Marrow Minded

Bone marrow transplantation, a powerful, yet relatively young technique in the fight against cancer, is already showing promise and potential. 
 
by Jon Nalick

Children on playgrounds everywhere know the value of granting a "do-over"-a second chance that corrects an unexpected disruption of game play, basically saying the disruption never happened.

And although cancer treatment is certainly no game, the Bone Marrow Transplant (BMT) Program at the USC/Norris Comprehensive Cancer Center is giving patients something similar to a "do-over" in their fight against the malignancy.

Bone marrow-the spongy tissue inside our hard bones-is responsible for creating oxygen-carrying red blood cells, infection-fighting white blood cells and blood-clotting platelets. And in the last few decades, physicians have radically refined the transplantation of this tissue, giving the procedure the potential to restore certain patients to health-almost as though their cancer had never happened.

"Through bone marrow transplants, more patients with cancers that were recently considered incurable may now be cured," says Dan Douer, M.D., associate professor of medicine and director of the BMT Program.

At the USC/Norris, BMT physicians can use a well-matched donor's marrow to replenish a patient's diseased marrow or may use a patient's own undamaged marrow to ensure a quick rebound after marrow-killing cancer therapies. Once reserved as a last resort for patients for whom all else had failed, bone marrow transplants increasingly have become part of routine treatments for blood diseases that affect tens of thousands of Americans annually. Diseases treated include: chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, myelodysplasia, non-Hodgkin's lymphoma, and severe combined immunodeficiency syndrome.

The BMT Program at the USC/ Norris began in 1988 and has grown to include a broad array of staff members, from physicians, nurses and pharmacists to social workers and dieticians.

"We have a patient-oriented program, with extremely high patient satisfaction and very low mortality compared to the average program nationwide," Douer says.

Matthew Carabasi, M.D., visiting associate professor of medicine, explains that there are two kinds of bone marrow transplants:

With both procedures, physicians use chemotherapy to attack the disease-a process that also destroys patients' existing bone marrow and, consequently, their immune systems as well. Afterward, patients receive new bone marrow cells-either from their own marrow taken before chemotherapy or from a donor-via a simple intravenous transfusion. They recuperate while their bone marrow function recovers. Because of the higher-than-normal doses of chemotherapy given, only patients in good physical condition can be considered for the procedure, says Carabasi, who heads the USC/Norris' Allogeneic BMT Program.

Each type of transplant has strengths and weaknesses.

Autologous transplants are safest because they do not involve injecting cells from another individual. All autologous transplants are by definition a perfect match for the recipient. As a result, physicians performing these transplants are able to use higher doses of chemotherapy.

On the downside, autologous transplants may have a lower chance of curing cancer than allogeneic ones for three reasons. First, some cancer cells are resistant to chemotherapy even when given at very high doses, causing the cancer to recur. Second, using the patient's own bone marrow cells carries the risk that a few cancerous cells might evade the filtration process and begin the disease anew when returned to the body. Finally, the patient's immune system still has the same blind spots that prevented it from identifying cancerous cells as foreign invaders and destroying them in the first place.

Even so, Douer notes that autologous transplants have shown great efficacy in combating some cancers, such as certain forms of lymphoma, multiple myeloma and acute leukemia, which were previously considered universally fatal.

"For example, in relapse cases of certain lymphomas, you knew that the patient was eventually going to die from the disease, but with autologous bone marrow transplants, as many as 50 percent of those patients can be cured, which is a major improvement in treatment," he says.

Douer says that studies are underway to determine whether such transplants will aid patients with breast cancer that has not yet metastasized, although preliminary results have been inconclusive.

Allogeneic transplants come from other individuals and carry their own risks, but also potentially greater rewards. Because the transplanted bone marrow comes from another person, it essentially replicates the donor's immune system in the body of the recipient, whose own immune system was destroyed by chemotherapy.

For years there has been evidence that donor cells have powerful anti-cancer properties-especially against certain leukemias-that may rival the effect of chemotherapy itself, Douer says.

"That led to our attempts to increase that activity while decreasing chemotherapy. And in the last two years, that form of treatment has become more widely used. It's less toxic and as a result patients who are older or more sick can still tolerate it," he says.

A new, transplanted immune system can often identify cancerous cells in the blood as invaders and can obliterate every trace of the cancer and keep it from coming back. This effect is so powerful that with some forms of leukemia, 80 percent of patients can be cured.

"With other diseases, the success rate may be considerably lower-but allogeneic transplant still may give patients their best chance for cure because without the procedure, their likelihood of survival may be zero," Douer says.

Unfortunately, Douer observes, allogeneic transplants carry the risk of graft-versus-host disease, in which the donor's immune cells proliferate but then perceive the patient's own tissues as foreign and begin attacking them.

The problem stems from the fact that the immune system's main function is to constantly patrol the body, finding and destroying what doesn't belong there. The immune system spots these invaders because they do not display the individual's unique antigens, or identifying characteristics. The invaders are most often infection-causing bacteria, viruses, tumor cells and objects such as splinters, whose antigens appear quite different. To do their work, immune cells look for specific proteins located on the outside of cells that identify which ones are constituents of the patient's body and which ones are foreign and need to be destroyed. Scientists call this process "self/non-self recognition."

Unless cells in the patient's body present the correct combination of antigens-ones that match the new immune cells from the donor-some of the patients' cells are often marked for destruction. This is why physicians strive so hard to find donors whose cell markers match those of the recipient as closely as possible, Douer says.

Graft-versus-host disease can appear during the first three months following an allogeneic transplant and can range from mild to potentially life-threatening. In serious cases, the new immune cells may attack the skin, liver, stomach and intestines.

To minimize the risk of the disease, allogeneic transplant patients are given drugs to suppress the immune system before and after the procedure. Use of these drugs, however, increases risk of infection and precautions are required to limit the patient's exposure to harmful bacteria, viruses and fungi. These often include the use of special air-filtering equipment in the patient's room, frequent hand washing and the use of masks and gloves by visitors and physicians.

Patients over age 30 are more likely to develop acute graft-versus-host disease than younger patients. Patients receiving marrow from a female donor who has had two or more viable pregnancies also are more likely to develop the illness.

Carabasi, who has been working in bone marrow transplantation for 12 years and has supervised more than 250 such procedures, says there is a crucial tradeoff: "Although there are ways to make graft-versus-host disease disappear, you lose most of the graft-versus-leukemia effect." Researchers in the Allogeneic Bone Marrow Transplant Program are now seeking ways to maximize the aggressive cancer-fighting

response, while minimizing the potentially harmful side effects.

"We're looking for new mechanisms to deal with graft-versus-host disease, and we are constantly refining our procedures to minimize the risk of this serious complication," he says. "The trick is to lose the part you want to get rid off without reducing the effectiveness of the treatment."

Carabasi also notes, "We now know that exact matches from your family are not always required to safely perform this procedure. This has been a crucial advance because, as the average family size in the U.S. shrinks, patients are less likely to have a perfect match in their family."

Douer agrees that most of the major changes in the last few years have

come in allogeneic transplantation. Researchers are expanding the pool of patients who can receive bone marrow transplants from alternative donors who are either unrelated to the patient or a family member who is not a perfect match. In the best circumstances, such transplants, combined with chemotherapy, can result in cure rates comparable to those seen with perfect family matches.

Still, Douer notes that for now the best donors are most frequently brothers and sisters, who can provide eligible matches roughly 30 percent of the time. Because parents and children share 50 percent of their genetic makeup, parent-child matches can also offer some hope of a match, albeit an imperfect one.

When relatives fail to provide a useable match, national and international registries contain the profiles of millions of volunteers who are willing to donate their marrow. However, the odds of successful matches from unrelated donors can vary wildly depending on ethnicity. For example, non-Caucasian ethnic groups are underrepresented in the registries and finding a match with someone of a different ethnic group is often extremely difficult. Still, the means to cope with such disparities are improving, he says.

While the actual BMT procedure is fairly ordinary in appearance, with a patient simply receiving the cells through a central venous catheter, marrow donations are somewhat more complicated. Donors receive either general or local anesthesia and are placed face down on an operating table. A needle is inserted into the pelvic bone for removal of as much as a quart of marrow. Most donors experience some pain and fatigue, although these symptoms typically diminish over the next several days. In the last few years physicians have learned how to collect the important cells in the bone from the blood, a procedure known as peripheral blood stem cell transplantation, which is being used more frequently than actual transplantation of bone marrow cells.

The storage of bone marrow depends on the type of transplant for which it will be used. With allogeneic transplants, the cells are collected from a donor and usually given immediately to the patient without freezing. In autologous transplants, the cells are frozen first, and can survive for at least 10 years. Usually, no modifications are made. There have been attempts to remove tumor cells from the products, but they have not improved survival, Carabasi says.

The BMT Program usually performs about 20 procedures each year, primarily on patients ranging in age from 18 to 70 years old. Although all transplants to date at the USC/Norris have been autologous, Carabasi has developed the allogeneic portion of the program and is now evaluating patients as potential candidates for the procedure.

Carabasi says that while BMT is a powerful tool in the fight against cancer and one that is undergoing rapid development, it is still a relatively young technique that carries significant risks. Even so, its promise and potential are already apparent.

"It has already given a lot of people a second chance they thought they'd never have," he says

For more information about the Bone Marrow Transplant Program at the USC/Norris Comprehensive Cancer Center, or to learn more about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).

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