When Judge Morris was diagnosed with leukemia 10 years ago, doctors told him he would need a bone marrow transplant to survive.

"It gave me hope for a cure, but the big question was whether I'd ever find the right donor," says Morris, 47. The odds of finding a marrow donor in the general population are typically 1 in 20,000. Because of a rare genetic makeup, Morris' odds were 1 in a million.

For the next four and a half years, the Tulsa, Okla., resident underwent chemotherapy treatments and waited. He prepared his family for the possibility that he might not be around to see his two children grow up. "Then an angel named Mike Giglio came into our lives," Morris says. The National Marrow Donor Program found Giglio through its network, and Morris received a bone marrow transplant from Giglio in March of 1993.

"The leukemia is gone, I'm off medication, and not a night goes by that I don't thank Mike for saving my life," Morris says. At seven years post-transplant, the chance that the leukemia will return, experts say, is less than 5 percent.

Each year, bone marrow transplants give patients a chance to beat diseases once believed to have no cure. Although the first successful bone marrow transplant didn't take place until 1968, the discovery of human leukocyte antigens (HLA) in 1958 was a major breakthrough because it allowed recipients to be matched with donors.

Since then, the procedure has steadily advanced as research uncovered ways to improve transplant techniques. Donor registries have grown significantly and drugs that prevent rejection and infection have improved. The Food and Drug Administration reviews new drugs used to prepare patients for bone marrow transplants, and drugs that aid in recovery. The FDA also reviews so-called growth factors, genetically engineered substances that stimulate growth of the transplanted cells.

Treating a Spectrum of Diseases

Bone marrow, a jelly-like substance in the cavities of our bones, contains hematopoietic (blood-forming) stem cells, commonly referred to as simply "stem cells." These cells are critical for life because they continually produce red blood cells, which carry oxygen; white blood cells, which help fight infections; and platelets, which act as clotting agents to stop bleeding.

Bone marrow transplants may help cure diseases that interfere with the production of any of these types of cells. These include cancers such as leukemia, Hodgkin's disease and other lymphomas. For Judge Morris and others with chronic myelogenous leukemia (CML), a common form of leukemia, abnormal white blood cells fill up the bone marrow, enter the bloodstream, and can invade organs and tissues. Transplants also may help patients with non-cancerous conditions characterized by a deficiency in blood cell production, such as aplastic anemia and inherited immune disorders.

Diseases of blood-making cells in the marrow are hard to cure because traditional treatment--chemotherapy or radiation--destroys not only abnormal cells, but also normal cells. A bone marrow transplant allows doctors to treat patients with high-dose therapy--effectively killing all the cells in the bone marrow--and then replace the damaged marrow with healthy marrow. Craig Mullen, M.D., a member of the pediatric bone marrow team at the University of Texas M. D. Anderson Cancer Center, likens the situation to having a weed in your garden. "You have to kill it, but in doing so, you'll kill the other plants around it," he says. "The only way to get a new garden is to plant new seeds and repopulate it."

In earlier years, transplants were more commonly performed in the late stages of disease. But the 1970s marked a shift toward performing transplants during remission from disease, a change that improved patient outcomes.

Doctors have also used bone marrow transplants in experimental treatments of patients with solid tumor cancers (breast and testicular, for example) that require aggressive treatment with high doses of toxic drugs. Transplants are used to try to "rescue" the patient from the high doses of chemotherapy needed to destroy the cancer, which also destroys the marrow. Werner Bezwoda, Ph.D., a South African researcher, gave the scientific community and cancer patients hope for this experimental procedure through his studies of breast cancer patients. Dating back to 1990, the studies showed an overall survival advantage for high-dose chemotherapy and transplant in women with breast cancer and stimulated a wide acceptance of this treatment. But in February 2000, Bezwoda's work was discredited after an external audit and his own admission to falsifying data. Many scientists, however, think the procedure may still have merit. "You can't rule the treatment out just because we didn't find evidence of it working in limited trials," says Grant Williams, M.D., an oncologist in FDA's Center for Drug Evaluation and Research. "We need further data before we can know whether it works or not."

Two Types of Transplants

Transplants usually are categorized as allogeneic or autologous. Allogeneic transplants use bone marrow cells from another person who is genetically similar. The transplant is called syngeneic if the donor is an identical twin, which makes for a perfect match. Autologous transplants, the most common type, use the patient's own cells, which are removed, frozen, and reinjected later. In 1998, there were approximately 37,000 autologous bone marrow transplants and 17,000 allogeneic transplants worldwide, according to the International Bone Marrow Transplant Registry.

FDA reviews devices used in the collection, processing, purging and storage of stem cell products. In July 1999, FDA approved two cell separation devices that can select stem cells and decrease the number of cancerous cells that may be inadvertently re-infused into a transplanted recipient. "With autologous transplants (in which a patient uses his or her own stem cells), there may be tumor cells circulating in the bone marrow or blood that we don't want to give back," explains Stephen Litwin, M.D., a medical officer in FDA's Center for Biologics Evaluation and Research. Cell separation devices allow doctors to separate healthy stem cells from tumor cells. Litwin notes that the long-term benefits of this tumor "purging" have not been proven in clinical trials.

The Transplant Process

"One misconception about bone marrow transplants is that the bone marrow is the only important part of this process," says Richard Jones, M.D., director of the bone marrow transplant unit at The Johns Hopkins Oncology Center. Bone marrow is certainly important, Jones says, but so is the chemotherapy or radiation treatment that precedes a transplant. "In many cases, the preparative therapy is the most important part" of the overall treatment. Therapy destroys cancer cells and defective marrow and makes room for new marrow.

This preparative regimen can be either high-dose chemotherapy or high-dose chemotherapy combined with total body irradiation, an x-ray procedure that exposes the whole body to radiation and penetrates all the body's cells. "The chemotherapy is about 10 times higher than doctors normally would give," Jones says. The anti-cancer drugs used for chemotherapy depend on the protocol of the treatment center and the type and stage of disease, but busulfan and cyclophosphamide are the most common. In February 1999, FDA approved an injectable form of busulfan. Previously used only in pill form, it's meant for use with cyclophosphamide as a conditioning procedure before allogeneic bone marrow transplants for CML.

Because side effects include severe nausea and vomiting, M. D. Anderson's Mullen says some researchers are rethinking the basic approach to transplants as it was laid out 30 years ago. "That approach was: Let's put together as toxic a drug regimen as we can and hope that the patient will survive," Mullen says. "Now some are asking whether such toxic doses are really necessary." He adds that some transplants in the adult program at the Anderson Center have been effective with lower doses of chemotherapy than were previously thought necessary. But the level needed depends on the stage and nature of the patient's disease.

Post-Transplant Recovery

After the transplant, it takes two to four weeks for engraftment--the process by which the new stem cells find their way to the bone marrow space and begin producing blood cells. Because the preparative regimen wipes out the patient's immune system, warding off infections during the recovery period is critical. Patty Clark, 41, of Baltimore, says her father served as a lymphocyte donor during her transplant. That means he gave her white blood cells to bolster her immune system, a common way to boost immunity. Her father's donated white blood cells helped protect her against infections while the new bone marrow took root and began producing its own white blood cells. Other precautions include practices such as having visitors wear a mask and gloves to protect patients from infection. Clark received an autologous transplant in spring 1999 as part of ovarian cancer treatment.

Other potential complications include organ damage from chemotherapy, bleeding problems, and two types of rejection related to the bone marrow transplant. "You're not only replacing the organ, but you're also bringing a whole new immune system with it," explains Dennis Confer, M.D., chief medical officer at the National Marrow Donor Program. One type of rejection occurs when the residual immune system of the person receiving the transplant rejects the donated marrow; a second, scarier form of rejection occurs when the donor marrow rejects the body of the patient, in what's known as Graft Versus Host Disease (GVHD). According to Confer, if the recipient rejects the marrow, blood counts will stay low. In GVHD, immune cells in the new marrow recognize the recipient as foreign and attack tissues in the body. Blood counts will come up, but the patient will experience symptoms such as a loss of appetite and energy, diarrhea, and a skin rash. If uncontrolled, GVHD will be fatal.

The immunosuppressive drug cyclosporine plays a major role in the success of an allogeneic transplant because it can help prevent GVHD and interstitial pneumonia, a lung infection caused by cytomegalovirus. "If you've had this virus and you undergo a marrow transplant, there's a high chance that it will reactivate," Confer says. Sometimes doctors also give patients growth factors, genetically engineered substances that stimulate a faster return of white cells. Examples are granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF).

As for success rates of bone marrow transplants, experts generally agree there is no clear-cut answer. These rates depend on many factors, including the type and stage of disease, the condition of the patient at the time of the transplant, the donor, and the age of the patient. Success can range from 80 to 90 percent for children with inherited abnormalities of the immune system to as low as 10 percent for patients with aggressive, resistant diseases.

Alternative Sources of Stem Cells

Researchers realized in the late 1980s that stem cells are not only found in bone marrow, but also in the bloodstream. When stem cells are collected from the bloodstream, they are called peripheral blood stem cells. "The challenge is that stem cells don't generally circulate in large numbers in the peripheral blood," FDA's Litwin says. Growth factors--also known as mobilizing agents--are given to stimulate the bone marrow to produce more cells, which are then released into the bloodstream. To collect these cells, blood is circulated through a cell separator that removes peripheral stem cells and returns the rest of the blood--including hemoglobin-containing red cells--to the body. The process is called apheresis.

FDA and the National Marrow Donor Program are studying peripheral blood stem cells as an alternative to bone marrow for initial transplants. This procedure has been most widely used as a follow-up transplant to supplement the marrow transplant, Confer says. The research aims to document the safety of this collection method and compare how donors view bone marrow transplants vs. peripheral stem cell transplants. "As we learn more," Confer says, "I anticipate we'll find out that there are some diseases for which peripheral blood is superior and others for which bone marrow is superior."

In the last decade, doctors have also used stem cells collected from umbilical cord blood for bone marrow transplants. This new field is expected to widen the donor pool, but it is still considered experimental. One limitation is that the number of stem cells found in cord blood is small because babies are small. "As a result, engraftment is slower than if you obtain stem cells from the bone marrow or the peripheral blood," Litwin says. Again, growth factors can help increase the number of cells. Under another FDA-sponsored study, the National Marrow Donor Program has invited cord blood banks to apply for membership to its registry. The program receives federal funding from the Health Resources and Services Administration to manage the registry.

FDA and the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, have co-sponsored a series of workshops on stem cells over the past several years. With the discovery of alternative sources, FDA proposed in 1997 to regulate stem cells collected from peripheral and umbilical cord blood. The proposed approach centers on preventing the transmission of communicable diseases and assuring that stem cell procedures are safe and effective. FDA continues to work on developing the best methods and practices to prevent contamination of tissue and preserve stem cell integrity.

The newest alternative source of stem cells involves taking existing cells--from either the bone marrow, peripheral blood, or cord blood--and expanding them in a lab. This procedure is already being used but is highly experimental and challenging. "So far, it's been easier to get stem cells to mature than to self-replicate," Confer says, "but the potential is tremendous. We want to be able to turn a million stem cells into 10 million."

Increasing the Donor Pool

About 30 percent of people who need a transplant have siblings who, because they are a tissue match, are suitable donors. But many people must look to registries of unrelated donors in order to survive. Increasing the donor pool has been a key part of advancing the search process, Confer says. The National Marrow Donor Program, which helps locate unrelated donors in the United States, had 8,000 registered donors when the program began in 1987. Now the registry is up to about 4 million.

Global cooperation has also been key, giving patients access to donors wherever they reside. "No one could have guessed 10 years ago that there would be 6 million international donors today," Confer says.

Donor shortages, however, do exist in racial and ethnic minority populations, including African Americans, Hispanics, Asians/Pacific Islanders, and American Indians/Alaska Natives. "It's not that an African American has to have an African American donor," Confer says, "but the best chance [for a match] would be within your group." The National Marrow Donor Program continues to conduct outreach and recruitment strategies for these populations. The program receives funds from the U.S. Navy for advancing the science of human leukocyte antigens and increasing diversity of the donor pool.

The National Marrow Donor Program is looking at ways to make the search for donors faster and more efficient. A search takes 100 days on average, but it can be as short as 20 to 30 days or as long as years, Confer points out. "But too many people have diseases that just won't stand for a long search."

Michelle Meadows is a writer in Laurel, Md.

Becoming a Donor

Mary Halet, of Minneapolis, Minn., says that being a bone marrow donor was one of the most important events in her life. After giving bone marrow in 1993, she arranged for a donor center coordinator to pass along an anonymous note to the recipient. "I wished her well and told her that this is a small part of me that I hope can be a big help to her," Halet says.

Unlike heart or lung transplants, bone marrow transplants don't involve surgery. Doctors remove marrow with a needle that is inserted into the hip bones in the pelvis, the most marrow-rich site in the body. The sternum, the bone in the middle of the chest, is another possible site. Marrow is then delivered intravenously to the recipient like a blood transfusion.

The removal of marrow for transplant is usually an outpatient procedure that takes about an hour and is performed under general or regional anesthesia. "It's important for donors to know and understand the risks," Halet says, "but many safety precautions are taken." Donors may experience back discomfort for three to five days. "I had the procedure on a Friday, and I was out riding my bike on Monday," Halet says. "If the goal is to help someone have a chance at life, then I can endure a few days of discomfort." Lost bone marrow replenishes itself in a few weeks.

In accordance with confidentiality rules, Halet only knew that her recipient was a 23- year-old female with chronic myelogenous leukemia. "Even though we never met, I have a kindred connection with her," says Halet, a former bone marrow researcher who now works as a search coordinator for the National Marrow Donor Program. Her recipient died 11 months after the transplant, and Halet still keeps in touch with her family. One year after a transplant is performed, donor and recipient families are allowed to meet.

For More Information

National Marrow Donor Program
3433 Broadway St., N.E., Suite 500
Minneapolis, MN 55413-1762
1-800-MARROW2 (1-800-627-7692)
www.marrow.org

International Bone Marrow Transplant Registry
Medical College of Wisconsin
PO Box 26509
Milwaukee, WI 53226
414-456-8325
www.ibmtr.org

The American Bone Marrow Donor Registry

Information for donors:

American Bone Marrow Donor Registry Headquarters
PO Box 8841
Mandeville, LA 70470-8841
1-800-745-2452
www.abmdr.org

Information for patients:

Caitlin Raymond International Registry
University of Massachusetts Medical Center
55 Lake Ave., N.
Worcester, MA 01655
1-800-726-2824
www.crir.org

Publication No. (FDA) 00-4273