipping cardiac biopsies in patients with low gene expression scores in tests run 30–180 days after transplantation. A low score was defined as 20 or less on a scale of 0–40 in the AlloMap test, which is marketed by XDx Inc.
XDx sponsored the Cardiac Allograft Rejection Gene Expression Observational (CARGO) study, which was designed to assess the ability of the gene expression test to diagnose rejection of a transplanted heart as it was occurring. The efficacy of the test for this purpose was first reported in 2005 at the annual meeting of the International Society for Heart and Lung Transplantation, and was published last January (Am. J. Transplant. 2006;6:150–60). Dr. Mehra and his associates reanalyzed the data from this study to see if the gene expression test could also predict future rejection episodes. Dr. Mehra received research support from and is a consultant to XDx.
The new findings are “very exciting and show a lot of promise,” commented Dr. A.G. Kfoury, medical director of the UTAH Cardiac Transplant Program at LDS Hospital in Salt Lake City.
“If we can avoid cardiac biopsies it would be a big help. Biopsies are very hard on patients,” commented Dr. Elizabeth H. Hammond, professor of pathology and an expert on rejections following heart transplants at Intermountain Healthcare in Salt Lake City.
The gene expression test looks at RNA levels in peripheral-blood mononuclear cells to assess the activity of 11 genes involved in five basic activities that affect the immune response to a foreign organ: T-cell priming, platelet activation, steroid responsiveness, stem cell activity, and cell migration. The panel was designed to flag active rejection, and not to predict rejection before it actually appeared, said Dr. Mehra, chief of the division of cardiology at the University of Maryland in Baltimore.
The reanalysis of CARGO data involved two separate assessments. First was a case-control analysis that included 39 of the patients in CARGO who eventually had heart rejection, and 65 who did not. The overall profile of both groups did not differ by age, gender, or race, and the steroid doses administered prior to any diagnosed rejections were similar. Dr. Mehra and his associates reviewed the results of gene expression profiles that were tested starting 1 month after transplant and retested periodically out to 1 year after transplant. Each test result was analyzed relative to whether a rejection episode occurred during the 2–12 weeks after the test was made.
Total gene expression scores were significantly lower in the patients who did not have rejections during the several weeks following each test. Test scores were most predictive during the first 6 months after transplantation. In this period, the most informative genes were the three that affect responsiveness to steroid therapy. “This may be a way to assess adequate treatment with steroids,” Dr. Mehra said.
The second analysis examined the predictive capacity of 192 consecutive test results that came from all patients in the study during the first 6 months following transplantation. This assessment showed that a gene expression test score of 20 or less predicted the absence of a rejection episode during the subsequent 12 weeks with 99% accuracy, Dr. Mehra reported.
The gene expression test performed consistently well for predicting subsequent rejections during the first 1–6 months after transplantation.
Dr. Mehra noted that the gene-testing panel was developed to measure current rejection. It's reasonable to speculate that efforts to optimize predictive capabilities may identify a different, more effective expression panel.