Treatment Options for Non-Hodgkin's Lymphoma

Stem Cell Transplantation in Non-Hodgkin's Lymphoma

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.

Many times, salvage regimens such as DHAP and MIME can generate sufficient stem cells to be harvested and saved for high-dose chemotherapy procedures. Other times, large doses of cyclophosphamide and myeloid growth factors, alone or in combination, generate sufficient stem cells in the bloodstream for harvesting and use after high-dose chemotherapy.

There are two primary types of stem cell transplantation procedures:

• Autologous stem cell transplantation
• Allogeneic stem cell transplantation

Autologous Stem Cell Transplantation

In this procedure, the source of the stem cells used for transplantation is the patient who serves as both the "donor" as well as the "recipient". Stem cells are harvested (removed) from the patient's bone marrow or bloodstream before treatment is initiated and the cells are frozen and stored for use after treatment has been completed. A marker on the stem cells called "CD34" can be measured and is a good indicator of having sufficient stem cells for engraftment after high-dose chemotherapy. The patient then undergoes a course of high-dose chemotherapy that is intended to kill the remaining lymphoma cells but also destroys the blood-forming cells in the bone marrow. After the patient completes their course of chemotherapy, the frozen stem cells are thawed and then infused (returned) back into the patient's body by an intravenous infusion.

Allogeneic Stem Cell Transplantation

In this procedure, 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 stem cell transplantation 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 stem cell transplantation. 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. Allogeneic bone marrow or peripheral blood stem cells are usually employed "fresh" although they can be frozen, especially if they must be shipped long distances. The patient (transplant recipient) then begins and completes a cycle of high-dose chemotherapy to destroy the remaining lymphoma 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.

Mini-Transplants

More recently, doctors have developed a newer type of allogeneic stem cell transplantation procedure called mini-transplants. These are also sometimes referred to as non-myeloablative transplants or reduced-intensity transplants. In contrast to a standard allogeneic stem cell transplant where the goal of treatment is to use high-dose chemotherapy to eradicate the remaining cancer cells and then restore the patient's stem cells that have been also destroyed by the chemotherapy, a mini-transplant uses significantly lower doses of chemotherapy (or radiation) and is, therefore, less toxic to the patient. This lower-dose or reduced-intensity approach kills only some of the remaining cancer cells but does not completely destroy the patient's diseased bone marrow blood-forming cells. The patient then receives a transplant of the donor's bone marrow or stem cells. The donor's transplanted immune cells serve as a "booster" to the recipient's own immune system by recognizing and destroying the remaining cancer cells that have not been killed by the low-dose chemotherapy or radiation therapy. This phenomenon is known as "graft-versus-tumor" effect because the donor's transplanted immune cells are used as a means of targeting and destroying the patient's residual cancer cells.

Although mini-transplants are becoming more common and have been used for patients with a wide range of cancers, they appear to be most effective for patients with chronic myelogenous leukemia (CML). The outcome for patients with other types of leukemias, non-Hodgkin's lymphomas, Hodgkin's disease, or multiple myeloma have varied depending upon the type of mini-transplant procedure used. In general, mini-transplants are reserved for older patients (over age 60) or patients with serious underlying conditions who cannot tolerate a standard allogeneic stem cell transplant.

Graft-Versus-Host-Disease

Graft-versus-host-disease (GVHD) is perhaps the most serious potential complication that may develop in patients receiving an allogeneic stem cell transplant. 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 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.

GVHD can develop within the first 3 months following allogeneic stem cell transplantation (acute GVHD) or it may develop after 3 months (chronic GVHD). Symptoms of acute GVHD include:

• 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 bone marrow transplantation include recurrent infections, interstitial pneumonitis, graft failure or rejection, veno-occlusive disease (complete blockage of the central veins of the liver leading to liver damage), and recurrence of the cancer following transplantation.