By Melissa Weber

Susan Williams didn’t want to take any chances. Four rounds of chemotherapy put her acute myelogenous leukemia—first diagnosed in 1998—into remission. At the time, doctors told the now 36-year-old from Scranton, Pennsylvania, she had a 20 percent chance of staying in remission.

“That wasn’t good enough for me. My chances for staying in remission increased to 80 percent with a donor transplant. I wanted that 80 percent chance.” Of her two siblings, Williams’ brother John was a perfect match and became her donor.

Referred to as bone marrow transplant for many years, the more correct term used today is hematopoietic stem cell transplant. Bone marrow, the spongy material inside the bone, is the natural home for hematopoietic stem cells, which are the parental cells that develop into three different types of blood cells: red blood cells (carry oxygen), white blood cells (fight infection) and platelets (help the blood to clot).

High doses of chemotherapy and/or radiation, while useful to destroy cancer cells, have the unwanted side effect of damaging or destroying a patient’s bone marrow stem cells. Thus, stem cell transplants “rescue” patients from this high-dose chemotherapy treatment. Stem cells for transplant can come either from a donor (allogeneic transplant) whose tissue type matches that of the patient (this is usually a sibling but can be an unrelated donor) or from the patient’s own body (autologous transplant).

A Look Back

While the world was caught up in swing music, Gone with the Wind and World War II, American scientists were making early attempts to use allogeneic marrow transplants for curative purposes. The atomic bomb explosions in Hiroshima and Nagasaki stimulated a great deal of interest in lethal irradiation and its treatment.

In 1957, E. Donnall Thomas, MD and his colleagues at Mary Imogene Basset Hospital in Cooperstown, New York, reported the first successful allogeneic bone marrow transplant in a patient with cancer. They achieved a remission in a leukemia patient who had received total body radiation to kill the leukemic cells followed by bone marrow transplant from an identical twin. (Identical twins were used because they share the exact genetic makeup as the patient and, at that time, methods for identifying compatible donors were not known.)

“Those early transplant patients had a very low survival rate,” says Frederick Appelbaum, MD, director of the Clinical Research Division at the Fred Hutchinson Cancer Research Center in Seattle and head of Medical Oncology at the University of Washington. “Leukemia would recur, and there were many complications, such as infection and bleeding.”

A year after Dr. Thomas’ findings were published, autologous bone marrow transplant was first reported. The autologous procedure involved collecting and freezing the patient’s marrow prior to cancer treatment, with reinfusion of thawed marrow after treatment.

“The phrase ‘bone marrow transplant’ originated in the actual method in which bone marrow was surgically removed,” says Edward Agura, MD, director of the Blood and Marrow Transplant Program at Baylor University Medical Center in Dallas. “The donor or patient was put to sleep, needles were put in their hips, marrow was sucked out and then the marrow was dripped in by transfusion into the recipient.”

But the method—and the name—started to change in the mid-’80s with the discovery of hematopoietic growth factors, which are hormone-like substances that naturally stimulate the growth and release of stem cells from the marrow into the blood. (Examples include Neupogen^® [filgrastim], Neulasta^® [pegfilgrastim] and Leukine^® [sargramostim].)

By increasing quantities of these hematopoetic stem cells in the bloodstream using growth factor, stem cells can be collected by passing the peripheral (circulating) blood through a cell-separating machine, thus avoiding the need for anesthesia and minimizing pain and discomfort to the donor. These stem cell collections can be done as an outpatient procedure.

“The stem cells are a small fraction of the cell types in the marrow, but they have the ability to grow and repopulate the normal marrow,” says Dr. Thomas, who won the 1990 Nobel Prize in Medicine for his work in bone marrow transplantation.

And so today, doctors have the choice of collection location—either from the bone marrow or by giving growth factors and collecting from the peripheral blood. “Neither source of stem cells is better than the other,” says Dr. Thomas, but Dr. Agura notes blood collection is easier on the donor as well as the patient with a large majority of today’s transplants done through blood collection.

From Start to Finish

The first step in the process of transplantation is a medical determination of what type of transplant a patient needs: autologous or allogeneic.

The second step is collection of stem cells from the patient or donor. If the cells are taken from the patient, they are frozen and stored for later use. If the stem cells are obtained from a donor, they are usually infused in the patient soon after collection and may not need to be frozen.

The third step is high-dose treatment in the patient to kill any remaining cancer cells, commonly referred to as conditioning. Conditioning may consist of high doses of chemotherapy drugs or a combination of total body radiation and chemotherapy. This typically takes three to seven days or longer depending on the regimen.

After the patient receives high-dose treatment, the stem cells are infused into the patient. The infusion procedure is fairly straightforward, and stem cells are put back in the circulating blood through an intravenous line. The cells find their way to the bone marrow, where they divide and mature into cells normally produced by healthy bone marrow in a process known as engraftment.

“Engrafting is like when you decide to grow your front lawn from seeds, and, in our case, the seeds are the stem cells,” says Dr. Agura. “You scatter the seeds by transfusing them back into the patient. You add a little water and sunshine and wait seven to 10 days for the seeds to sprout. What we’re waiting for after the transfusion itself is for the cells to grow to the point to make the patient healthy.”

Engraftment almost always occurs in autologous transplants because “the patient’s own marrow or blood stem cells are the most compatible cells,” says Dr. Thomas. And although engraftment does occasionally fail in allogeneic transplantion, Dr. Agura says, “If it does happen, it’s not difficult to turn to the donor and say, ‘May we have some more please?’” However, a second transplant may not be successful because of the complications of prolonged lack of a functioning marrow.

Because a patient’s immune function is low for several weeks to months after the transplant, isolation in a protected environment was previously thought necessary, but isolation as it used to be practiced is no longer needed.

“We found isolation didn’t help,” explains Dr. Appelbaum. “It decreased a little bit the incidence of infection, but did not improve survival. Patients do have their own private room, and family members can be with them easily and hold them and touch them.” Dr. Appelbaum also points out the importance of exercise and encourages patients to walk the hospital hallways every day.

Follow-up periods differ from one cancer center to the next, but autologous transplant patients are typically followed closely for about one month after transplantation before being sent back to their regular oncologist for care. Longer and more intensive follow-up is needed after allogeneic transplant, and patients may need to return to the transplant center regularly for at least three months and then continue their follow-up at less frequent intervals for up to a year and beyond.

Transplant Benefits Various Malignancies

Stem cell transplants are used predominantly in patients with cancers arising from the blood or plasma cells, including lymphoma, leukemia, myeloma and Hodgkin’s disease. Although allogeneic or autologous transplants can be done for patients with hematological malignancies, patients with leukemia usually undergo allogeneic transplant while those with lymphoma and myeloma typically receive autologous transplant.

In the past, autologous transplants were tried in high-risk breast cancer patients, but studies failed to show any clear benefit of transplant in this group. Transplant has also been tested in ovarian cancer and small-cell lung cancer with no proven benefit.

Allogeneic transplants are commonly done for both acute and chronic lymphocytic and myelogenous leukemias (see CURE, Fall 2002). Although most allogeneic transplants still use sibling donors, today’s trend toward smaller families is making it harder to find compatible sibling donors.

Only about one in three patients who need a donor transplant have a matched family donor, which has resulted in an increase in the use of unrelated donors. In order to determine a match, doctors use a special blood test to identify sets of proteins called human leukocyte-associated (HLA) antigens. The greater the number of matching HLA antigens, the better the chance the patient’s body will accept the donor’s stem cells.

The National Marrow Donor Program (NMDP) maintains a central database of the millions of individuals who have agreed to provide their stem cells on a volunteer basis to patients who need them. While those needing a donor can frequently find one through the NMDP, it is often difficult to find unrelated donors for minority patients. NMDP is making a major effort to encourage volunteers from various ethnic backgrounds to participate as potential donors.

“When a potential match is identified,” says Dr. Thomas, “confirmation of typing is carried out and arrangements made to collect the marrow. Marrow can safely be transported so that the collection can be made in the donor’s hometown and taken to the patient’s hospital for infusion.”

Allogeneic Transplant

Beth Schrader, diagnosed in 1998 at age 25 with chronic myelogenous leukemia, was told chemotherapy would buy her five to 10 years. But the Fort Wayne, Indiana, resident was determined to raise her then 2-year-old daughter.
“I told my doctors I needed a cure,” she says.

Fortunately, Schrader was able to undergo allogeneic transplantation in April 1999 from an unrelated matched donor.

Schrader and Williams were ideal candidates for allogeneic transplant—they were young and healthy enough to withstand the rigors of the process. But for older patients in their 60s and 70s, some forms of leukemia and lymphoma can be treated using minitransplant (see sidebar), a procedure that uses low as opposed to high doses of radiation or chemotherapy before infusing stem cells.
However, Dr. Agura points out that “this type of transplant appears to work primarily on slow-growing cancers and is still being tested in clinical trials.”

Graft Versus Host Disease

A sometimes life-threatening side effect associated with allogeneic transplant, graft versus host disease (GVHD), occurs when the new donor cells (the graft) recognize the patient’s existing cells (the host) as foreign. Particular graft cells called T cells may attack the host cells, damaging a patient’s skin, liver, lungs or other organs. GVHD occurs more frequently and more severely in older patients.

“Using a donor’s stem cells avoids the problem of contamination [with cancer cells] but introduces the problem of incompatibility,” notes Dr. Thomas.

Dr. Agura adds, “When you’re doing an allogeneic transplant, you’re basically moving an entire immune system ‘army’ from the donor into the patient. And it takes some time for this ‘army’ to settle down and be happy in its new home. During this adjustment period, graft versus host reaction may occur.”

Depending upon age, about one in three adults will get GVHD that requires treatment with immunosuppressive agents. Ironically, a little bit of graft versus host reaction may actually benefit the patient since residual cancer cells are also targeted by the attack. “The risk of cancer recurrence seems to be lower in patients who have mild GVHD,” explains Dr. Agura, “although the graft versus tumor effect, as it is called, is not all-powerful and can only remove a limited amount of residual cancer.”

Researchers continue to explore ways to improve the effectiveness of stem cell transplants, making use of the force of T cells but controlling them at the same time.

Autologous Transplant

“When a patient is getting his or her own blood cells back,” says Dr. Agura, “all we’re really doing is helping to speed recovery from chemotherapy.” In this setting, the only anticancer effect comes from the conditioning regimen itself.

One concern with autologous transplant is that the stored stem cells may be contaminated with cancer cells, leading to the eventual “reseeding” of the cancer when the cells are transfused back into the patient. Therefore, for many years, physicians performed trials in which collected stem cells were “purged” by a variety of laboratory methods in order to remove contaminated cancer cells.

By and large, however, these methods did little to change the cancer recurrence rate following autologous transplantation. Today, for tumor types such as B-cell non-Hodgkin’s lymphoma, tumor cell purging can be performed “in vivo”—or in the patient—using newer drugs such as Rituxan^® (rituximab) that target lymphoma cells in the marrow prior to stem cell collection. And, although the problem of cancer recurrence remains with autologous transplant, no risk exists for GVHD or marrow failure, making this type of transplant more feasible for older patients.

Making Progress

Advances in the technologies used to perform stem cell transplant have made it safer, more available and more effective for a broader range of cancer patients.

“In our center, we were doing 10 transplants a year in the early 1990s,” says Richard Champlin, MD, professor and chairman of Blood & Marrow Transplantation at M. D. Anderson Cancer Center in Houston. “Now we’re doing more than 600 a year.”

Dr. Champlin adds that when the procedure was initially developed, it was reserved for end-stage patients, but “as results of treatment have been refined, we now recommend people have it done earlier, either as the initial treatment or after the first round of chemotherapy.”

Dr. Appelbaum is quick to point out “the most important part of the art of transplant is understanding when to apply it, and we are sometimes disturbed that patients aren’t referred early enough, and it’s only tried as a last resort when success is very low. Patients need to be proactive in talking to their physician, and they need to undertake it with a full understanding.”

But he praises the strides made in providing supportive care needed after patients undergo a transplant. Doctors now have methods to fight infections that used to be fatal.

Williams didn’t suffer from infection or side effects and credits her optimism and support network of family and friends with getting her through the transplant process. “I think having a positive attitude is half the battle.”

Schrader is celebrating her fifth year of being cancer-free since her transplant. “Undergoing a transplant was absolutely the best treatment decision I could have made,” she says. “If I had to go through it all again, without question, I would.”