From BMT Newsletter September 1994 Issue #25 - BMT's for Acute Myelogenous Leukemia Reprinted by NYSERNet with permission from BMT Newsletter
In 1994, an estimated 28,600 new cases of leukemia will be diagnosed. More than 19,000 deaths are expected to occur from the disease.
Leukemia is a disease of the bone marrow - the organ that produces the body's blood cells. There are four main types of leukemia: acute myelogenous leukemia, acute Iymphocytic leukemia. chronic myelogenous leukemia and chronic Iymphocytic leukemia.
This issue of BMT Newsletter will discuss the use of bone marrow transplantation (BMT) to treat acute myelogenous leukemia (AML). also called acute non-lymphocytic leukemia (ANLL ). Future issues will discuss bone marrow transplantation for the other leukemias.
Blood is composed of many different kinds of cells. each with a specific function. The most numerous are red blood cells (erythrocytes) which transport oxygen to tissues throughout the body. White blood cells (leukocytes) help fight infection Platelets (thrombocytes) are needed to control bleeding.
Mature blood cells evolve from primitive cells in the bone marrow called pluripotent stem cells. Pluripotent stem cells produce myeloid stem cells and Iymphoid stem cells that, in turn. produce cells that mature into red blood cells, white blood cells or platelets. Millions of new blood cells are produced hourly.
The Iymphoid stem cells produce three types of white blood cell.s: T-lymphocytes (T-cells), B-lymphocytes (B-cells). and natural killer cells (NK cells). The T-lymphocytes are the body's main defense against infections caused by viruses and protozoa. The B-lymphocytes produce proteins called antibodies which help destroy harmful foreign organisms in the body. Natural killer cells play a role in the destruction of tumor cells.
Myeloid stem cells produce red blood cells and platelets. as well as four different types of white blood cells: monocytes, neutrophils (also called granulocytes). eosinophils, and basophils. Monocytes are large cells that engulf and destroy invading bacteria and fungi. Neutrophils (granulocytes) also play an important role in killing bacteria. Eosinophils and basophils play a role in regulating allergic reactions such as asthma, hives, hay fever and drug reactions.
Blood cells that have not yet matured are called blast cells. Acute leukemia occurs when blast cells replicate themselves uncontrollably rather than evolve into normal, mature blood cells. The leukemic blast cells crowd out and interfere with the production and activity of normal blood cells. making the patient anemic. susceptible to infection and/or prone to bleeding. If undetected or left untreated. acute leukemia can be fatal within a matter of weeks or months.
If the defective blood cell is produced by the Iymphoid stem cell. the condition is called acute lymphocytic leukemia. If it is an offspring of the myeloid stem cell. the diagnosis is acute myelogenous leukemia. occasionally. leukemias may involve both defective Iymphoid and myeloid cells.
More than 10,000 new cases of acute myelogenous leukemia are diagnosed annually in the US,. accounting for 45 percent of all cases of leukemia. AML is more common among men than particularly over the age of 50.
Although the cause of AMLis unclear, there is some evidence linking AML to radiation, benzene, and radon exposure. Persons with certain hereditary disorders such as Down's syndrome, Fanconi's anemia. and Bloom's syndrome have an increased risk of developing AML. Patients treated with intensive chemotherapy for Hodgkin's disease, non-Hodgkin's Iymphoma, ovarian cancer. breast cancer, and myeloma also have a greater risk of developing AML than the general population.
The symptoms of AML are similar to symptom.s associated with many common illnesses: fatigue, malaise, fever, respiratory infection, pale complexion, dizziness. headaches and bone pains. Some patients experience unusual bruising. petechiae (small red dots on the skin), or severe hemorrhages such as nosebleeds. A complete blood count and the removal of a small sample of bone marrow are necessary to accurately diagnostic leukemia.
AML is classified into several subtypes (M0 through M7), depending on the type of blood cell involved and the stage at which maturation stalled. With the exception of subtype M3 (acute promyelocytic leukemia). there is little correlation between the subtype of AML and the responsiveness of the disease to treatment. Breaks or rearrangements of chromosomes in the leukemic cells of AML patients are common and may predict how the disease will respond to treatment.
The usual course of treatment for AML involves one or two rounds of "induction" therapy followed by "post-remission" therapy. The goal of induction therapy is to achieve a complete remission, ie. to eliminate all evidence of the disease. The goal of post-remission therapy is to eliminate undetected leukemic cells that linger after the patient has achieved a complete remission.
Induction therapy usually consists of 5 to 10 days of treatment with the chemotherapy drug cytarabine (Ara-C), combined with daunorubicin (Daunomycin), doxarubicin (Adriamycin), idarubicin (Idamycin), or mitoxantrone (Novantrone). A complete remission of the disease can be achieved in 70 to 80 percent of patients who have no prior history of cancer, are under the age of 65, have normal liver and renal function, and are otherwise in good health. Fewer complete remissions (35 to 55 percent) are achieved among older patients, those with a prior history of cancer, and those with liver. renal or other health problems.
Bone marrow transplantation (BMT) is being used increasingly to treat patients with AML who are in first remission, or who have relapsed.
Most patients with acute promyelocytica leukemia (M3) have a particular genetic abnormality in the leukemic cell that may permit a different induction therapy. In a national clinical trial, patients are being randomized to either standard chemotherapy or to treatment with an oral vitamin-A derivative called alltransretinoic acid that causes leukemic cells to mature into healthy, normal cells. Patients may then undergo a round of consolidation therapy (see below).
The majority of AML patients who achieve a complete remission following induction therapy subsequently relapse. Several different post-remission therapies have been used in an effort to extend the period of remission or provide a cure.
Most patients receive a second round of chemotherapy called consolidation or intensification chemotherapy. The same drugs used in induction chemotherapy are often used in the second round of chemotherapy, although the schedule and dosage may differ. Thirty percent of adults and 40 to 50 percent of children with AML are cured following consolidation or intensification chemotherapy.
Maintenance chemotherapy - 2 to 3 years of low dose chemotherapy - is sometimes offered following consolidation chemotherapy. However, to date, there is no evidence that maintenance chemotherapy improves upon the results achieved with consolidation chemotherapy alone.
Bone marrow transplantation (BMT) is being used increasingly to treat patients with AML who are in first remission or who have relapsed. Cure rates range from 10 to 70 percent, depending on the stage of the disease, the patient's age and general health, the source of the bone marrow used in the transplant, and the institution performing the BMT.
Allogeneic BMT's are those in which bone marrow from a donor is transplanted into the patient. An allogeneic BMT is an option for patients who have a brother or sister with a matching marrow type who can serve as a bone marrow donor. It may also be an option for patients with a sibling or other relative whose marrow nearly matches the patient's (a mis-matched donor), or for those who can locate an unrelated donor with a matching marrow type through the National Marrow Donor Program.
In an allogeneic BMT, the patient's diseased bone marrow is destroyed with a "preparative regimen" of either high dose chemotherapy and radiation, or high dose combination chemotherapy. Cyclophosphamide (Cytoxan) is the chemotherapy drug most often used in combination with TBI. Programs that use high dose chemotherapy without radiation usually combine cyclophosphamide with busulfan (Myleran) or Etoposide (VP-16).
The donor's marrow is then infused into the patient in a manner similar to a blood transfusion. The donor 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 an allogeneic BMT are infection and 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 drugs prophylactically (before infection occurs) to reduce the incidence of bacterial infection.
Approximately 50 percent of patients undergoing an allogeneic BMT experience some form of graft-versus-host disease (GVHD). The incidence of serious GVHD is somewhat 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 properly function 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. While completely removing T-cells reduces the risk of GVHD significantly, it increases the likelihood that the donor's marrow will fail to engraft and produce new blood cells. At least one center has tackled this problem by removing only certain T-cells (the cell called CD-8) from the bone marrow pre-transplant. This technique appears to reduce the risk of serious GVHD without significantly increasing the likelihood of graft rejection.
Relapse rates are lower among patients who experience significant GVHD than among those who experience only mild or no GVHD following transplant, although long-term survival rates do not differ significantly due to the sometimes fatal complications caused by severe GVHD. Since relapse rates are lower among patients who experience GVHD, many centers do not remove T-cells from the donor bone marrow, preferring to treat GVHD if and when it occurs. There is evidence that the T-cells responsible for GVHD also confer a graft-versus-leukemia (GVL) benefit on the patient. Research is underway to determine how to eliminate the dangerous complications associated with severe GVHD without losing the graft-versus-leukemia benefit.
The optimal time to transplant patients with AML is an unresolved question. Many physicians believe patients should undergo a BMT while in first remission. Several small studies conducted over the past ten years report disease-free survival rates of 50 to 70 percent following an allogeneic BMT in first remission, using marrow from a matched sibling donor. Disease-free survival rates of 45 percent have been reported among patients using unrelated bone marrow donors, with survival rates highest among patients under 30 years of age.
Other physicians recommend postponing a BMT until after the first relapse, since consolidation chemotherapy can cure 30 percent of adults and 40 to 50 percent of children. The upside of waiting until after first relapse is that pa tients who are curable with consolidation chemotherapy are not exposed to the risks of a BMT. The downside is that the disease may be more widespread and difficult to eradicate following relapse, and the patient may be in poorer overall health and less able to withstand the rigors of a BMT. Twenty five to 30 percent of patients under the age of 50 who undergo an allogeneic BMT with a matched sibling donor immediately following first relapse can be cured.
"We don't yet know which strategy is optimal: transplanting all AML patients while they are in first remission or transplanting only those who relapse follow- ing consolidation chemotherapy," says Herbert Kaizer MD, Rush-Presbyterian St. Luke's Medical Center, Chicago IL. "Since a substantial number of patients are cured following consolidation chemotherapy, and many of those who relapse can be rescued with a BMT, transplanting AML patients in first remission must produce much higher cure rates than conventional therapy in order to be optimal."
Although most patients with AML undergo a BMT during first remission or immediately after first relapse, BMTs have also been used successfully to treat AML patients who fail to achieve a complete remission, those in second relapse, and those who relapse more than a year following their first BMT. Ten to 20 percent of such patients can achieve long term disease free survival following an allogeneic BMT.
Although an allogeneic BMT is an effective treatment for AML, only 25 to 30 percent of AML patients have a brother or sister with a matching marrow type who can serve as a donor. The use of mis-matched and unrelated donors increases the opportunity for an allogeneic BMT only slightly. AML patients in complete remission who have no donor, and those who are beyond the acceptable age limit for an allogeneic BMT may be eligible for an autologous BMT.
In an autologous BMT, the patient's own bone marrow is used during the transplant. The marrow is "harvested" or extracted from the rear hip bone while the patient is under general anesthesia, and frozen until needed for transplant. At some BMT centers, the marrow is "purged" in an effort to remove any leukemic cells that may be present in the marrow sample.
Following the bone marrow harvest, the patient undergoes 5 to 10 days of high dose chemotherapy, with or without radiation, to destroy the remaining bone marrow. The same chemotherapy drugs used in conjunction with allogeneic BMTs are used in autologous BMTs. The harvested bone marrow is then thawed and reinfused or "transplanted" into the patient through a vein, much like a blood transfusion. The marrow eventually migrates to the cavities of the long bones where it engrafts and begins producing new blood cells.
There is considerable controversy over whether purging marrow prior to reinfusing it into the patient provides any benefit. Some have argued that relapse is caused primarily by leukemic cells remaining in the patient's body following high dose chemotherapy. One recent study suggests that reinfused leukemic cells may cause relapse following an autologous BMT. Good results have been achieved both by centers who purge marrow prior to transplant and those who do not.
"The observation that leukemia relapse occurs in about half of patients given identical twin transplants for AML supports the concept that residual leukemia is the major problem after autologous BMT," says Andrew M. Yeager MD, Emory University School of Medicine, Atlanta GA. "We need to pursue innovative strategies following autologous BMT, such as immunotherapy, to decrease the incidence of relapse."
Patients undergoing an autologous BMT are not at risk of developing graft-versus-host disease (GVHD), and thus are susceptible to infection for shorter periods of time than allogeneic BMT patients. (Drugs given to allogeneic BMT patients to control GVHD also suppress their immune system, hampering its ability to fight infection.) Autologous BMT patients al.so do not get the graft-versus-leukemia benefit that allogeneic BMT patients who have significant GVHD seem to receive. Tests are beginning at several BMT centers to determine whether administering Interleukin-2 to AML patients following an autologous BMT reduces the incidence of relapse. Interleukin-2 is believed to stimulate natural killer cells to destroy cancerous cells in the body.
The optimal time for AML patients to undergo an autologous BMT is still being debated. Although an autologous BMT is clearly superior to standard chemotherapy when a patient is in relapse, not all physicians agree that a patient should undergo an autologous BMT while in first remission. Cure rates ranging from 35 to 65 percent have been reported following an autologous BMT in first remission, although some of those cured would have been cured by standard consolidation chemotherapy alone. Several pilot studies have suggested that an autologous BMT is superior to standard dose consolidation chemotherapy for AML patients in first remission, and several large, prospective, randomized trials are underway to confirm these findings.
"People often think that leukemia is universally fatal, but many patients with AML can be cured," says Martin Tallman MD, Northwestern University Medical School, Chicago IL. "Research is underway to identify those patients most likely to benefit from a BMT, the optimal time to transplant, and new methods to reduce the incidence of post-BMT relapse."
"Recent advances in controlling infection and GVHD decrease the risks associated with a BMT," adds Patrick Stiff MD, Loyola University Medical Center, Maywood IL. "This should produce even better long-term survival rates for AML patients who undergo a BMT."
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.