Since the first successful bone marrow transplant in 1959, thousands of patients with lethal diseases such as severe leukemia, aplastic anemia, and inherited immune deficiencies have been successfully treated with hematopoietic stem cells (HSC). But for all the success stories, transplant physicians seeking to make HSC safer and more widely available continue to grapple with the problems of a limited donor pool, graft rejection, and graft-vs.-host disease (GVHD). Bone marrow for many years was virtually the only source of HSC-self-renewing, unspecialized cells that give rise to all of the hematologic and immunologic cells-but transplant physicians increasingly are making use of stem cells collected from peripheral blood or the umbilical cord.
TOP OF THE LIST: Wisconsin's Mary Horowitz notes that breast cancer is the No. 1 indication for a hematopoietic stem cell transplant.
Autologous transplantation involves removing a cancer patient's own HSC-now, almost always derived from peripheral blood-administering high-dose chemotherapy that kills tumor and stem cells alike, and reinfusing the stem cells to repopulate the patient's marrow.
The effectiveness of the therapy for metastatic breast cancer has yet to be proved in randomized clinical trials, however. "Although the results of autologous transplants look better than historic results of conventional therapy," explains Horowitz, "there's a certain selection process in deciding who gets a transplant that may bias that interpretation" (K.H. Antman et al., Journal of Clinical Oncology, 15:1870-9, 1997). Two large, randomized National Cancer Institute (NCI) trials should finish accrual this year, according to Horowitz, with results available in "a couple of years."
One of the major roadblocks to more widespread use of allogeneic transplants is the scarcity of human leukocyte antigen (HLA)-matched donors. Ideally, donors should be HLA-matched siblings. The incidence of GVHD, a life-threatening illness in which donor-derived natural killer (NK) and T cells launch an attack on the recipient's own cells, is highly correlated with the degree of genetic disparity between donor and recipient HLA antigens.
BROADENING AVAILABILITY: Allegheny's Suzanne Ildstad says her program aims to make bone marrow transplantation possible for more patients.
In the past, scientists tried to prevent GVHD by depleting the bone marrow of NK and T cells prior to the transplant, but the stem cells invariably failed to engraft. Ildstad has proposed that the procedure used to deplete T and NK cells from the bone marrow also removed a cell-which she calls a facilitator cell-critical for engraftment (M. Neipp et al., "Graft Engineering: Requirements for Hematopoietic Stem Cell Engraftment: The Role of Graft Facilitating Cells," in R.E. Champlin, A.D. Ho, eds., Hematopoietic Stem Cell Therapy, Cambridge University Press, in press). Ildstad believes that facilitator cells "keep the stem cells primitive. We have very strong evidence that if we mix facilitating cells with purified stem cells, it keeps them in [a stable resting] phase."
Ildstad has transplanted T cell-depleted bone marrow cells highly purified for stem and facilitator cells into 11 patients with highly advanced malignancies who lacked suitably matched donors. "Our preliminary data looks very encouraging," she says. "Historically, there is a 70 percent failure of engraftment when a T cell-depleted marrow is transplanted into highly mismatched recipients. We have a 100 percent engraftment rate." Although the seven surviving patients have varying degrees of GVHD, Ildstad says it is "controllable." Ildstad was slated to present her data in a poster session at the 39th annual American Society of Hematology (ASH) meeting in San Diego, which started December 5.
HIGH POTENTIAL: Duke's Joanne Kurtzberg is investigating use of umbilical cord blood in infants with genetic disease.
Last year, Kurtzberg reported that cord blood transplants from unrelated (and, for the most part, HLA-mismatched) donors successfully engrafted in more than half of a group of high-risk patients, most of them children (J. Kurtzberg et al., New England Journal of Medicine, 335:157-66, 1996). Despite the HLA incompatibility, GVHD was mild. But Horowitz points out that children are at lower risk for GVHD than adults, anyway. "I would have to say that the question is still unanswered," she says.
Although individual units of cord blood contain adequate numbers of HSC for transplantation in children, adults generally require higher doses. Patrick J. Stiff, an associate professor of medicine and director of the bone marrow transplant program at Loyola University Medical Center, is evaluating the use of cord blood cells expanded ex vivo for use in adults who do not have other appropriately matched bone marrow donors. (Kurtzberg heads up the pediatric arm of the project.) The studies, sponsored by Aastrom Biosciences Inc. of Ann Arbor, Mich., use a device designed to expand small numbers of cord blood or bone marrow stem cells ex vivo.
In a previously reported study (P.J. Stiff et al., Proceedings of the American Society of Clinical Oncology, 16:89A, 1997), Stiff used the Aastrom system to expand a small amount of bone marrow-about 38 cc-collected from patients with advanced breast cancer who were about to undergo high-dose chemotherapy. Conventional bone marrow transplant procedures generally require a liter of bone marrow. "This may make it possible to convert stem-cell collections into a brief outpatient procedure," says Stiff. There also is evidence, he points out, that the procedure eliminates malignant cells remaining in the bone marrow. Stiff was scheduled to present an updated report of the study at the ASH meeting this month.
Hematopoietic stem cell transplants may become the treatment of choice for at least some patients with sickle cell disease (SCD) and other hemoglobin disorders, including thalassemia. Last year, an international group of researchers published a study showing that 16 of 22 children with SCD were cured by bone marrow transplants from HLA-identical siblings, with stable engraftment of normal blood-forming cells (M.C. Walters et al., N. Engl. J. Med., 335: 369-76, 1996). Four of the children rejected the grafts (and continue to have SCD), and two died shortly after the transplant. Because of the inherent risks associated with transplantation itself, the patients selected for the trial had already experienced at least one stroke, several episodes of acute chest syndrome, or painful crises-three of the most common and disabling symptoms of SCD.
"We knew that by selecting patients who already had significant disease, we probably wouldn't get the good results we might otherwise get if we chose asymptomatic kids," explains Keith M. Sullivan, a professor of medicine at the University of Washington and member of the Fred Hutchinson Cancer Research Center in Seattle, who was principal investigator of the study. Since that paper was published, the group has added another 12 children to the study. "We have not had a single graft rejection or death in this most recent study," Sullivan reports.
For most of the children, the greatest barrier to the study was having an HLA-identical sibling, not the cost associated with the transplant. "We were pleasantly surprised," Sullivan acknowledges. Fewer than 10 percent of the patients were turned down by their insurance carriers for the trial. Indeed, Sullivan explains, state and insurance agencies were often supportive of the National Institutes of Health-approved study. "About two-thirds of the kids on this study had been on transfusions at the time of transplant," says Sullivan, "because they'd had a previous stroke." The standard of therapy for children with SCD who have suffered a stroke is transfusion and chelation therapy, at a cost of $30,000 to $40,000 a year.
| Aastrom Biosciences Inc.|
P.O. Box 376
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Fax: (313) 665-0485
American Society of Hematology
International Bone Marrow Transplant Registry (IBMTR)
ADVANTAGEOUS APPROACH: M.D. Anderson's Richard Champlin uses donor lymphocyte infusion for patients who can't tolerate very-high-dose chemotherapy.
One of the advantages of this approach, according to Champlin, is that it can be used with people who can't tolerate very-high-dose chemotherapy. Champlin has used this method to treat about 50 patients in a series of trials, and while he says that longer follow-up will be needed to assess the long-term effectiveness of the approach, about 40 percent of the patients in the largest trial are alive and free of disease.
Separating the GVL effect from GVHD remains a challenge. One novel approach now undergoing evaluation in clinical trials uses suicide gene therapy to eliminate the GVHD-causing T cells (C. Bordignon et al., Human Gene Therapy, 6:813-9, 1995). The donor lymphocytes are transduced with the herpes simplex virus thymidine kinase (TK) gene, rendering them sensitive to ganciclovir treatment. Any ensuing GVHD can be stopped by ganciclovir treatment.
Government funding for clinical trials remains inadequate, many researchers stress. Corporations such as Aastrom are actively funding trials that may allow them to license their products, but "there isn't enough money for truly innovative research," says Champlin. "The drug companies are looking to license their product, so they often want to study a very narrow, simple, straightforward application, as opposed to the more innovative applications we would propose ourselves."
Sullivan's experience notwithstanding, since the early 1990s most insurance companies have excluded coverage of treatment administered as part of a clinical trial from their health insurance policies. "They don't want to fund anything that would be outside the existing standards of care," comments Champlin, "and we all know that the standard of care in cancer treatment in virtually every disease is not satisfactory. Participation in clinical trials is in fact the best care patients can receive. We all understand that the war against cancer is far from being won, and although we're making a lot of progress, we need to sustain that progress in order to translate that into actual patient benefit."
Sara Latta is a science writer based in Champaign, Ill.