Treatment of Chronic Myelogenous Leukemia

Transplantation-Based Therapies for Chronic Myelogenous Leukemia

What are Stem Cells?

Stem cells are immature, special cells located in the bone marrow (the spongy material found inside long-bones) that mature into the three major types of blood cells:

• Red blood cells - carry oxygen to all tissues and organs of the body
• White blood cells - components of the body's immune system responsible for fighting infections
• Platelets - specialized cells in the bloodstream that are responsible for clotting of blood (stop bleeding when a person sustains a cut or an injury to blood vessels)

High-dose chemotherapy used to destroy cancer cells, unfortunately, also kills most the patient's blood-forming bone marrow and stem cells. Without these critical cells, the patient is susceptible to a variety of potentially life-threatening problems including increased susceptibility to infections and bleeding complications. Bone marrow and stem cell transplantation enables doctors to replace the critical blood-forming cells after high-dose chemotherapy to kill cancer cells has been completed.

The source of stem cells used for transplantation is either bone marrow usually harvested (removed) from the hip bone (bone marrow transplantation) or the stem cells can be obtained from the peripheral bloodstream via a procedure called apheresis (peripheral blood stem cell transplantation). In both cases, the stem cells are frozen and stored for later use until the patient has completed their course of high-dose chemotherapy and are then administered to the patient by intravenous infusion. For the purposes of this discussion the terms "bone marrow transplantation" and "stem cell transplantation" are used interchangeably.

There are two primary types of stem cell transplantation procedures:

• Allogeneic stem cell transplantation
• Autologous stem cell transplantation

Allogeneic Stem Cell Transplantation

Currently, allogeneic stem cell transplantation (allogeneic SCT) is the only treatment with known curative potential for chronic myelogenous leukemia. A drawback of this treatment option, however, is that a suitable donor (either related or unrelated) must be identified whose tissue type closely matches that of the intended transplant recipient. However, only about 30% to 40% of patients who would otherwise benefit from an allogeneic SCT will actually have a suitably matched donor. The National Marrow Donor Program www.marrow.org serves as a valuable resource for identifying matching unrelated donors for patients who lack a related (sibling) donor.

In allogeneic SCT, the source of the stem cells used for transplantation is another person who serves as the "donor". In order to prevent complications related to rejection of the transplanted stem cells, a suitable donor must be identified whose tissue type closely matches that of the recipient. To ensure maximum success of an allogeneic transplant, the donor and recipient's tissue type must be compatible with respect to certain cell antigens or "markers" know as histocompatibility antigens (HLAs). Currently, recipient-donor compatibility for allogeneic SCT is determined by a blood test that measures the compatibility or "match" of six different major HLA markers.

The most successful allogeneic transplants are achieved in those cases where there is a "perfect match" between the donor and recipient for all six HLA markers. Successful transplants can also be achieved where only 4 or 5 HLA markers match exactly, however, the risk of complications, such as graft-versus-host-disease, is much higher. Close relatives of the patient (such as a brother or sister) are more likely to be an exact or close match than unrelated donors for allogeneic SCT. In the event that the patient who requires a stem cell transplant has an identical twin, the twin is an ideal donor because the donor and recipient HLA markers match exactly. This type of stem cell transplant is called a syngeneic transplant.

Once a suitable donor has been identified, stem cells are harvested (collected) from either the bone marrow or from the bloodstream and the cells are frozen for later use. The patient (transplant recipient) then begins and completes a cycle of high-dose chemotherapy to destroy the remaining leukemic cells. Patients are also given antirejection drugs such as tacrolimus or cyclosporine (sometimes in combination with prednisone or methotrexate) in order to reduce the likelihood that the patient will reject the donor's transplanted stem cells. The donor's frozen stem cells are then thawed and infused into the recipient via an intravenous line.

Although success rates of allogeneic SCT after initial chemotherapy for chronic myelogenous leukemia vary among different transplant centers, data from the International Bone Marrow Transplant Registry www.ibmtr.org indicates that about 60% of patients in the early chronic phase of chronic myelogenous leukemia who received transplants from a related (sibling) donor were alive and disease-free at 5-years post-transplantation. Unfortunately, the success rate of allogeneic SCT is not as favorable for accelerated phase chronic myelogenous leukemia and blastic phase chronic myelogenous leukemia as compared to the chronic phase of the disease.

In the United States, many transplant centers recommend that allogeneic SCT should be performed in the early chronic phase of chronic myelogenous leukemia within 12-months of diagnosis. The most successful results are achieved in patients 40 years or younger who are transplanted in the early chronic phase within one-year of diagnosis.

Unfortunately, allogeneic SCT is still a procedure that is associated with significant potential complications the most serious of which is graft-versus-host-disease (GVHD). As mentioned previously, in an allogeneic transplant, the source of the stem cells used for transplantation is another individual who serves as the donor. Graft-versus-host disease (GVHD) occurs when the donor's transplanted cells (the graft) begins to attack the recipient's (the host's) own tissues and organs. It should be noted that GVHD can occur with an allogeneic transplant even in cases where the donor and recipient's HLA markers are a "perfect match". This is because currently the degree of compatibility (match) between the donor and recipient is determined on the basis of evaluating similarities of tissue types for six major HLA markers. However, there are other markers (antigens) present on the donor's transplanted cells which may differ slightly from those of the recipient's own cells that can lead to the development of GVHD.

Graft-versus-host disease that develops within the first 3 months following allogeneic SCT is called acute GVHD; if it develops 3 or more months after allogeneic SCT it is called chronic GVHD.

Symptoms of acute GVHD include:

• An itchy, red rash on the hands and feet
• Nausea, diarrhea, and severe stomach cramps
• Jaundice (due to liver damage)

The chronic form of GVHD can be very severe and disabling and, in some cases, may even be fatal. Patients who develop GVHD are treated with various combinations of immunosuppressive drugs such as cyclosporine, methotrexate, and corticosteroids.

In addition to GVHD, other potential complications of allogeneic SCT include:

• Recurrent infections
• Interstitial pneumonitis - a severe inflammation of the lungs
• Graft failure or rejection
• Veno-occlusive disease -complete blockage of the central veins of the liver leading to liver damage
• Recurrence of the cancer following transplantation.

Autologous Stem Cell Transplantation

Autologous stem cell transplantation (autologous SCT) is a treatment option that is usually reserved for elderly patients who cannot tolerate a standard allogeneic transplant or patients for whom a suitable HLA-matched donor cannot be found. In an autologous transplant, stem cells are obtained from the marrow or peripheral blood of the patient during the chronic phase of chronic myelogenous leukemia. The stem cells are then treated with special chemicals in a technique called "purging" that destroys the leukemic cells but does not harm the small proportion of residual normal stem cells in the marrow or blood sample. The purged stem cell sample is then frozen and stored for later use. The stem cells are returned back into the patient's body by intravenous infusion when the disease has progressed to the accelerated-phase. Essentially, this treatment modality is used to restore patients who have progressed to the accelerated phase of chronic myelogenous leukemia back to the chronic phase of the disease and, therefore, prolong survival. Although autologous SCT does not cure chronic myelogenous leukemia, it can achieve sustained control of the disease in many patients.

Reduced-Intensity Transplants

More recently, a newer type of allogeneic SCT procedure has become available known as a reduced-intensity transplant or non-myeloablative transplant. Sometimes, this is also referred to as a "mini-transplant". The primary difference between a standard allogeneic SCT and a reduced-intensity transplant is that in the latter procedure, much lower doses of chemotherapy (or sometimes radiation therapy) are used to reduce ("debulk") the number of leukemic cells in the patient's marrow and blood (the "leukemic burden") prior to performing the stem cell transplant.

A reduced-intensity transplant is advantageous because it is less toxic to the patient and causes fewer side effects since much lower doses of chemotherapeutic drugs or radiation are used to prepare the patient for the transplant. The "trade-off" with the use of lower intensity doses is that fewer numbers of leukemic cells are destroyed than would otherwise be destroyed by higher-intensity doses that are used in preparation for a standard allogeneic SCT. To destroy the residual leukemic cells remaining in the patient's body, stem cells are harvested from the bone marrow or peripheral blood of a suitable HLA-matched donor and then infused back into the patient (the transplant recipient). The donor's transplanted stem cells serve as a "booster" to the recipient's own immune system to help destroy the residual leukemic cells in the patient's body. This phenomenon is know as the "graft-versus-tumor" effect because the donor's transplanted stem cells (the graft) helps the patient's immune system destroy the residual leukemic cells (the tumor).

In general, reduced-intensity transplants are usually reserved for patients over age 60 or patients who cannot otherwise tolerate a standard allogeneic SCT. Currently, there is no general consensus among transplant centers regarding the most optimal reduced-intensity preparatory regimen to use prior to transplantation and this remains an area of active research.