Reduced-Intensity Transplants

A reduced-intensity transplant is a bone marrow or cord blood transplant (also called a BMT) that uses less intense treatment to prepare for transplant than a standard transplant does. While a standard transplant uses the pre-transplant treatment to destroy most of the disease cells, a reduced-intensity transplant relies on the donor's immune cells to fight disease. The standard pre-transplant treatment is hard on a person's body. Some patients are not healthy or strong enough to go through this treatment. Reduced-intensity transplants — also called non-myeloablative transplants or mini-transplants — may be an option for these patients.

Patients and diagnoses treated

Clinical studies suggest that reduced-intensity transplants work better to treat some diseases than others. A reduced-intensity transplant may not work well for patients with lots of disease at the time of transplant (such as leukemia in blast phase) or with a fast-growing disease.

There is good evidence of an effective graft-versus-leukemia (or graft-versus-tumor) effect in: 

• Chronic myelogenous leukemia
• Acute myelogenous leukemia
• Non-Hodgkin's lymphoma
• Multiple myeloma
• Renal cell cancer

Reduced-intensity transplants are more often used with patients who could not tolerate a standard transplant: 

• Older patients — Making transplant an option for older patients is important because many diseases that can be treated with transplant occur more often as people get older.
• Patients whose organs do not work well — This could include patients with health problems such as heart disease and patients whose organs were damaged by previous treatments.
• Patients who have already had one or more transplants.
• Other patients who cannot tolerate a standard transplant because of their disease stage or poor overall health.

How reduced-intensity transplants work

Before a standard transplant, patients receive high doses of chemotherapy and sometimes radiation therapy. This treatment is called a preparative regimen or a conditioning regimen. The preparative regimen destroys the diseased cells (such as cancer cells). It also destroys the patient's immune system so it cannot attack the donor's cells during the transplant.

In contrast, the preparative regimen for a reduced-intensity transplant does not destroy many diseased cells. It is just strong enough to suppress (weaken) the patient's immune system so it cannot attack the donor's cells. The cells for a reduced-intensity transplant can come from a family member, an unrelated donor or, less often, a cord blood unit. (Transplants using donated cells are called allogeneic transplants.) The donor's cells grow a new immune system. The new immune cells destroy the diseased cells.

The donor's cells are called a graft. When the donor's immune cells attack the diseased cells, it is called the graft-versus-leukemia effect or graft-versus-tumor effect.

Steps of a reduced-intensity transplant

1. Preparative Regimen
   The patient gets a preparative regimen of low doses of chemotherapy and sometimes radiation therapy. Often the treatment is mild enough for patients to get it in an outpatient setting. However, the treatment varies among transplant centers and treatment plans from very low intensity (a non-myeloablative regimen) to treatments only somewhat milder than the standard regimen.
2. Transplant
   The patient gets a transplant of blood-forming cells from a donor or, less often, a cord blood unit.
   
   For the next two to three months, the patient gets drugs to prevent graft-versus-host disease (GVHD), a common complication of allogeneic transplants. GVHD is when the donor's cells (the graft) attack the patient's body (the host). The anti-GVHD drugs also keep the patient's immune system from attacking (rejecting) the donor's cells.
3. Growth of the Donor's Cells
   The donor's cells begin to grow new immune cells. For the first 6 to 12 weeks, both the patient's and the donor's immune cells exist in the patient's body. (This is called mixed chimerism.)
   
   About 6 to 12 weeks after the transplant, the donor's immune cells take over. (This is called full chimerism.) The new immune cells attack the diseased cells. This is called the graft-versus-leukemia effect (or graft-versus-tumor effect).

Graft-versus-leukemia effect

The graft-versus-leukemia effect relies on immune cells called T cells. T cells are one kind of lymphocyte, which is a type of white blood cell. T cells see that diseased cells do not belong in the body and attack them. Sometimes, however, there can be problems along the way, such as: 

• The donor's immune cells do not take over (cannot achieve full chimerism).
• The graft-versus-leukemia effect may not be strong enough to destroy all the diseased cells. This happens most often if the patient has lots of disease at the time of transplant.

If either of these problems occur, doctors can reduce the doses of anti-GVHD drugs. This may give the donor's immune cells a better chance to grow. Doctors may also give the patient more of the donor's T cells. This is called a donor lymphocyte infusion (DLI). The extra T cells may be enough to destroy the diseased cells. Sometimes, the donor's immune cells don't take over, but a mixed chimerism is enough to destroy the diseased cells.

Graft-versus-leukemia effect and GVHD

The positive graft-versus-leukemia effect and the transplant complication called graft-versus-host disease (GVHD) often occur together. This is because the T cells that create the graft-versus-leukemia effect can also attack the patient's body.

Even though a donor's cells may be closely matched to the patient's, they are not an exact match (unless the donor and patient are identical twins). When the T cells see this difference, they may attack the patient's healthy cells. T cells that are working well to destroy diseased cells are often active enough to cause GVHD, too. In the same way, when the T cells do not attack the patient's body (causing GVHD), they may not work well to destroy the diseased cells either. This is why doctors often see mild GVHD as a good thing after a transplant. It is a sign the donor's T cells are working. Patients who get GVHD may be less likely to have a relapse of their disease.

 

Risks and questions

Reduced-intensity transplants carry many of the same risks as standard transplants. The most common risks that patients who receive reduced-intensity transplants face are:

• Infection — This risk may be lower for reduced-intensity transplants, but infection is still a serious risk.
• Graft-versus-host disease  — GVHD is a risk after all allogeneic transplants, but the risk may be different after a reduced-intensity transplant. Some clinical studies have suggested the risk is higher, while others have suggested the risk is lower.
• Complications caused by chemotherapy — This risk is lower after reduced-intensity transplants.
• Disease relapse — This risk may be higher after reduced-intensity transplants. It depends on the status of the disease at the time of transplant.

Many people treated with reduced-intensity transplants have done well. However, this treatment has been used only since the late 1990s, and all of the risks and benefits are not known. It is still being studied in clinical trials. Doctors still want to learn: 

• The best type and dose of preparative regimen. This treatment varies widely between different transplant centers and different clinical trials.
• Whether patients will stay in remission from their disease for the long-term.
• How to better prevent and treat GVHD after reduced-intensity transplants.