Innovative Strategies Improve Outcomes and Reduce Complications Associated With Stem Cell Transplants

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 at the 51st Annual ASH Meeting took a closer look at complications of stem cell transplants, including veno-occlusive disease and graft-vs-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.”

Tregs Prevents Graft-vs-Host Disease After Haploidentical Transplants
Bone marrow transplant is often recommended to patients with acute leukemia who are at high risk for recurrence, but a common complication of the procedure is graft-vs-host disease. When a patient and donor are mismatched (haploidentical transplants), high doses of stem cells  can overcome rejection, a principle that has been successfully pioneered in animal models.  However, in order to prevent graft-vs-host disease, the donor stem cells must be extensively depleted of T cells, which play an important role in immune response. As a result, 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-regulatory cells (Tregs) in an effort to improve immune recovery without causing graft-vs-host disease (abstract 4).

For the first time in humans, researchers in this phase I/II clinical trial evaluated the impact on graft-vs-host disease prevention and immunologic reconstitution of an infusion of donor T-regulatory cells (CD4/CD25+). T-regulatory cells were infused immediately after isolation from donors, 3 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, 5 with acute lymphoblastic leukemia, and 1 with high-grade relapsed NHL. All patients underwent a conditioning regimen that included total-body irradiation (8-Gy single fraction) and a chemotherapy regimen of thiotepa (4 mg/kg × 2), fludarabine (40 mg/m² × 5), and cyclophosphamide (35 mg/kg × 2). Patients were then infused with CD4/CD25+ immune-selected T-regulatory cells (5 patients received 4 × 10⁶/kg;  22 patients received a 2 × 10⁶/kg; 1 patient received a 1 × 10⁶/kg ). Three days later, patients received immune-selected CD34+ cells (median 8.2 cells) together with donor mature T-cells (5 patients received 2 × 10⁶/kg; 17 patients received 1 × 10⁶/kg; 4 patients received 0.5 × 10⁶/kg; 2 patients did not receive donor mature T-cells because the T-regulatory cell infusion was contaminated with donor mature T cells).

Results revealed that long-term protection from graft-vs-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-vs-host disease. No graft-vs-host disease was observed in 25 of 26 patients who could be evaluated. Two patients developed self-limited acute cutaneous graft-vs-host disease, which was left untreated in accordance with current recommendations. One patient developed severe graft-vs-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 posttransplant 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 head of 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.”

Defibrotide to Prevent Hepatic Veno-Occlusive Disease in Pediatric Stem Cell Transplantation
The 100-day survival rates for pediatric patients who have received stem cell transplants has steadily increased. However, it is still associated with significiant mortality and morbidity including complications such as veno-occlusive disease, a disease in which the small vessles in the liver become obstructed. This life-threatening condition has a particularly high incidence in children undergoing allogeneic stem cell transplantation. In this study, researchers from the University of Ulm in Germany assessed the safety and efficacy of defibrotide, an investigational drug, for the prevention of this disease in the largest-ever, international, multicenter study of high-risk pediatric patients undergoing stem cell transplants (abstract 653).  

A total of 360 high-risk patients with a median age of 5 years were enrolled in the study (24% infants, 52% children ages 2–11, and 23% adolescents ages 12–18). Approximately 68% of the patients underwent allogeneic stem cell transplant, and 31% received an autologous stem cell transplant. Patients were prospectively randomized prior to stem cell transplantation to receive either defibrotide or no preventive therapy for veno-occlusive disease. The patients who were randomized to the defibrotide arm received intravenous infusions (25 mg/kg/d) from the start of conditioning until 30 days post–stem cell transplant or discharge from the hospital, whichever came first. In the control arm, patients did not receive any preventive therapy. The primary endpoint of this study was to measure the incidence of veno-occlusive disease after 30 days. Secondary endpoints of the study were to measure veno-occlusive disease–associated morbidity, mortality, and the incidence and severity of graft-vs-host disease.

Preventive use of defibrotide resulted in a 40% reduction in the overall incidence of veno-occlusive disease in these pediatric patients. Consistent with the role of defibrotide in protecting endothelial cells, both the incidence of renal failure (1% with defibrotide vs 6% in controls) and also the overall incidence and severity of acute graft-vs-host disease (32% with defibrotide vs 43% in controls) were significantly lower in the defibrotide arm. In addition, the safety of defibrotide was confirmed by the lack of significant toxicity; the defibrotide and control arms had similar numbers of adverse events reported. Results from this study also confirm that the mortality at 100 days posttransplant in patients who developed veno-occlusive disease was four times higher than the mortality in patients who had not developed this disease.

“For pediatric stem cell transplant patients who develop veno-occlusive disease, we unfortunately have limited diagnostic tools, poor understanding of potential risk factors and mechanisms of the disease, and no established therapies to help prevent or treat this condition,” said lead study author Selim Corbacioglu, MD, assistant professor of the department of hematology, oncology, immunology, and stem cell transplantation at the University of Ulm in Germany. “Our study confirms that defibrotide is safe and effective for preventing veno-occlusive disease in this high-risk population.”