Alicia Ault

May 20, 2004 (Boston) — Half of the 36 patients with type 1 diabetes who have received islet cell transplants under the Edmonton Protocol are insulin-free, researchers reported here Tuesday.

An overview of the ongoing multicenter study was presented by lead investigator James Shapiro, MD, from the University of Alberta in Edmonton, at the 2004 annual meeting of the American Transplant Congress, the joint meeting of the American Society of Transplant Surgeons and the American Society of Transplantation.

Researchers from the University of Miami and University of Minnesota also presented results from their own islet cell transplant protocols.

Dr. Shapiro reported that half of the first 23 patients were insulin-free. Five became independent after one infusion of islet cells, five after two infusions, and two after three infusions. Six patients rejected their transplants, and there were two drop-outs and three who reduced their insulin dose.

Enrollment in this phase I/II study ended in January 2003 and has now reached its goal of 36 patients, Dr. Shapiro told attendees. Nineteen of the 36 patients who have received transplants are insulin-free. Five of those 19 received one infusion, seven received two infusions, and seven received three infusions. Seven of the 36 are insulin-dependent; six patients had primary islet nonfunction, and four patients withdrew from the study.

For those still taking insulin, there has been a decrease from 36 units at baseline to an average 21 units per day now, he said. For patients who are insulin-free, glucose control has been excellent, with fasting glucose and hemoglobin A 1c levels within the normal range, said Dr. Shapiro.

There is still no clear indication why the six patients rejected their islets, although two patients failed to achieve initial trough levels of tacrolimus or sirolimus, he said.

Patients in the study have experienced a range of adverse events, including six patients who had procedure-related bleeding (during 76 transplants), two with portal vein thrombosis, but not in the main portal, and one with a biliary leak. There were 23 serious adverse events, including neutropenia, diarrhea, and mouth ulceration, which was the most common event. But there has been no cytomegalovirus or Epstein Barr virus infection, and no opportunistic infections, lymphomas, or death.

The success rate across the nine participating sites has ranged from zero to 100%, Dr. Shapiro said. "Clearly, there's a spectrum of success," he said, but did not elaborate, stating that he'll give a more in-depth presentation at next month's American Diabetes Association annual scientific meeting in Orlando.

Eugene Barrett, MD, PhD, president of the American Diabetes Association, who did not attend the American Transplant Congress, said the initial enthusiasm for Edmonton has been tempered in the last year, but that it was encouraging that other centers could replicate Dr. Shapiro's results, at least in some cases.

Dr. Barrett, who is also a professor of medicine at the University of Virginia in Charlottesville, said he regards the Edmonton studies as "very important and a big step forward," because they are offering the potential of islet transplantation as therapy for severe diabetics.

"There's still room for guarded optimism," Dr. Barrett told Medscape in an interview. "My only concern is it doesn't seem to me that this is ready for prime-time implementation as a therapy yet."

Bernhard Hering, MD, from the University of Minnesota in Minneapolis, reported that 18 of the 20 patients who received islet transplants at his center (using a slightly different protocol) are insulin-free, and that 11 who received a single infusion have remained insulin-free at one year posttransplant. There were no incidences of portal vein thrombosis or bleeding at Minnesota, Dr.Hering said.

At the University of Miami, 14 of the 15 patients in a slightly different protocol were initially insulin-free, said Rodolfo Alejandro, MD. Thirteen patients received two infusions, and one patient received just one. But nine of the 14 patients had a deterioration of glucose control that required them to go back on insulin, Dr. Alejandro said. Two of those patients subsequently dropped out.

Five patients were given a third infusion of islet cells, and two are being considered for another transplant. Dr. Alejandro said that it is not clear why glucose control worsened, noting that the patients had negative panel-reactive antibodies. But monitoring had revealed an elevated expression of cytotoxic lymphocyte genes.

Miami and Minnesota are also among the nine sites participating in the Edmonton Protocol. The others are Harvard Medical School in Boston, Massachusetts; Washington University in St. Louis, Missouri; the Pacific Northwest Research Institute in Seattle, Washington; Justis-Liebig University in Giessen, Germany; the Universita Vita Salute San Raffaele in Milan, Italy; and University Hospital in Geneva, Switzerland.

The study is being funded largely by the Immune Tolerance Network, which was established through a $120 million grant from the National Institutes of Health in 2000. The study also receives funding from the Juvenile Diabetes Foundation International.

ATC 2004: Abstracts 1434, 1435, 1438. Presented May 18, 2004.

Reviewed by Gary D. Vogin, MD

Alicia Ault is a freelance writer for Medscape.