From: BMT Newsletter, November 1994 Issue # 26 - BMTs for Acute Lymphocytic Leukemia. Reprinted by NYSERNet with Permission from BMT Newsletter
In 1995, more than 2,000 new cases of acute Iymphocytic leukemia (ALL) will be diagnosed in the U.S. Although primarily a childhood disease, ALL also afflicts adults, particularly those over 50.
Improvements in treatment over the past 20 years have made ALL the most curable type of leukemia. Nearly 70 percent of children and 35 percent of adults who have ALL can be cured with standard chemotherapy alone. Approximately 40 percent of those who relapse following standard chemotherapy can be rescued with a bone marrow transplant (BMT).
Acute Iymphocytic leukemia is a disease of the bone marrow - the organ that produces the body's blood cells. The symptoms of ALL may appear suddenly or present themselves slowly over time. Frequent infections, fatigue, weakness, bleeding, easy bruising, blood blisters, bone pain and irritability are common. The symptoms may fluctuate, particularly in children, with fatigue and fever present one day and absent the next. In some cases, Iymph nodes may swell, and the spleen or liver may become enlarged.
A blood test is the first step in diagnosing ALL. If the results suggest the possibility of ALL, a sample of bone marrow will be extracted - usually from the patient's rear hip bone - and examined for leukemic cells. Once a diagnosis of ALL is confirmed, a sample of spinal fluid will be removed to determine if the leukemic cells have spread to the central nervous system.
Patients with ALL first undergo a round of chemotherapy called "induction chemotherapy" to kill as many leukemic cells as quickly as possible. Various combinations of chemotherapy drugs including vincristine, prednisone. L-as-paraginase and daunomycin are administered during this phase of treatment over a four- to six-week period. Some are administered orally, others intravenously. The patient is usually hospitalized for part of this treatment period to ease infection control and administration of blood products, however much of this therapy can be given on an outpatient basis.
The leukemic cells sometimes infiltrate the central nervous system (CNS) and accumulate in the brain. Since the drugs used for induction chemotherapy do not penetrate the "blood-brain" barrier in sufficient quantities to destroy leukemic cells in the brain, most ALL patients undergo radiation and/or "intrathecal" chemotherapy (injection of drugs into the spinal fluid) using drugs such as Cytosine arabinoside (Ara-C) or methotrexate. This phase of treatment is called CNS prophylaxis and reduces the risk of leukemic cells multiplying in the brain to less than 5 percent.
Ninety to 95 percent of children and 70 to 80 percent of adults achieve a complete remission (there is no evidence of leukemia in their body) following induction chemotherapy. However, without further treatment, virtually all will eventually relapse (the disease will return).
To reduce the risk of relapse, patients are given one to six courses of "consolidation chemotherapy." followed by 21 to 36 months of "maintenance chemotherapy." Consolidation chemotherapy may be administered on an outpatient basis or while the patient is hospitalized. Various combinations of drugs such as tenoposide, etoposide, idarubicin, cyclophosphamide (Cytoxan), cytosine arabinoside (Ara-C) and methotrexate are used for consolidation chemotherapy. Maintenance chemotherapy often consists of methotrexate administered orally or through injections into muscle tissue, and 6-mercaptopurine taken orally.
Despite advances in the treatment of ALL, approximately 30 percent of children and 65 percent of adult patients relapse following standard treatment. Relapse can occur in the bone marrow or in "extramedullary sites" such as the central nervous system or testes. Factors that increase the likelihood of relapse include age over 30, a high white blood cell count at the time of diagnosis, disease that has spread beyond the bone marrow to other organs, genetic abnormalities in the leukemic cells such as the presence of the Philadelphia chromosome, and the need for four or more weeks of induction chemotherapy in order to achieve a first complete remission.
Second complete remissions are achieved in 50 to 70 percent of children and 40 to 50 percent of adults following a second round of standard chemotherapy. Children who relapse three or more years after achieving a first complete remission have a good chance of achieving a second complete remission with standard chemotherapy and a few may be cured of the disease. Those who relapse less than 18 months following initial treatment, especially those who relapse while on chemotherapy have less than a 5 percent chance of becoming long-term disease-free survivors following a second course of standard chemotherapy.
Relapsed adults may achieve a second remission following another course of standard chemotherapy. The duration of remission, however, is usually short - less than six months.
Bone marrow transplantation is a promising treatment option for patients who achieve a complete remission following standard chemotherapy and subsequently relapse, "high risk patients" who are unlikely to be cured by standard chemotherapy alone, and patients who fail to achieve a complete remission following standard chemotherapy. There are three types of bone marrow transplants (BMTs): allogeneic, syngeneic and autologous BMTs.
Allogeneic BMTs are those in which bone marrow from a donor is transplanted into the patient. Patients who have a brother or sister with a matching marrow type are candidates for an allogeneic BMT. Allogeneic BMTs can also be a treatment option for patients with a sibling or other relative whose marrow type nearly matches the patient's (a mismatched donor), or for those who can locate an unrelated donor with a matching marrow type through the National Marrow Donor Program.
In syngeneic BMTs, the bone marrow donor is the patient's identical twin. Because the twin's marrow type exactly matches the patient's, a major complication of allogeneic BMTs - graft-versus-host disease (GVHD) - is avoided.
Patients who undergo an autologous BMT use their own bone marrow for the transplant. Autologous BMTs are a treatment option for patients who do not have a suitable bone marrow donor or who, for reasons of age or physical condition, would have difficulty tolerating complications such as graft-versus-host disease associated with allogeneic BMTs.
Regardless of the type of BMT, the procedure is essentially the same. Bone marrow is extracted or "harvested" from the rear hip bone of the donor (or patient if it is an autologous BMT) where large quantities of marrow are concentrated. If an ALL patient's own marrow is harvested for an autologous BMT, it is usually "purged" after removal from the body in an effort to eliminate any leukemic cells that may be present in the sample. It is then frozen until needed for transplant.
The patient then undergoes a "preparative regimen" of radiation and/or high dose chemotherapy to destroy the remaining bone marrow and any leukemic cells that may have migrated to other organs. The preparative regimen for ALL patients typically consists of total body irradiation plus high dose chemotherapy using either cyclophosphamide (Cytoxan), cytosine arabinoside (ara-C), or etoposide (VP-16). At some centers, busulfan is substituted for total body irradiation.
Following the preparative regimen, the fresh donor marrow (or the patient's own stored purged marrow) is infused or "transplanted" into the patient in a manner similar to a blood transfusion. The infused marrow migrates to the cavities of the patient's long bones where it sets up housekeeping or "engrafts" and begins producing healthy new blood cells.
The primary complications associated with a BMT are infection, and in the case of allogeneic BMTs, graft-versus-host disease (GVHD). To reduce the risk of infection, BMT centers limit the patient's exposure to infectious agents by using special air filters, screening blood products given to the patients, requiring visitors and hospital personnel to wash with antiseptic soap and/or wear protective clothing when visiting the patient, and prohibiting live plants, fruits, vegetables and some foods in the patient's room. In addition, most centers administer antibiotics prophylactically (before infection occurs) to reduce the incidence of bacterial infection.
CMV or cytomegalovirus is a common cause of infection in BMT patients. Patients who have been previously exposed to the CMV virus are twice as likely to develop a CMV infection post-transplant than those who have not. Patients undergoing an allogeneic BMT are more likely to develop a CMV infection than autologous BMT patients, particularly if they receive bone marrow from a mismatched donor.
A CMV infection can develop in several different organs including the liver, colon, eyes and lungs. CMV in the lungs is particularly worrisome, since CMV pneumonia is very difficult to treat and usually fatal. Two to 4 percent of autologous BMT patients and 10 to 20 percent of allogeneic BMT patients develop CMV pneumonia. The incidence of CMV infections is less in children than in adults.
Twenty to 50 percent of ALL patients undergoing an allogeneic BMT experience some form of graft-versus-host disease (GVHD). The incidence of serious GVHD is higher in allogeneic BMTs using unrelated or mis-matched donors. In GVHD, the donor's bone marrow, which has been programmed to destroy anything that does not belong in the donor's body, perceives the patient's body as foreign material. It begins attacking organs and tissues, impairing their ability to function properly and increasing the risk of infection. Most cases of GVHD are mild or moderate, and can be controlled with drugs.
Some BMT centers remove T-cells - the cells believed responsible for causing GVHD - from the donor's marrow before infusing it into the patient. However, completely removing T-cells increases the likelihood that the donor's marrow will fail to engraft. Other centers remove only certain T-cells from the bone marrow pre-transplant. This appears to reduce the risk of serious GVHD without significantly increasing the likelihood of graft failure or rejection.
There is evidence that T-cells responsible for GVHD also confer a graft-versus-leukemia (GVL) benefit on the patient. Relapse rates are lower among patients who experience significant GVHD than among those who experience only mild or no GVHD post-transplant. To preserve the possibility of a graft-versus-leukemia benefit, some centers do not remove T-cells from the donor bone marrow, preferring to treat GVHD if and when it occurs. Other centers remove T-cells from the donor marrow to reduce the risk of GVHD, and administer new agents to induce a graft-versus-leukemia effect after BMT.
BMTs during first remission are often recommended for "high risk" patients, ie. those likely to relapse following standard treatment. Some centers also recommend a BMT for all adult ALL patients in first remission, since the likelihood of long term disease free survival for these patients following standard chemotherapy is only 30 to 35 percent.
Various studies have shown long-term disease free survival rates of 60 percent for adults and 80 percent for children following an allogeneic BMT in first complete remission, and approximately 40 percent following an autologous BMT. These results compare favorably with the 20 to 30 percent chance of long term survival for high risk patients following multiple rounds of chemotherapy. A BMT in first complete remission is particularly appropriate for ALL patients with genetic abnormalities such as the Philadelphia chromosome in their leukemic cells, since the prognosis for these patients is very poor with standard chemotherapy.
Physicians sometimes advise patients to wait until relapse occurs and a second complete remission is achieved before considering a BMT. Thirty to 40 percent of patients who undergo an allogeneic transplant during second complete remission achieve long term disease-free survival. The upside of this strategy is that patients who would otherwise be cured with standard chemotherapy are not exposed to the risks associated with an allogeneic BMT. The downside is that there's no guarantee the patient will achieve a second remission after relapse, or be healthy enough at that time to undergo a BMT. If patients wait until their third complete remission before undergoing an allogeneic BMT, their chance of long term disease free survival drops to 20 percent or less.
Patients who fail to achieve a first complete remission with standard chemotherapy may also undergo an allogeneic BMT. Long term disease free survival can be achieved by approximately 40 percent of such patients following transplant.
Patients who lack a suitable bone marrow donor and are in remission may undergo an autologous BMT. Autologous BMT patients typically experience fewer treatment related complications than allogeneic BMT patients, but their relapse rate after treatment is higher. Most relapses occur during the first year following the BMT.
A bone marrow transplant provides a cure for many patients with ALL. However, approximately 60 percent relapse following treatment. Work is under way to identify new preparative regimens that can more effectively destroy leukemic cells pre-transplant, more effective purging techniques for autologous bone marrow, and better methods of controlling graft-versus-host disease. In addition, researchers are studying the possibility of using biological agents such as interferon or interleukin-2 post-transplant to stimulate certain white blood cells in the body called "natural killer" cells to destroy residual leukemic cells.
The electronic version of this document was created by NYSERNet, Inc. through a grant funded by the New York State Science and Technology Foundation as part of the Breast Cancer Information Clearinghouse.