Patients Receiving mTOR Inhibitors Exhibit Fewer Early Malignancies Than Those Receiving Cyclosporine-Based Regimens

September 6, 2004

TOR Inhibitor Maintenance Immunosuppression is Associated with a Reduced Incidence of Post-Transplant Malignancies. Authors: H. Myron Kauffman, M.D(1)., Wida S. Cherikh, Ph.D(1)., Yulin Cheng, B.S.(1) Douglas W. Hanto, M.D(2)., Bertram L. Kasiske, M.D(3), Barry D. Kahan, M.D., Ph.D(4).

(1)United Network for Organ Sharing, Richmond, VA, (2)Beth Israel Deaconess Medical Center, Boston, MA, (3)Hennepin County Medical Center, Minneapolis, MN, (4)University of Texas Medical School at Houston

VIENNA, Austria /PRNewswire/ -- New data presented today from the OPTN/UNOS (Organ Procurement and Transplant Network/United Network for Organ Sharing) database show that the relative risk of developing cancer following transplantation is substantially reduced in patients receiving maintenance immunosuppression with mTOR inhibitors as compared to patients receiving treatment with traditional calcineurin inhibitors. Conventional immunosuppressive therapies, like cyclosporine or tacrolimus, can be associated with increased rates of cancers, resulting in late death for a number of transplant recipients, particularly patients with identified factors of increased malignancy risk.

These are the conclusions of a study presented by researchers from the United Network for Organ Sharing (UNOS) and three other U.S. transplant programs at the International Congress of the Transplantation Society, held this week in Vienna.

"We know that transplant patients have a greater risk of developing cancer than the general population, and unfortunately excessive immunosuppression, particularly with certain drugs, is a substantial contributing factor," said Dr. H. M. Kauffman, a Senior Research Scientist at UNOS. "As newer drugs have become available, and new innovative regimens are developed, we wanted to see if they could impact this cancer rate. This is the largest analysis of its kind, comparing the different regimens, and it clearly shows that the mTOR inhibitors offer a significant benefit in reducing short-term malignancy rates in transplant recipients. The study also identified other factors that significantly increased the risk of post transplant malignancy such as male gender, white race, older age groups, a history of a previous malignancy, and treatment for early acute rejection."

The retrospective study looked at more than 36,000 patients who received a primary solitary kidney transplant between 1996 and 2002. The data showed that only 0.78% of those treated with the mTOR inhibitors (more than 97% receiving sirolimus) developed new cancers during the two years of follow up. This was significantly lower than patients treated with calcineurin inhibitors (cyclosporine or tacrolimus, 1.84%; p<0.001). There was a significantly reduced incidence in skin cancer and de novo solid cancer (prostate, lung, kidney, breast, colon) but no reduced incidence in post-transplant lymphoproliferative disease (PTLD).

In a risk adjusted multivariate analysis, patients treated with mTOR based immunosuppressant therapy had a 47% reduced relative risk of developing new cancers (relative risk 0.529, 95% CI 0.355, 0.788) than those given calcineurin-based therapy. This was a highly significant reduction in relative risk p=0.0017.

"These short-term results will need to be both evaluated long-term and be evaluated in other transplanted organs such as liver, heart, and lung," said Dr. Kauffman.

Animal evidence suggests that conventional calcineurin immunosuppression promotes rather than inhibits the development of cancer. Calcineurin inhibitors have been shown to induce cancer progression and increase transforming growth factor-B (TGF-B) expression that is associated with cellular changes that are characteristic of invasiveness. In contrast, mTOR inhibitors appear to have a negative growth effect on malignant cells. mTOR inhibitors, in animals, reduce TGF-B and vascular endothelial growth factor (VEGF) expression and inhibit tumor angiogenesis.

About Malignancies and Transplantation

Transplant recipients have an increased risk of developing cancer in general (one to two percent per year) and a 15-20 fold higher incidence of certain types of cancer. The general incidence of all malignancies after kidney transplantation increases with advancing time and seems to be dependent on both duration and intensity of immunosuppression. Skin cancer and post transplantation lymphoproliferative disorders such as non-Hodgkin's lymphoma are the most prevalent types of cancer seen post transplantation. The risk of cervical, breast cancer and colorectal cancer are also increased.

About UNOS

A private, nonprofit organization, UNOS manages the nation's organ transplant system and oversees the world's most comprehensive database of clinical transplant information under contract with the federal government. UNOS operates the 24-hour computerized organ sharing system, matching donated organs to patients registered on the national organ transplant waiting list. UNOS seeks to increase organ donation through education and improve transplant success rates through outcomes-based research and policymaking. The strength of the transplant database relies on the conscientious reporting of 469 UNOS member institutions. This work was supported in part by Health Resources and Services Administration Contract 231-00-0115.

Source: United Network for Organ Sharing.

Copyright © 2004 Yahoo Inc.

Copyright © 2004 PRNewswire.

This article posted October 10, 2004.