Current Controversy

When Are Bone Marrow Transplants Considered?

very year doctors in the U.S. tell thousands of patients that a bone marrow transplant, and not conventional therapy, may eradicate their disease. The side effects of such a transplantwhich for some cancers is still experimentalcan be substantial, even lethal. Nevertheless, a relatively young and otherwise healthy person faced with a deadly disease will often opt for this chance to be cured. At one time, the term bone marrow soup of developing blood cells [see The Stem Cell, by David W. Golde; Scientic American, December 1991]. Bone marrow can, however, become diseased by aplastic anemia, a condition in which marrow, having degenerated into scar tissue, produces too few blood cells; by leukemia, a disease characterized literally by too many in blood (emia) white (leuk) cells; or by several other disorders. Chemotherapy and radiation, widely used for treating diverse cancers, can also harm marrow. Because blood cells made in the marrow are responsible for ghting bacteria, viruses and other invaders and for causing blood to clot, DONOR damaged marrow results STEM CELLS (FROM MARROW in a high risk of death from OR BLOOD) infection or bleeding, or both. TRANSPLANTATION When the marrow itself is diseased, a transplant is intended to replace it CHEMOTHERAPY with healthy blood-formOR RADIATION ing tissue supplied by a donor. In other cases, a bone marrow transplant PATIENT is done to compensate for the toxic effects of unusually intense chemotherapy. These high levels of drugs kill not only cancer cells but also other fast-growing cells such as those generating blood or hair or lining the mouth, stomach or intestines. The resulting side effects, such as TRANSPLANT PROCEDURE begins with the patient hair loss, nausea or diaror donor providing stem cells. These blood-forming rhea, can be unpleasant cells are stored while the patients malignant cells are or worse; most seriously, killed. The stem cells are then returned to the patient to however, a patient without speed the recovery of bone marrow. enough blood cells would die of infection or bleedtransplant did indeed refer to the mar- ing within a few weeks. Transplant of row found within cavities of the bone; stem cells after chemotherapy helps to today, however, the term often denotes a speed recovery of the blood supply. stem cell transplant. Marrow is rich in To begin a transplant, doctors rst hematopoietic, or blood-forming, stem collect stem cells from a donor or from cells, primitive cells that multiply and the patient. The stem cells may come metamorphose into the different com- from the marrow, or they may be exponents of blood: red cells, which carry tracted directly from the blood. The paoxygen; white cells, which ght infec- tient is then given high levels of radiation; and platelets, which help blood to tion or drugs to destroy any cancerous clot. Although some stem cells also cir- cells. Afterward, the stem cells are inculate in the blood, they reside primari- jected into the bloodstream; they home ly in the marrow, where they generate a to the bony cavities and settle there, re124 Scientific American September 1996
Copyright 1996 Scientific American, Inc.

generating the marrow. Reseeded with stem cells collected from the blood, marrow generally recovers in two weeks, but recovery takes ve weeks if the stem cells come from the marrow itself. (Researchers suspect that some of the stem cells in the blood are more mature and so take less time to complete their development.) Consequently, fewer patients transplanted with stem cells from blood die in the vulnerable period following the treatment, when the blood cells are still too sparse to ward off infections. Unfortunately, because circulating blood sometimes cannot supply enough stem cells for a full transplant, marrow may have to be used. For a patient whose marrow is diseased, a brother, sister or unrelated person with a matching tissue type may be able to donate stem cells, enabling what is called an allogeneic transplant. But even if the major indicators of tissue typeas measured by a procedure called human leukocyte antigen (HLA) typingsignal a perfect match, there may still be minor mismatches. In that case, the immune cells generated by the donated stem cells might recognize the host tissue as foreign and attack it, primarily damaging the skin, bowel and liver. The risk of this complication, called graft versus host disease (GVHD), increases if the marrow comes from an unrelated donor. The risk is also considerably higher for older patients. To test for the likelihood of GVHD, a doctor will typically mix a few donor cells with tissue from the recipient; only donors whose cells have no reaction are accepted. Even so, serious GVHD occurs about half the time, leading to death in about 20 to 30 percent of recipients of allogeneic tissueor in a higher percentage of patients if the tissues match imperfectly. Oddly enough, however, mild or moderate GVHD can be benecial to leukemia patients. The new immune cells also attack the cancerous leukemia cells, resulting in a graft versus leukemia (GVL) effect and thereby reducing the risk of a relapse. In the unlikely event that a patient has an identical twin, he or she can donate stem cells that are perfectly matched, in a procedure called a syngeneic transplant. These cells are safe in that they cannot cause GVHD. (But syngeneic

ROBERTO OSTI

JENNIFER C. CHRISTANSEN

When Are Bone Marrow Transplants Considered?

transplants also cannot give rise to GVL, and thus recipients run a high risk of relapse.) Hematopoietic stem cells can also be obtained from the placenta and umbilical cord discarded after a baby is born: such cord blood transplants appear to pose a lower risk of GVHD. But whereas the number of stem cells obtained from a placenta are enough to perform transplantation on a child, they may be too few for an adult. The most common form of marrow transplant done today is an autologous transplant, in which the stem cells come from the patient, having been withdrawn before chemotherapy. Because marrow obtained from the patient is perfectly matched, there is no risk of GVHD. Unfortunately, marrow from a cancer patient may be contaminated by tumor cells, which at least in theory may cause a relapse (in practice one cannot tell if a cancer recurred because marrow was contaminated or because some cancerous cells in the body survived chemotherapy). But overall, autologous transplant patients have the lowest risk of death from complications. For breast cancer, the mortality for the procedure is generally between 1 and 7 percent; for lymphomas, it is about 10 percent. Marrow transplants are standard for

a few cancers but available in research studies for many. To treat some cancers, doctors usually choose to perform the procedure if the patient can tolerate it. For example, the only curative treatment for chronic myeloid leukemia, in which the white blood cells that ght bacteria are diseased, is an allogeneic bone marrow transplant. An allogeneic transplant is often preferred for patients with severe aplastic anemia or myelodysplasia (a condition marked by abnormal marrow cells, often degenerating to aplastic anemia or leukemia). High-dose chemotherapy or radiation, combined with autologous transplants, is benecial for treating myeloma, recurring Hodgkins disease or aggressive non-Hodgkins lymphoma (malignancies of the lymph system). Advanced or recurring testicular cancer and neuroblastomaa childhood cancer that after a certain point cannot be cured by conventional chemotherapyalso respond to such a combination of intensive therapy and a stem cell transplant. In some other cancers, initial results with the therapy-and-transplant regimen have been promising but remain controversial. In North America, most marrow transplants are prescribed for breast cancer. For women whose cancer has metastaBREAST CANCER sized, conventional chemotherapy can keep the disease NON-HODGKINS LYMPHOMA in check for several years, occasionally a decade or more; however, virtually all such ACUTE MYELOGENOUS LEUKEMIA patients eventually succumb to it. Data from the AutoloCHRONIC MYELOGENOUS LEUKEMIA gous Blood and Marrow Transplant Registry of North OTHER MALIGNANCIES America show that ve years after a marrow transplant, beACUTE LYMPHOBLASTIC LEUKEMIA tween 15 and 20 percent of AUTOLOGOUS the women were still in remis(TOTAL 6,000) HODGKINS DISEASE sion. Physicians are concerned ALLOGENEIC that these results might have (TOTAL 4,000) been skewed by selection of NONMALIGNANT DISEASE relatively healthy women for the transplants. But one small 0 500 1,000 1,500 2,000 2,500 randomized clinical trial NUMBER OF TRANSPLANTS conducted in South Africa IN NORTH AMERICA IN 1994 also reported in 1995 an imSOURCE: International Bone Marrow Registry and Autologous Blood proved, three-year survival and Marrow Transplant Registry of North America MARROW TRANSPLANTS are most often used rate for breast cancer pafor treating breast cancer, even though the efcacy of tients who underwent marthis application is controversial. The transplants are, row transplants as compared on the other hand, known to be benecial for treat- with those who received conventional chemotherapy. ing several cancers involving blood or lymph cells.
JENNIFER C. CHRISTANSEN

Bone marrow transplants can help to compensate for the damaging effects of intense chemotherapy.
Still, the paucity of randomized data on the effectiveness of bone marrow transplants for breast cancer makes this treatment one of the most contentious issues in modern medicine. More than 10 large-scale randomized trials are currently under way, some of which examine transplants for treating locally advanced breast cancers as well as metastasized malignancies. But American researchers are having trouble recruiting enough patients for these trials. Some women do not want to risk being in the control groupand thus not receiving what they consider to be the best treatment. At the same time, some women do not wish to receive a transplant if it is not known to be a better option. The uncertainties of the procedure, however, can be resolved only if the clinical trials can be completed. For some other cancers, patients with little chance of survival through conventional treatments can obtain high-dose chemotherapy with a marrow transplant in research studies. These diseases include ovarian cancer and brain tumors. Recent research has raised hopes of alleviating one risk from bone marrow transplants. An article in the August 3, 1995, New England Journal of Medicine describes how scientists are starting with small amounts of marrow cells and attempting to grow them in the laboratory so that the patient can be given both stem cells and mature cells. This combination would eliminate the period during which he or she is at risk from infections. At present, however, given that the side effects remain daunting, a patient should choose a bone marrow transplant only when the disease is life-threatening and when the potential benets exceed the expected risk. Even so, to some patients with little to hope for, bone marrow transSA plants do offer a new lease on life. KAREN ANTMAN is director of the Columbia-Presbyterian Comprehensive Cancer Center at Columbia University.
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When Are Bone Marrow Transplants Considered? Copyright 1996 Scientific American, Inc.

Scientific American September 1996