Stem cell transplant #ASH09

The methods and outcomes for stem cell transplants are constantly improving as leading experts continue to investigate new approaches for reducing the serious adverse events associated with the procedure. Research presented today at the 51st Annual Meeting of the American Society of Hematology takes a closer look at complications of stem cell transplants, including veno-occlusive disease and graft-versus-host disease.

“While stem cell transplant is one of the best treatment options we have available for many blood cancers, unfortunately, it can sometimes result in severe complications,” said moderator of the press conference Armand Keating, MD, Director, Division of Hematology, and Professor of Medicine at the University of Toronto, Ontario, Canada. “The results of these studies are exciting because they highlight several new, innovative approaches we are taking that not only help reduce these life-threatening complications, but ultimately result in improved outcomes for our patients.”

Bone marrow transplant is often recommended to patients with acute leukemia (a rapidly progressing disease that results in the accumulation of immature, functionless cells in the marrow and blood) who are at high risk for recurrence. A common complication of bone marrow transplantation is graft-versus-host disease, which occurs when donor’s immune system reacts against the patient’s body. When a patient and donor are mismatched (known as haploidentical transplants), high doses of stem cells  can overcome rejection, a principle that has been successfully pioneered in animal models by study co-author Yair Reisner, MD.  However, in order to prevent graft-versus-host disease, the donor stem cells must be extensively depleted of T cells, which play an important role in immune response. As a result of this extensive reduction in T-cells, the recovery of the patient’s natural immune response against infectious agents is delayed, leading to a high incidence of infection-related deaths. Researchers from the University of Perugia in Italy and the Weizmann Institute of Science in Rehovot, Israel, have addressed this key challenge by infusing donor T cells in an effort to improve immune recovery without causing graft-versus-host disease.

For the first time in humans, researchers in this phase I/II clinical trial evaluated the impact on graft-versus-host disease prevention and immunologic reconstitution of an infusion of donor T-regulatory cells (CD4/CD25+), which are a type of T cell that suppresses the body’s immune response and has been shown in several mouse studies to control graft-versus-host disease. T-regulatory cells were infused immediately after isolation from donors, three days before administering the stem cell  graft, which consisted of  donor mature T-cells and a megadoseof hematopoietic stem cells CD34+.

Twenty-eight patients with leukemia or lymphoma enrolled in the study: 22 with acute myeloid leukemia, five with acute lymphoblastic leukemia, and one with high-grade relapsed non-Hodgkin lymphoma. All patients underwent a conditioning regimen that included total body irradiation (8Gy single fraction) and a chemotherapy regimen of thiotepa (4mg/kg x 2), fludarabine (40 mg/m² x 5), and cyclophosphamide (35 mg/kg x 2). Patients were then infused with CD4/CD25+ immune-selected T-regulatory cells (five patients received 4x10⁶/kg;  22 patients received a 2x10⁶/kg; one patient received a 1x10⁶/kg ). Three days later, patients received immune-selected CD34+ cells (median 8.2 cells, range 5.0-19.1) together with donor mature T-cells (five patients received 2x10⁶/kg; 17 patients received 1x10⁶/kg; four patients received 0.5x10⁶/kg; two patients did not receive donor mature T-cells because, for technical reasons, the T-regulatory cell infusion was contaminated with donor mature T cells).

Results revealed that long-term protection from graft-versus-host disease and robust immune system reconstitution can be achieved. For the first time, high doses of T cells were administered in patients who underwent a haploidentical transplant (stem cells from a relative who is a partial match only), which included freshly purified T-regulatory cells to prevent graft-versus-host disease. No graft-versus-host disease was observed in 25 of 26 patients who could be evaluated. Two patients developed self-limited (limiting own growth) acute cutaneous (skin) graft-versus-host disease, which was left untreated in accordance with current recommendations. One patient developed severe graft-versus-host disease.

In addition, the speed of immune recovery was enhanced. More specifically, researchers observed rapid and sustained immunological reconstitution in terms of CD4 and CD8 lymphocyte counts and high frequencies of specific CD4+ and CD8+ cells against microbial agents together with a significant reduction in post-transplant cytomegalovirus reactivation.

“This study demonstrates that T-regulatory cell-based therapy may be an innovative strategy to improve the outcome of patients who undergo bone marrow transplants,” said Massimo F. Martelli, MD, Professor and Headof the Hematology and Clinical Immunology Section at the University of Perugia in Italy and senior author of this study. “We hope that this new method will reduce infection-related mortality and thus improve overall survival.”