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The Transplant Procedure

How Stem Cells are Collected
Blood stem cells are located in the bone marrow. Until about 20 years ago, the only way to collect these stem cells was to have the patient or donor receive a general anesthetic and undergo as many as 50 to 100 bone marrow aspirations from the back of the pelvic bone to remove enough bone marrow and stem cells to use for future transplant. This was obviously painful, frightening, and inconvenient. The discovery that stem cells could be collected from the bloodstream by giving a patient donor injections of stem cell growth factors or colony-stimulating factors such as Neupogen®, Neulasta®, or Leukine® to trigger the release of bone marrow stem cells into the bloodstream was a major breakthrough. With refinements over the years, this has become the standard method. It is rarely necessary to use the old method of direct bone marrow harvesting from the pelvic bone.

Methods of collecting stem cells from the blood stream (peripheral blood stem cells[PBSC])
There are three main methods for collecting stem cells: 1) giving growth factors alone, 2) giving growth factors with chemotherapy, or 3) using a mobilization agent with growth factors.

  • Growth factors alone.
    Growth factors are drugs that stimulate blood stem cells both to grow and to be released into the blood stream. There are red cell and white cell growth factors. These medications are administered subcutaneously (under the skin). Growth factors are often used for patients receiving chemotherapy to hasten their white and red cell count recovery. The white cell growth factors (Neupogen, Neulasta, Leukine) used in high doses stimulate the release of stem cells from the bone marrow into the bloodstream. This process is called “mobilization.” The injections are given daily for three or more days. Stem cells are usually collected on the 4th or 5th day after starting the injections. The collections and injections will continue daily until sufficient stem cells are obtained.
  • Using chemotherapy plus growth factors.
    Chemotherapy with growth factors may also be used to release stem cells from the bone marrow into the bloodstream. The doctor will explain why it may or may not be appropriate to use chemotherapy in addition to growth factors. The doctor will explain the chemotherapy that will be administered to mobilize the blood stem cells and its potential benefits and side effects. Following chemotherapy for stem cell mobilization, a white cell growth factor is given by injection under the skin daily for approximately ten days. This procedure is therefore longer and much more intensive than using growth factors alone. The patient or someone who agrees to be responsible may be taught how to give the growth factor injection so that it can be administered at home. Some patients may receive their injections at the clinic/hospital or from visiting nurses. Once the number of stem cells in the blood stream is high enough, they will be collected over 2 to 5 days, while the patient is still receiving the growth factor injections.
  • Using a mobilization agent plus growth factors
    Mozobil® (plerixafor) is a recently approved stem cell mobilize that is used in combination with growth factors to release stem cells into the blood so they can be collected and used for transplant in patients with myeloma (as well as patients with no-Hodgkin’s lymphoma). Patients are treated with growth factors for 4 days prior to receiving Mozibil. Mozobil is injected subcutaneously 11 hours before the planned stem cell collection for up to 4 consecutive days. Mozobil increased the number of stem cells that can be collected.

The Collecting or Harvesting Procedure
In medical language, the harvesting is called apheresis or leukapharesis – literally the removal of white cells from the blood stream. Apheresis is a procedure whereby blood from the patient or donor passes through a special machine that separates (using a centrifuge technique) and then removes stem cells. The rest of the blood is immediately returned to the patient or donor. Compared to direct bone marrow harvesting, this is a remarkably simple and pain-free procedure.

Apheresis/Leukapheresis: Prior to the start of apheresis, a thin flexible plastic tube called a catheter is inserted through the skin and into a vein so that the blood can be taken out. The catheter is usually inserted into the chest just below the collarbone. Insertion of the catheter is usually done as an outpatient procedure, and only a local anesthetic is necessary. The site where the catheter enters the skin may be sore for a few days; the discomfort may be relieved with medications like acetaminophen (Tylenol®). The catheter may be kept in place for several weeks because it can be used to give chemotherapy after stem cells have been collected. Sometimes the same catheter is used during the transplant procedure as well. During this procedure, blood is collected through the catheter and processed through a blood-processing machine to remove the stem cells. The rest of the blood is returned through part of the same catheter (the lumen not being used in a double lumen catheter) or by using a different catheter. The apheresis procedure will last 3 to 4 hours each day for 1 to 5 days. Aphresis is usually done as an outpatient procedure.

The most common side effects experienced during apheresis are slight dizziness and tingling sensations in the hands and feet. Less common side effects include chills, tremors, and muscle cramps. These side effects are temporary and are caused by changes in the volume of the patient’s blood as it circulates in and out of the apheresis machine, as well as by the blood thinners added to keep the blood from clotting during apheresis.

Processing stem cells: After collection, the peripheral blood (or occasionally direct bone marrow material) is taken to the processing laboratory, which is usually located within the hospital or local blood bank. I the processing laboratory, the bone marrow or blood cells are prepared for freezing (cryopreservation). The stem cells are mixed with a solution containing the chemical DMSO (dimethyl sulfoxide) to prepare the stem cells for freezing. The stem cells are then frozen and stored in liquid nitrogen. The stem cells will be frozen until the time they will be needed for the transplant. They can be stored frozen for as long as necessary. There is some deterioration with time, but excellent function of stems cells is retained for at least ten years.

How many stem cells do I need? Over the years, a number of studies have been completed to determine the number of stem cells you need to safely undergo high-dose therapy. The number of stem cells is quantified by a special laboratory technique called “CD34+ cell analysis by flow cytometry.” A small sample of the stem cell collection is tested for the number of CD34+ cells in the product. We know that a minimum number of stem cells to safely complete a transplant is 2 million CD34+ cells per kilogram of body weight. The number of CD34+ cells is checked in each daily collection and the number tallied. The stem cell collection process continues daily until the planned number of stem cells is collected – usually 1 to 4 days. Some transplant centers check the number of CD34+ cells BEFORE starting leukapheresis to make certain there will be a good collection that day. Most transplant physicians collect enough stem cells for two transplants (over 4 million CD34+ cells per kilogram body weight)..

Administering High-Dose Chemotherapy
After the stem cells are frozen and stored, the patient is ready to receive high-dose chemotherapy. This treatment is designed to destroy myeloma cells more effectively than standard-dose chemotherapy. The purpose of high-dose chemotherapy is to kill myeloma cells inside the patient’s body. The most common type of high-dose chemotherapy used to treat myeloma is melphalan administered at a dose of 200 milligrams per square meter (mg/m2) of body surface area (size of patient). Depending on the type of myeloma and other factors, some patients may receive a second transplant 3 to 6 months after the first transplant (double or tandem transplant). A patient should discuss with the doctor the pros and cons of more than one transplant planned and performed back-to-back versus the possibility that the cells will be stored for a potential second transplant at a later time.

Autologous Stem Cell Transplant or Infusion
Since high-dose treatment destroys the normal bone marrow in addition to the myeloma cells, the blood stem cells must be given back to restore the bone marrow. The previously collected stem cells will be unfrozen and given back, through a catheter, into the bloodstream (as one would receive a blood transfusion) one to two days after administration of the high-dose chemotherapy. This procedure is often referred to as the transplant. The transplant takes place in the patient’s room: it is not a surgical procedure. The frozen bags of bone marrow or blood cells are thawed in a warm water bath, and then injected into the bloodstream through the catheter. Upon thawing, the DMSO (freezing agent) evaporates into the air and creates a distinct and somewhat unpleasant garlic smell. Most centers infuse one bag at a time. It usually takes 1 to 4 hours for the infusion. Infused stem cells travel through the bloodstream, and eventually, to the bone marrow, where they begin to produce new white blood cells, red blood cells, and platelets. It takes 10 to 14 days for the newly produced blood cells to enter the bloodstream in substantial numbers. Growth factors may again be given to the patient to speed up this process. In addition to obliterating the bone marrow, high-dose chemotherapy can cause other severe side effects, which may require that some patients be admitted to the hospital for treatment during this period. (Not all transplant centers require that patients remain in the hospital after the infusion of stem cells; some have facilities close by where patients may stay and be monitored daily at the hospital on an out-patient basis, while others allow patients who live close to the hospital to sleep at home and be monitored at the hospital). The average time in the hospital (or a nearby facility) for the chemotherapy, transplant, and recovery is approximately 3 weeks. Shortly before starting chemotherapy, patients usually are given large amounts of fluid to prevent dehydration and kidney damage from the chemotherapy. Some of the more common side effects of chemotherapy include nausea, vomiting, diarrhea, mouth sores, skin rashes, hair loss, fever or chills, and infection. Medications designed to prevent or lessen some of the expected side effects of treatment are given routinely. Patients are very closely monitored during and after the administration of high-dose chemotherapy. Monitoring includes daily weight measurement as well as frequent measurements of blood pressure, heart rate, and temperature.

Preventing Infection
During the first 2 to 3 weeks after transplantation, the re-infused stem cells migrate to the bone marrow and begin the process of producing replacement blood cells, a process called engraftment. Until engraftment of the stem cells takes place, patients are very susceptible to developing infections. Even a minor infection like the common cold can lead to serious problems because the body’s immune system is so weakened by the effects of the high-dose chemotherapy. Therefore, special precautions are necessary during recovery. Since the patient’s immune system is very weak, patients may remain in the hospital until the white blood cell counts reach a level safe enough for the patient to be discharged.

To prevent infection, the following supportive care measures may be required:

• Antibiotics are often prescribed to help prevent infection.
• Visitors should wash their hands and may be asked to wear masks and rubber gloves to protect the patient.
• Fresh fruits, vegetables, and flowers may be prohibited from the patient’s room as these can carry infection (bacteria and fungi).
• If infection and/or fever occurs (as the result of lowered white cell counts), the patient may be admitted to the hospital and be given intravenous antibiotics.

Engraftment and Recovery
Once the stem cells have been re-infused, it will take about two weeks for blood counts to recover. Many transplant centers will again use white blood cell growth factors (Neupogen, Neulasta, Leukine) after the transplant to help stimulate the bone marrow to produce normal blood cells. These injections (under the skin) will continue until the white blood count returns to normal. During this time, red blood cell and/or platelet transfusions may be necessary.

Waiting for the transplanted stem cells to engraft, for blood counts to return to safe levels, and for side effects to disappear is often the most difficult time for both patients and their family and friends. During this period patients will feel weak and very fatigued. Having a support network is very important during this period. Recovery can be like a roller coaster ride: one day a patient may feel much better, only to awake the next day feeling as sick as ever. It is important during this period to take things one day at a time. Once new blood cells are being made, symptoms will resolve, the risk of serious infections will be reduced, and transfusions will no longer be needed.

After being discharged from the hospital, a patient continues recovery at home for two to four months. Although patients may be well enough to leave the hospital, their recovery will be far from over. For the first several weeks the patient may be too weak to do much more than sleep, sit up, and walk a little around the house. Frequent visits to the hospital will be required to monitor progress. Patients usually cannot resume normal activities or return to fulltime work for up to three to six months after the transplant, although this varies from individual to individual.

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