Q:Please tell me the success rate for bone-marrow transplants in patients with leukemia. L G, Norwich.
A:Since the Eighties, bone-marrow transplants have become the medical flavour of the month for all sorts of illnesses, particularly cancers. For non-malignant diseases, the procedure is used for patients with severe aplastic anemia (hence its periodical necessity with AIDS patients given AZT, which suppresses red blood cell production), inherited diseases like thalassemia and sickle cell anemia, and immunodeficiency diseases in children. However, the treatment has really come into its own with a variety of malignant diseases: a number of types of leukemia (acute myeloid, acute lymphoblastic and chronic myelogenous leukemias; non-Hodgkin's lymphoma, the disease that killed Jacqueline Kennedy, and Hodgkin's disease, all sorts of solid tumours like ovarian and cervical cancer, brain tumours, and most recently (and controversially) for breast cancer.
In the procedure some 100 million to 300 million blood progenitor [parent] cells from bone marrow the soft tissue filling the spaces in the spongy part of bone shafts, where the blood cells are made are taken by needle from the lower back or even the breast bone, then intravenously infused in order to re-establish bone-marrow function in a patient whose blood cell making capabilities are damaged or defective.
There are two means of getting such cells: either through the transfer of marrow from a donor (allogeneic transfer) or from the patient himself (autologous transfer), where the patient's own marrow is used to re-establish blood cell regeneration.
The greatest problem with donor marrow is finding a good match. The most successful donor is a genetic double an identical twin but otherwise, the donor must have genetically identical or similar material on one of his chromosomes (something called the HLA antigen). Next to twins, there is about a one-in-four chance of this match among each brother or sister. Otherwise, the patient must find someone unrelated with a similar HLA-matched bone marrow willing to donate some of it.
This can be a difficult task since the combination of HLA types is larger than the entire population of the world, acording to Dr James Armitage, in a recent New England Journal of Medicine review of bone-marrow-transplant studies (24 March 1994). Nevertheless, says Armitage, people from similar ancestry tend to have a similar HLA type hence the development of the National Marrow Donor Program in the US, which provides a registry of bone-marrow donors.
The patient receiving the bone-marrow donation must undergo a succession of risky procedures in order to ensure that the graft "takes". High doses of chemotherapy or radiotherapy (or often both) are given to suppress the patient's immune system, basically so that there won't be active enough cells to destroy the graft. However, this ballistic approach supposedly ensures that there won't be any lingering cancer cells and also that there is space for the new marrow to grow, says Armitage. Some studies suggest that the infused cells have an anti-cancer effect.
The biggest problem with foreign transplants, as with any transplants, is the risk of graft versus host disease, in which, in effect, the patient is "allergic" to the transplant. These side effects include skin lesions with swelling, open sores, redness and scaling, loss of hair, a variety of gastrointestinal disturbances, and problems with the liver, the joints and the heart. However, the most life-threatening complication, says Armitage, is often profound immune suppression. In order to guard against developing this syndrome, patients receiving donor bone marrow get just-in-case therapy with cyclosporine (an immunosuppressant for organ transplants see Cover Story, p 1), the chemotherapy drug methotrexate and steroids. Another favourite safeguard is to remove T-cells (the white blood cells which make up the body's immune system response) from the graft.
Nevertheless, most adults develop graft versus host disease, particularly those over 55, generally considered the threshold for safe donor bone-marrow transplants. Untreated, the condition is fatal, says Armitage. This means that patients getting foreign bone marrow are likely to need further powerful drug treatment this time with steroids like prednisone, cyclosporine or even thalidomide.
The other possibility is that the host will simply reject the graft, a possibility more likely if the patient has some active immune system cells, has had previous blood transfusions and more mild preparatory drugs, such as chemotherapy, rather than true immunosuppressants like cyclosporine.
Other side effects include a variety of complications in the lungs, such as a form of pneumonia, and a complication of the liver (veno-occlusive disease), afflicting as many as 50 per cent or more of patients undergoing bone-marrow transplantation, and possibly causing fatal liver and kidney failure.
One recent study at the Marrow Transplant Program at the University of Minnesota in Minneapolis, Minnesota, examining autologous transplants in 200 patients with chronic myelogenous leukemia the largest study to date claimed that autologous transplants provide the best survival rates of all conventional treatments for the condition. The study concluded that the patients in their programs had a high rate of the transplants "taking" and low mortality. Seventy-five per cent of young and old patients reported prompt return to normal activity (The Lancet, 11 June 1994).
Although the report considers mortality "low", 75 patients or more than a third of the study group died after transplant. The median survival rate was 42 months that is, on average, treatment prolonged life by three and a half years, with younger patients surviving longer. Furthermore, the majority of patients still had evidence of recurrent CML, suggesting that the bone marrow transplant at best bought a few years of time, and not as much as other conventional therapies. This is a far cry from a "cure".
Another study comparing the use of intereron alfa-2a against conventional chemotherapy (the most common treatment to date) showed the best results with interferon. Among 322 patients, those given interferon lived an average of six years, compared to four and a quarter years with chemotherapy (New Eng J of Med, 24 March 1994). (Interferon has its own set of side effects, considered worse than those of chemotherapy: lowered blood cell count, flu-like symptoms, head and joint aches, nausea, anorexia, diarrhea and weight loss, plus certain neurological symptoms, including depression and confusion, and even coma and death.)
Obviously, bone-marrow transplantation isn't a therapy to be considered lightly, since it may be riskier or offer a poorer quality of life than the life-threatening situation which it is used to treat. It seems to work best with aplastic anemia (50 per cent of patients have disease free survival, according to Armitage's review of the literature) and thalassemia (75 per cent survival) and sickle cell anemia. In cases of malignant diseases, it offers the best hope for patients in a first complete remission of acute myeloid leukemia (40-70 per cent), but less well (20-40 per cent) in those in a second remission stage. Many doctors hence offer bone-marrow transplants only after chemotherapy has failed in patients with this disease and other forms of leukemia. The reverse is true with non-Hodgkin's lymphoma and Hodgkin's disease, in which doctors believe that patients should get high doses of chemotherapy and bone-marrow transplants early on in the course of the disease.
Bone-marrow transplants have even less success with breast cancer or testicular cancer. Although Armitage claims that autologous transplants result in a higher rate of "complete response" than with chemotherapy, only 10-30 per cent of breast-cancer patients have survived after at least two years with this therapy, and only 10-20 per cent of patients with testicular cancer. In America, insurance companies consider the treatment controversial for breast cancer and have refused to accept it and thus reimburse for it as a standard therapy.