A Closer Look
When Allogeneic Stem Cell Transplants Fail
The field of hematopoietic stem-cell transplantation (HSCT) has come a long way since the first successful procedure was performed on a patient with severe combined immunodeficiency syndrome in 1968.
In patients with cancers of the blood, such as leukemia and lymphoma, HSCT was initially used to allow for higher doses of chemotherapy and radiation therapy during treatment; today, oncologists also use it to take advantage of a phenomenon known as the graft-versus-leukemia/lymphoma (GVL) effect, in which the new immune cells produced by a matched donor (allogeneic) transplant can recognize cancer cells as a threat to the body and destroy them, reducing the rate of disease relapse.
Six clinical trials are part of a new program at NCI focusing on the problem of relapse after allogeneic hematopoietic stem cell transplantation. One of these trials, featured in this issue of the NCI Cancer Bulletin, will examine the ability of an antitumor vaccine to increase the efficacy of donor lymphocyte infusion. The vaccine is designed to trigger an immune response against a protein called WT1, which is produced by many blood cancers but not by normal cells. [Enlarge]
At the same time, reduced-intensity conditioning regimens that don’t completely destroy a person’s bone marrow are being used more commonly before allogeneic transplantation, making the procedure itself safer—cutting the risk of treatment-related death—and extending the benefit of the GVL effect to older patients who could not undergo more intensive conditioning regimens.
Unfortunately, despite the GVL effect, the number one cause of death following HSCT is relapse, with more than a third of patients eventually dying from recurrent disease. And the risk of relapse after reduced-intensity regimens is up to double that seen with higher-dose conditioning, reducing the survival benefit gained from the lower risk of death during treatment.
When patients do relapse after HSCT, the only standard treatment available to them is a procedure known as donor lymphocyte infusion (DLI), in which additional immune cells from the donor are re-infused in hopes of triggering additional GVL activity. But this option is effective only in a minority of patients, mostly those with chronic myelogenous leukemia.
For these reasons, several new initiatives are under way to bring together leaders in the transplantation and oncology communities for a more organized approach to address the problem of relapse after HSCT.
Creating a Road Map for the Field
NCI-sponsored International Workshop Focused on Relapse
More than 250 participants came to the workshop in Bethesda, MD, including transplantation experts but also scientists working in tumor immunology, tumor biology, and non-immunotherapeutic approaches to treating hematologic cancers. The focus areas included:
- The biology underlying recurrence of malignant disease following allogeneic HSCT: factors related to the graft-versus-leukemia effect
- The biology underlying recurrence of malignant disease following allogeneic HSCT: factors unrelated to the graft-versus-leukemia effect
- The epidemiology and natural history of relapse
- Strategies and therapies used in the prevention of relapse
- Methods and strategies for monitoring relapse following allogeneic HSCT
- Treatment of disease relapse following allogeneic HSCT
Each of the six focus groups from the workshop will publish a review article in the journal Biology of Blood and Marrow Transplantation in 2010. The articles will outline the current state of the science, ongoing research, and areas where additional focus and collaborative research efforts are most needed.
Two of the six articles, on the biology of the graft-versus-leukemia effect and the epidemiology and natural history of relapse, were published online in February and April, respectively.
NCI sponsored the First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in November 2009.
“We wanted to bring the transplant community together, but also bring in fresh ideas,” explained Dr. Michael Bishop of NCI’s Center for Cancer Research (CCR), who served as co-chair of the workshop along with Dr. Sergio Giralt from the University of Texas M. D. Anderson Cancer Center.
The workshop covered six major areas of focus, and the proceedings from those discussions will be published throughout 2010. (See the sidebar.) “We wanted to create a reference manual for everyone who is doing transplantation—where we are in terms of the science, and where we need to be,” said Dr. Giralt.
The workshop is only one part of a larger NCI effort to tackle the problem of relapse after transplant in a more organized, systematic fashion, said Dr. Alan Wayne, clinical director of the Pediatric Oncology Branch in CCR.
“Researchers have been developing clinical trials focused on this problem for many years, but for the most part these trials have been driven by individual investigators in the context of relatively specific research questions,” he explained. “It became clear to us that we didn’t really have an organized program that crossed branches of NCI and other institutes at NIH.”
Under the leadership of Dr. Bishop, Dr. Wayne, and Dr. Nancy Hardy from CCR, a new program that aims for cross-institutional organization now includes a tumor board where doctors can present cases to a group and discuss recommendations for care, including treatment in clinical trials, and a special clinic for patients who have relapsed after allogeneic HSCT.
The team is also writing a dedicated protocol to study the natural history, biology, and treatment of patients with relapse after allogeneic HSCT across age groups and institutes. “This will serve as a mechanism to recruit, study, and treat these patients in a more systematic, organized way,” said Dr. Wayne.
The program currently has six new clinical trials in progress, including one trial examining the ability of a vaccine to enhance the efficacy of DLI after relapse, and more planned for the near future.
“Less than five percent of patients with relapsed, progressive disease after allogeneic transplantation are currently treated on institutional review board-approved clinical trials,” said Dr. Bishop. “This is an area that needs significant research focus to systematically address what remains the primary cause of death after transplant.”