Surgery News - May 2008 - (Page 11)

M AY 2 0 0 8 • SURGERY NEWS TRANSPLANT 11 Regimens Permit Immunosuppression-Free Transplants Conditioning seems to create an immune-system chimerism supportive of long-term graft survival. B Y M I C H E L E G. S U L L I VA N Else vier Global Medical Ne ws A series of scientific papers focusing on immunosuppression-free transplant survival has the transplant community buzzing, but experts—including some of the researchers who published the studies—say the tolerance-inducing protocols aren’t ready for prime time. “It’s really remarkable that they were able to succeed in doing this and that at least some of these patients are off all immunosuppressive drugs, but I don’t think the whole transplant community should be rushing out to try these regimens,” said Dr. Kenneth A. Newell, an ACS Fellow and director of the living donor kidney program at the Emory Transplant Center, Atlanta. “For the majority of patients, what we have now as the current regimen should remain the standard of care. We just don’t know enough about the longterm outcomes in these patients to make any large-scale changes.” Stanford (Calif.) University’s Dr. Samuel Strober agrees that the immune-tolerance regimen he helped develop should still be considered experimental. But, he said in an interview, with a few more years of research, it may be ready to go mainstream. “The next step is to increase the number of transplants we’re doing and accumulate longer follow-up,” Dr. Strober said. “If it continues to look good, I imagine other major medical centers will want to give the protocol a trial as well. But I think it will take a while—at least 5 years—before this will happen.” The papers describe patients who, either naturally or through conditioning protocols, achieved a state of mixed chimerism that seems to support long-term graft survival without immunosuppressive drugs. In each case, the patient’s native immune system was impaired enough to allow donor hematopoietic stem cells to engraft into recipient bone marrow, eliminating immunoreactivity toward the transplanted organ. The most unusual case described was that of a 9-year-old Australian girl who achieved complete hematopoietic chimerism after she received the liver of a 12-year-old male. Viral hepatitis destroyed her own liver, and plunged her immune system into a prolonged state of severe lymphopenia (N. Engl. J. Med. 2008; 358:369-74). Nine months after the transplant, her blood type had switched from O, Rh-negative, to O, Rh-positive—the donor’s type. Within another month, she developed a severe hemolytic anemia, and physicians stopped immunosuppressive therapy to allow complete engraftment. Five years after the transplant, the patient is well, with normal liver function tests. Two other papers describe regimens designed to induce a similar phenomenon at the time of kidney transplant. Both included infusions of donor hematopoietic stem cells and suppression of the recipient’s immune system, promoting a state in which donor and recipient cells coexist. This induces a natural tolerance to the transplanted organ, said Dr. Strober, professor of immunology and rheumatology at Stanford, and leader of one of the studies. In his report of six Stanford patients who underwent the conditioning regimen, those who developed mixed chimerism have been off their immunosuppressive drugs with good results during follow-up of 7 months to more than 2 years (N. Engl. J. Med. 2008;358:362-8). The Stanford protocol called for 10 posttransplant lymphoid irradiation treatments, followed by an infusion of cryopreserved donor cells highly enriched for CD34+ hematopoietic progenitor cells. Antirejection drugs were given for 6 months, with gradual tapering after 3 months. The Stanford patient with the longest follow-up period—2 years—received an HLA-identical kidney from his older brother. Mixed chimerism developed within a month after the surgery and has persisted, Dr. Strober said; up to 85% of the patient’s B cells and 70% of his granulocytes are of donor origin. Two years after the transplant, he is completely off antirejection medications and has consistently maintained normal kidney function. In the third study, five transplant patients received HLA single-haplotype mismatched kidneys at Massachusetts General Hospital, Boston. Their conditioning regimen consisted of cyclophosphamide on preoperative days 5 and 4, and anti-CD2 monoclonal antibody on preoperative days 2 and 1, as well as postoperative day 1. The day before surgery, they received cyclosporine and thymic irradiation. A bone marrow transplant followed immediately after the kidney transplant (N. Engl. J. Med. 2008;358:353-61). Although one patient in this study lost cause patients apparently lose their imhis graft because of acute humoral rejec- munoreactivity to the donor organ, the tion, the other four have discontinued costs associated with chronic rejection their immunosuppressive therapy. Each should also plummet, he said. “We don’t know for sure that our pahas stable kidney function with no signs of tients will have no complications, but so far rejection, with follow-up of 2-5 years. All of these patients “represent points they are doing extremely well,” Dr. Sachs on a continuous spectrum,” Dr. Thomas said. “At least in our animal studies, those E. Starzl said in an interview. “The key animals that have become immunotolerant event in the mechanism of organ en- do not develop chronic rejection.” All the Stanford patients received HLAgraftment was microchimerism.” But inducing this state “is dangerous and com- matched grafts, which may increase the plex” on a clinical level and time chance of successfully withdrawing imconsuming and expensive on an adminis- munosuppressive therapy, Dr. Sachs said. trative level, said Dr. Starzl of the Thomas While matched transplants certainly have E. Starzl Transplantation Institute at the a higher chance of success, they are the exUniversity of Pittsburgh. “You are talking ception rather than the rule, he noted. The Massachusetts General protocol about adding this to a therapy—kidney transplant—that has been applied over a adds more than 2 weeks to the transplant million times worldwide. But changing process: 5 days for the conditioning prothat therapy to a protocol that requires all tocol, and at least 2 weeks in isolation this time and expense could just close while the immune system recovers. The down a program—it couldn’t exist under postoperative Stanford protocol doesn’t extend hospitalization as long, Dr. Strober these circumstances.” Still, said Dr. David Sachs, the payoff for said. “In our hands, the patients are diseliminating a lifetime of expensive antire- charged at around the same time a conventionally treated patient would be.” jection medication could be enormous. “The cost up front is higher because we are DATA WATCH transplanting bone marrow as well as a kidney, Global Transplant Immunosuppressant Market but within a few years Expected to Increase More Than 60% the overall cost be(revenue in billions) comes less because $6.5 $5.9 you’re not buying ex$5.3 pensive antirejection $4.8 drugs,” said Dr. Sachs, $4.4 $4.0 senior author of the third study and director of the Transplantation Biology Research Center at Massachusetts General Hospital. Eliminating these 2002 2004 2006 2008 2010 2012 medications also eliminates the potentially seNote: Numbers are not adjusted for inflation. rious adverse effects Source: Kalorama Information they can have. And be- ELSEVIER GLOBAL MEDICAL NEWS http://www.NashvilleSurg.com

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Surgery News - May 2008 Contents New Lung Approach Speeds Extubation Innovative GI Procedures May Improve Diabetes Quality Programs Differ on Risk Data Crystal Ball Medical Modeling Ventricular Valve Taking Stock

Surgery News - May 2008

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