Researchers Extending Potential for Stem Cell Transplants

by Claire Keller, RN, MN, OCN, and Stacy Thieszen, National Marrow Donor Program (NMDP)

In December 2002, physicians attending the annual meeting of the American Society of Hematology (ASH) shared their latest findings on treating people with blood disorders. This article highlights several research studies investigating approaches that may improve outcomes for people treated with stem cell transplants.

Non-Myeloablative Transplants

Non-myeloablative transplants, also called mini-transplants or reduced intensity transplants, continue to be studied as an option for older people and others whose disease stage, previous transplants or other medical conditions make them ineligible for a standard transplant. With standard transplants, patients receive pre-transplant conditioning consisting of very strong chemotherapy and/or radiation therapy to suppress their immune systems and destroy diseased cells. Non-myeloablative transplants use less intense pre-transplant conditioning. Because this conditioning is less toxic to a patient's body, it may enable people who could not tolerate the standard pre-transplant conditioning to receive a transplant. Although researchers have seen positive results using non-myeloablative transplants for several years now, they are still trying to determine several things:

• The ideal type and intensity of pre-transplant conditioning. The conditioning regimens used vary widely between transplant centers and studies.
• Whether patients who receive non-myeloablative transplants will stay in remission from their disease long-term.
• How to better reduce and treat graft-versus-host disease (GVHD), a common complication following allogeneic stem cell transplants (transplants using related or unrelated donors). There are two types of GVHD: acute GVHD, which typically appears about three months after transplant, and chronic GHVD, which usually develops later. Chronic GHVD has appeared at higher rates following non-myeloablative transplants than after standard transplants.

At the ASH annual meeting, researchers from six transplant centers presented results from a study involving 89 patients who were ineligible for standard transplants because of older age, advanced disease stage, previous transplants or other medical conditions (Abstract 275, Maris). Patients were given very mild pre-transplant conditioning (a low dose of fludarabine for three days and total body irradiation on the day of transplant). They then received a transplant using bone marrow or peripheral blood stem cells (PBSC) from unrelated matched donors. Though not all patients benefited from this treatment, the results suggest that for some patients not eligible for a standard transplant, non-myeloablative transplants could be a treatment option.

• The rate of severe acute graft-versus-host disease (GVHD) was low, with a rate of 44 percent of grade II GVHD, 8 percent for grade III GVHD and 2 percent for grade IV GVHD. (The severity of GVHD is ranked grade I-IV, with grade IV the most severe.).
• The rate of chronic GVHD was within the range expected for standard transplants, with 57 percent of patients getting chronic GVHD that required therapy.

A second study of non-myeloablative transplants was done at City of Hope in California (Abstract 277, Rodriguez). In this study, 22 patients who were ineligible for standard transplants were treated with reduced intensity conditioning (fludarabine for five days and a standard dose of melphalan) prior to a transplant using a matched unrelated donor. Researchers reported that the side effects of the pre-transplant conditioning were limited and the rate of GVHD was within the expected range.

• 41 percent of patients had severe acute GVHD.
• 27 percent of patients had extensive chronic GVHD.

Outcomes from the study were encouraging. Thirteen of 22 patients were alive, with 12 in complete remission an average of 11 months post-transplant. Though this was a small study, the results were especially encouraging for patients who had previous autologous transplants (transplants using the patient's own stem cells), because these patients often have very poor outcomes from second transplants. Of the 14 patients who had previous autologous transplants, eight were alive and in remission at an average follow-up of 10 months.

Cord Blood Transplants for Adults

A cord blood transplant uses the blood collected from a newborn infant's umbilical cord, which is rich in blood stem cells. The blood is collected from the umbilical cord after the baby's birth and frozen for potential use in stem cell transplants.

Cord blood transplants have been used mostly for children or smaller adults because of the limited number of stem cells in a cord blood unit. The number of stem cells in relation to a patient's weight is important in achieving engraftment (the point when the transplanted stem cells begin to grow and make new blood cells).

Cord blood transplants are an exciting area of investigation because cord blood may not need to be as closely matched to the patient as marrow or PBSC. This may enable more patients who cannot find a matched donor to receive a transplant. Because it is already stored, cord blood also is usually available for transplant more quickly than volunteer unrelated donors. Because of these potential advantages, some centers are looking at the possibility of using cord blood for adults. The three studies described here are part of this investigation.

The largest of the three was a French study that compared results of unrelated donor cord blood transplants in 81 adults to unrelated donor bone marrow transplants in 162 adults. All had acute leukemia (Abstract 148, Rocha). The researchers found:

• The time to engraftment was shorter for patients who received bone marrow.
• Even though the donors for bone marrow transplants were more closely matched to the patients than the cord blood transplants, the probability of disease relapse and patient survival outcomes were similar for the two groups.

The authors of the study advised that cord blood units that met minimum size requirements and had no more than a two out of six HLA antigen mismatch could be used as an alternative to bone marrow for adults with acute leukemia. They recommended that searches for unrelated PBSC or bone marrow donors and cord blood units be done simultaneously. (Searches for unrelated donors conducted through the NMDP automatically return results for both volunteer donors and cord blood units.)

A study done by the Cord Blood Transplantation (COBLT) group included 34 adults (Abstract 146, Cornetta). Because using cord blood in adults is still under investigation, this study and the University of Minnesota study described below both involved patients who were considered to be at high risk because their disease was relapsed or resistant to treatment. Most patients in this COBLT study received transplants using cord blood units that were mismatched at two out of six HLA antigens (this would be a high rate of mismatch for marrow or PBSC transplants). The severity of GVHD was low compared to that expected using mismatched bone marrow or PBSC. The authors reported that 22 of the 34 patients survived 42 days or longer after transplant, and they all engrafted between days 13 and 55 post-transplant. Only four patients were alive 373 days or more after transplant; however, this was believed to be partly because the patients treated were high risk. Given these risks, the researchers considered the low rate of GVHD and fairly high rate of engraftment encouraging enough to suggest further studies with patients at more standard risk.

A study at the University of Minnesota investigated another approach to cord blood transplants for adults (Abstract 142, Barker). Because one cord blood unit was not likely to have enough stem cells for the patients in this study, researchers tried combining two cord blood units to see whether the higher number of stem cells would improve engraftment. Twenty-three high risk adult patients received transplants using two cord blood units. The patients who received standard pre-transplant conditioning engrafted at an average of 24 days (similar to engraftment using a single cord blood unit, but a few days longer than usual for marrow or PBSC). Some patients received milder non-myeloablative pre-transplant conditioning, and these patients engrafted at an average of 13.5 days. The rates of GVHD were roughly the same as would be expected if the patients had received bone marrow or PBSC. The estimated survival rate at one year for these patients was 33 percent, which is lower than would be expected for patients in remission or with disease responsive to treatment. However, considering the limited treatment options for these high-risk patients, the authors felt that results suggested the rate of engraftment was improved by using two cord blood units. This experimental treatment may eventually allow more adults to be treated with cord blood, but further investigation is needed.

Severe Sickle Cell Disease

Researchers are also investigating whether it is possible to successfully treat patients with severe sickle cell disease with a stem cell transplant. Sickle cell disease is an inherited blood disorder that causes chronic anemia and episodes of pain. Children with severe symptoms of sickle cell disease are at risk for stroke, acute chest syndrome (a painful and life-threatening complication similar to pneumonia) and damage to organs. There is no known cure for severe sickle cell disease, but stem cell transplant is one of the potential treatments being investigated. Researchers in France reported very positive results using stem cell transplants (Abstract 4, Bernaudin). Since 1988 they have used stem cell transplants from matched sibling donors to treat 60 children with severe sickle cell disease. The authors reported an 85 percent survival rate. Six of the 60 children died, four of them because of GVHD. The surviving children had no signs of disease, no further strokes and some improvement in organ function.

Abstract Details

The abstracts described above are available online from the American Society of Hematology (ASH) web site, http://www.hematology.org/meet ing/abstracts.cfm. After creating a user name and password, you can find the abstracts by searching on the author's name.

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