From BMT Newsletter March 1995 Issue # 28 - BMTs for Chronic Myelogeneous Leukemia Reprinted by NYSERNet with Permission from BMT Newsletter
Chronic myelogenous leukemia (CML), also called chronic granulocytic leukemia, accounts for 20 percent of all leukemias. It occurs most often in adults between the ages of 30 and 60. More than 5,000 new cases of CML are diagnosed each year in the US alone.
In patients with CML, an excessive number of white blood cells called granulocytes or neutrophils are produced in the bone marrow and released into the bloodstream. These cells often invade other organs such as the liver or spleen, causing them to enlarge and malfunction.
CML is distinguished from other leukemias by the presence of a genetic abnormality in most blood cells called the Philadelphia chromosome. The Philadelphia chromosome is a "translocation" or swap of genetic information between two chromosomes in the cell (chromosomes 9 and 22) that results in the production of a new gene called BCR-ABL. The protein produced by this new gene may play a role in the abnormal growth of white blood cells in CML patients.
Symptoms of CML include those common to many diseases: fatigue, weakness, irritability, headaches, perspiration, night sweats, chronic low grade fevers, and weight loss. If the leukemic cells have caused the spleen to enlarge, the patient may feel a lump in the upper left portion of the abdomen, loss of appetite or a bloated feeling. In the earliest stages of the disease, the patient may experience no symptoms at all.
CML is a disease that develops slowly. The initial or "chronic" phase of the disease usually persists 3 to 5 years after diagnosis. During the chronic phase, the overproduction of white blood cells can usually be kept in check with oral drugs such as hydroxyurea or injections of alpha-interferon. In most cases, however, the disease accelerates and can no longer be controlled with these drugs.
The second stage or "accelerated phase" is usually brief, and is sometimes skipped altogether. During the accelerated phase, the number of white blood cells and immature or "blast cells" in the bloodstream increases. Increased doses of hydroxyurea, or administration of 6-mercaptopurine (Purinethol) or cytosine arabinoside (Cytosar-U or ara-C) may temporarily decrease the white blood cell count, and removal of the spleen may eliminate the discomfort caused by its enlargement. Blood transfusions may be necessary to relieve the fatigue and weakness caused by the decreasing number of red blood cells, and the number of platelets (the cells that enable blood to clot) may be unusually high or low.
The final phase is called the "transformation phase," "acute phase" or "blast crisis". During this phase, the white blood cells fail to mature properly. The immature or "blast" cells flood the bloodstream, invade other organs and tissues and disrupt their normal functions. This phase is usually resistant to chemotherapy, although occasionally combination chemotherapy returns the disease to the chronic phase for a short time. Typically, patients in blast crisis survive less than 6 months.
Chemotherapy and alpha-interferon slow the progress of CML, but only a bone marrow transplant can cure the disease. 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 US National Marrow Donor Program (NMDP) or similar unrelated marrow donor registries in other countries. The risk of serious complications are greater for CML patients who undergo an allogeneic BMT with a mismatched or unrelated donor than for those transplanted with marrow from a matched, related donor.
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. However, CML patients who develop some GVHD following an allogeneic transplant are less likely to relapse than those who do not develop GVHD. This phenomenon, called the graft-versus-leukemia (GVL) benefit is absent in syngeneic BMTs.
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 associated with an allogeneic BMT such as graft-versus-host disease.
Some patients undergo an autologous "peripheral blood stem cell transplant" (PBSCT) rather than an autologous bone marrow transplant. In this procedure "stem cells"-the cells that repopulate the patient's bone marrow and bloodstream with normal blood cells following transplant-are collected from the circulating or "peripheral" blood rather than from the bone marrow.
Regardless of the type of transplant, the procedure is essentially the same. Bone marrow is extracted or "harvested" from the rear hip bone of the donor (or the patient, if it is an autologous BMT). If the patient is undergoing a peripheral blood stem cell transplant, stem cells are collected by extracting blood from the patient's arm, filtering it through a machine to remove the stem cells, and returning the remaining blood components to the patient through a needle in the other arm. If a CML patient's own bone marrow or peripheral blood stem cells are being used for the transplant, the center may treat the sample in an effort to destroy leukemic cells. It is then frozen at a very low temperature (cryopreserved) until needed for transplant.
Prior to transplant, the patient undergoes a "preparative" or "conditioning" regimen to destroy the leukemic cells in the bone marrow and any leukemic cells that may have migrated to other organs. In allogeneic BMTs, the preparative regimen is also designed to suppress the patient's immune system so that the donor bone marrow will not be rejected by the patient's body. The preparative regimen for CML patients typically consists of high-dose cyclophosphamide (Cytoxan) plus either total body irradiation (TBI) or high-dose busulfan (Myleran) administered over several days.
The bone marrow or peripheral blood stem cells are then infused or "transplanted" into the patient in a manner similar to a blood transfusion. The transplanted cells migrate to the cavities of the patient's bones where they "engraft" or set up housekeeping, and begin 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.
A CMV infection can develop in several different organs including the liver, colon, eye and lungs. CMV in the lungs is particularly worrisome, since CMV pneumonia is very difficult to treat and usually fatal. BMT patients are usually given a drug called ganciclovir to reduce the risk of developing a CMV infection.
Patients undergoing a BMT using marrow from a related donor often experience some form of graft-versus-host disease (GVHD). In most cases, patients develop only a mild or moderate form of the disease that can be controlled with drugs. The incidence of serious GVHD is significantly higher in allogeneic BMTs using unrelated or mismatched donors.
In GVHD, certain white blood cells in the donor's bone marrow called T-cells perceive the patient's body as foreign material. They attack organs and tissues in the patient's body, impairing their ability to function properly and increasing the risk of infection.
Although donor white blood cells can cause GVHD, they also confer an important benefit on CML patients called the "graft-versus-leukemia" (GVL) effect. CML patients who develop both short term (acute) and long term (chronic) GVHD are much less likely to relapse following their transplant than those who do not experience GVHD.
Long-term leukemia free survival is achieved by approximately 50 to 70 percent of CML patients who undergo a BMT in the chronic phase using marrow from a related donor, and 20 to 60 percent of those using marrow from an unrelated donor marrow. Those who are transplanted in the chronic phase and within a year of their initial diagnosis fare better than those transplanted later. Patients who receive marrow from a matched related donor fare better than those transplanted with marrow from an unrelated or mismatched donor, due to the higher incidence of GVHD and infections in unrelated and mismatched transplants. Younger patients are better able to withstand the rigors of an allogeneic BMT than older patients.
There is controversy over whether CML patients who have a matched sibling donor should be treated with alpha-interferon in the chronic phase of CML or immediately undergo a bone marrow transplant. "Alpha-interferon can delay the need for a BMT and, in a small fraction of patients, produce a complete remission that may last several years," says Richard Champlin MD, M.D. Anderson Cancer Center, Houston TX. "However, while on interferon, the patient's disease can become more resistant to treatment or progress from the chronic phase to blast crisis, decreasing the likelihood of a successful BMT. For this reason, most BMT centers recommend that CML patients under the age of 50 who have a matched sibling bone marrow donor undergo an allogeneic BMT as soon as possible."
Twenty to 40 percent of patients who undergo an allogeneic BMT during the accelerated phase of CML survive long-term. Approximately 10 to 20 percent of those who wait until blast crisis to be transplanted become long-term disease-free survivors.
Between 10 and 20 percent of patients transplanted during the chronic stage of CML, and 60 to 80 percent of patients transplanted in blast crisis relapse following an allogeneic BMT. Historically, those who relapsed into a chronic stage of the disease survived 3 to 6 years. Those who relapsed into blast crisis typically survived less than 6 months.
A second allogeneic BMT may be an option for patients who relapse a year or more post-transplant. Approximately 20 to 30 percent of patients undergoing a second BMT for CML are alive and disease-free four years post-transplant. A new therapy for treating CML patients who've relapsed following a BMT is exciting many researchers, and may improve long-term survival rates. Relapsed patients are given infusions of donor white blood cells that suppress the growth of leukemic cells. Although the donor white blood cells can also cause GVHD, this therapy has reportedly produced durable complete remissions in up to 70 percent of patients. "Based on early results, this appears to be a very promising therapy for relapsed CML patients," says Wendy Stock MD, Loyola University Medical Center, Maywood IL.
An autologous BMT is now a treatment option for CML patients. Although the majority of CML patients who undergo an autologous BMT eventually relapse, a recent analysis of results from eight BMT centers concluded that CML patie nts who underwent an autologous BMT survived significantly longer than might have been expected had they been treated with conventional therapy (i.e., hydroxyurea).
Several new strategies are being investigated to reduce the incidence of relapse following an autologous BMT for CML. One approach is to reduce the number of cancerous cells in the bone marrow or peripheral blood sample prior to infusion.
This may be accomplished by "purging" the marrow with chemotherapy drugs, interferon, or even DNA strands called "antisense" designed to kill or inactivate leukemic cells. Another approach is to grow the marrow prior to transplant in a special culture that enhances the ability of normal blood cells to grow.
Yet another strategy, prompted by promising results from Italian researchers, is now being investigated in the U.S. and Europe. Patients are first treated with intensive "priming" doses of combination chemotherapy, after which autologous bone marrow or peripheral stem cells are collected from the patient and stored. Patients are then given high-dose combination chemotherapy and total body irradiation, followed by an autologous bone marrow or stem cell transplant. After transplant, patients receive injections of alpha-interferon or other anti-leukemia agents in an effort to prevent recurrence of the disease.
"Although these and other studies are at an early stage, autologous BMTs may well become standard treatment for CML patients who are ineligible for an allogeneic BMT," says Michael Barnett B.M., University of British Columbia, Vancouver, Canada.
"Fifteen years ago, CML was considered an incurable disease," says Philip McGlave MD, University of Minnesota Hospitals & Clinics, Minneapolis MN.
"Today, with bone marrow transplantation, a substantial number of CML patients can be cured. Further developments in donor and autologous transplantation should lessen the risk and cost of BMT and increase the number of CML patients eligible for transplant."
The electronic version of this document was created by NYSERNet, Inc. as part of the Breast Cancer Information Clearinghouse.