First Human Treg Infusion Improves Haploidentical Bone Marrow Transplant in Acute Leukemia

Zosia Chustecka

December 07, 2009

December 7, 2009 (New Orleans, Louisiana) — An innovative strategy of transfusing T-regulatory cells might improve the outcome of leukemia patients who undergo partially incompatible (haploidentical) bone marrow transplants. First results from humans were presented at a plenary session here at the American Society of Hematology (ASH) 51st Annual Meeting by the team that pioneered haploidentical bone marrow transplants 15 years ago.

Dr. Massimo Martelli (Courtesy of ASH)

Bone marrow transplantation is often the only hope of a cure for patients with acute leukemia who are at a high risk for relapse; these patients often have a dismal prognosis with conventional chemotherapy, explained lead researcher Massimo Martelli, MD, professor and head of hematology and clinical immunology at the University of Perugia in Italy.

"But many patients do not have an matched donor, so 15 years ago, working with the Weizmann Institute of Science in Rehovot, Israel, we successfully pioneered transplantation from a partially incompatible family member to extend transplantation to almost all patients," he told journalists at an ASH press briefing.

"Key features of this procedure are infusion of a mega-dose of highly purified hematopoietic progenitor cells to overcome the barrier of incompatibility and ensure engraftment and, second, the removal of donor T lymphocytes from the donor graft to prevent graft-versus-host disease, which is particularly severe in this setting," Dr. Martelli explained. This depletion of T cells is essential; without it there is such a high incidence of graft-versus-host-disease that these haploidentical transplants are impossible to perform, he added.

However, the down side of this strategy is that the T donor cells that are removed are the building blocks of the posttransplant immune reconstitution and, without them, patients face a prolonged immune recovery and are at risk for life-threatening infections, he said.

So the challenge in this study was to transfuse high numbers of donor T lymphocytes to speed up the posttransplant immune reconstitution but to avoid triggering graft-versus-host disease in these patients. "With our innovative protocol, we successfully managed to do just this," Dr. Martelli told journalists.

He explained that the new step involved infusing only a small subgroup the donor T cells, the donor immune-selected T regulatory cells (CD4/CD25+), known as Tregs, which are very important in the control of immune responses. These Tregs were infused into patients immediately after they were isolated from donors, and 3 days before the patients underwent the bone marrow transplant.

The transplant consisted of donor mature T cells and mega-doses of hematopoietic stem cells (CD4+). Patients were prepared for the transplant in the usual way, with high-dose chemotherapy and total body irradiation, Dr. Martelli explained.

A total of 28 patients were treated in this study: 22 with acute myeloid leukemia, 5 with acute lymphoblastic leukemia, and 1 with high-grade relapsed non-Hodgkin's lymphoma.

In 26 of the 28 patients, the transplant led to "a primary and sustained engraftment with a rapid rise in neutrophil and platelet counts," Dr. Martelli reported.

The incidence of graft-versus-host disease was extremely low, in only 2 of the 26 evaluable patients, he said.

Usually in a mismatched situation such as this, without the Tregs, even a small number of donor T cells would trigger a graft-versus-host reaction, he explained. "So we achieved our first goal of giving high numbers of mature donor T lymphocytes without triggering a graft-versus-host reaction, and for the first time we demonstrated that adopted transfer of these Tregs can control the alloreactivity of huge numbers of mature T lymphocytes."

Previously, this has only been achieved in animal models; this is first time it has been achieved in humans, he emphasized.

"More importantly, immune recovery was rapid and sustained, and these patients had normal levels of peripheral T cells within a relatively short period of time," he said. Also, patients had fewer cytomegalovirus episodes than has been seen in historic controls, he added.

Dr. Armand Keating (Courtesy of ASH)

This is a provocative and important study.

With longer follow-up, there is hope that these results will eventually translate into a significant reduction in transplant mortality and improvement in event-free survival, Dr. Martelli noted.

Armand Keating, MD, director of hematology and professor of medicine at the University of Toronto in Ontario, who moderated the press briefing, said: "This is a provocative and important study."

"This is the first example of adoptively transferred regulatory T cells, with preliminary evidence that it results in a situation where there is minimal graft-versus-host disease and, from what we can gather, a reduction in infectious complications, which also bedevil this transplant strategy," he said.

"If these observations can be corroborated, then this suggests that haploidentical transplantation may become more generally feasible if graft-versus-host disease can be minimized to the extent that Dr. Martelli has shown."

Dr. Martelli and Dr. Keating have disclosed no relevant financial relationships.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 4. Presented December 6, 2009

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