Stem cell transplantation

                                                          1. INTRODUCTION
1.1 Stem cells

In the past few years, stem cells have generated great excitement among researchers, physicians, patients, the media and the general public. These rare and powerfully therapeutic cells are immature “master” cells that can renew themselves and develop into a variety of cell types. Most stem cells occur in the bone marrow, although they have been identified in other organs, as well. Marrow stem cells produce all of the body’s oxygen-carrying red blood cells, infection-fighting white cells and the platelets necessary for clotting. (20)

1.2 Stem cell transplant

A stem cell transplant is a complex procedure to replace unhealthy stem cells with healthy ones. Find out what the process is like, including conditioning, and what complications may arise.

When you think of a transplant, you may have an image of a major surgical procedure to replace a diseased organ. But stem cell transplants don't involve surgery. And the "organ" involved is bone marrow — not a solid organ such as a liver.

If your bone marrow stops working, your body won't produce enough healthy stem cells. And that means you may not have enough healthy white blood cells, red blood cells or platelets, putting you at risk of life-threatening infections, anemia and bleeding.

A stem cell transplant is the infusion of healthy stem cells into your body. If all goes well, these healthy stem cells take hold in your body and begin normal production of blood cells. (20) Although the procedure is generally called a stem cell transplant, it's also known as a bone marrow transplant or an umbilical cord blood transplant, depending on the source of the stem cells. (20)



1.3 Reasons for a stem cell transplant

Stem cell transplants are used to treat people whose stem cells have been damaged by disease or treatment of a disease. Stem cell transplants can benefit a variety of both cancerous (malignant) and noncancerous (nonmalignant) diseases. For instance, in aplastic anemia, a noncancerous condition, your bone marrow stops making enough new blood cells. A stem cell transplant destroys the dysfunctional marrow, and healthy stem cells are infused. If all goes well, the new stem cells migrate to the marrow and begin working normally. Similarly, in leukemia, the unhealthy bone marrow is destroyed because it doesn't work properly and may contain cancer cells. When healthy stem cells are transplanted, normal cell production can resume. In addition, immune factors in the transplanted cells may help destroy any cancer cells that remain in your bone marrow.(20)

1.4 Bone Marrow Transplant vs Stem Cell Transplant

Stem cells are a self-renewing population of cells that reside in the bone marrow, but can be found in blood in other parts of the body (peripheral stem cells) in certain circumstances. It can also be found in cord blood, which lowers the risk of graft-vs-host disease, but the amount of stem cells found in cord blood is small. Because bone marrow was the original stem cell source since the 1960s, “bone marrow transplant” is the term most often used, but it is the stem cells taken from the bone marrow and other blood sources that is actually transplanted.(15)

1.5 Stem Cell Sources

Since the first published reports of bone marrow transplants in 1968, the traditional source of stem cells has been bone marrow. However, during the past decade, stem cells from peripheral blood or umbilical cord blood have been used for autologous and allogeneic stem cell transplantation.

Hematopoietic stem cells are very immature cells found in the cavities of the body’s bones, which is the bone marrow. Bone marrow is a substance that resembles blood and produces the body’s blood components, including red blood cells (which carry oxygen), platelets (which are essential for blood clotting), and white blood cells (which are the main agents of the immune system).

Hematopoietic stem cell transplants are used to treat patients whose marrow stops producing the correct amounts or types of various blood cells, or those who have solid tumors and whose marrow is destroyed by high doses of chemotherapy. Treatment with chemotherapeutic agents, growth factors, or both can cause stem cells that were in the bone marrow to circulate in the bloodstream. (7)



2.Stem cell transplantation

2.1 Stem cell transplantation

Stem cell transplantation performed as support for high-dose chemotherapy, is a treatment option for many patients with myeloma. Studies have shown that this treatment improves both the response rate and survival in myeloma over that obtained with conventional chemotherapy.(23)

2.2 significance

A stem cell transplant is a procedure that is used in conjunction with high-dose chemotherapy, which is frequently more effective than conventional chemotherapy in destroying myeloma cells. Because high-dose chemotherapy also destroys normal blood-producing stem cells in the bone marrow, these cells must be replaced in order to restore blood cell production.

The first step in the process of stem cell transplantation is the collection of stem cells from a patient or a donor. When a patient's own stem cells are used, they are frozen and stored until needed. Stem cells can be collected from a donor when they are needed. The patient then receives high-dose chemotherapy and the stem cells are infused into the patient's bloodstream. The stem cells travel to the bone marrow and begin to produce new blood cells, replacing the normal cells lost during high-dose chemotherapy.

High-dose chemotherapy and stem cell transplantation are typically performed following several cycles of conventional chemotherapy (also known as induction therapy). Induction therapy is performed first in order to reduce the tumor burden. (23)

3. Transplantation process

Stem cell transplantation is a complex process that involves several steps. The process is similar for both autologous and allogeneic stem cell transplants. However, in the case of autologous transplants, the patient will undergo the stem cell collection procedure prior to receiving high-dose chemotherapy and their cells will be frozen and stored until needed. In allogeneic transplants, a stem cell donor will typically undergo the collection procedure just before the transplant will be performed. Since autologous transplants are performed more frequently, we'll focus mainly on this process and indicate where allogeneic transplants are different.(24)

Stem cell transplantation is a complex process that involves six major steps.

A.Collection

Most stem cells in the human body reside in the bone marrow. Until recently, the only way to obtain stem cells for transplantation was to remove a portion of the bone marrow. However, through recent medical advances, it is now possible to collect stem cells from the blood. At present, most stem cells for myeloma transplants are collected from the blood. However, there may be rare cases where stem cells may need to be collected from both the blood and bone marrow in order to obtain a sufficient number of cells.(24)

B.(a) Collecting stem cells from peripheral blood

Stem cells that are collected from peripheral blood are referred to as peripheral blood stem cells or PBSC. Harvesting stem cells from the blood takes approximately 1 week, and it often can be done in an outpatient setting so no overnight hospital stay is necessary.(24)
Stem cells sufficient for two transplants are usually collected. Because most stem cells reside in the bone marrow, it is necessary to move stem cells from the bone marrow to the bloodstream prior to their collection. This procedure is called mobilization.(24) A commonly used mobilization technique is to administer a medication specifically designed to increase the number of stem cells in the blood. This medication is called a colony-stimulating factor, or “growth factor,” and it is usually injected under the skin, much like an insulin injection for diabetes. In the case of autografts, a cycle of chemotherapy may be administered along with a growth factor in order to increase the number of stem cells that can be recovered while order to increase the number of stem cells that can be recovered while reducing the patient’s tumor burden. Once a sufficient number of stem cells are mobilized from the bone marrow to the bloodstream, the stem cells are collected using a non-surgical procedure called apheresis. Apheresis is a procedure in which blood from the donor passes through a cell separator machine where the white blood cell component enriched for stem cells is separated out and the rest of the blood flows back into the donor. Apheresis is a relatively painless procedure. For allogeneic transplants, the donor undergoes a PBSC collection process that is similar to a normal blood donation. A needle is placed in a vein (typically in the arm) to collect the blood. (24) Another needle is placed in the opposite arm to return the remaining blood components.In the case of an autologous transplant, the collection process is slightly different, since the patient serves as his or her own donor. Prior to starting the patient serves as his or her own donor. Prior to starting apheresis, a flexible plastic tube called a catheter (or port) is inserted through the skin and into a large vein so that blood can be collected without the need for needles. 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 needed. The site where the catheter enters the body may be sore for a few days. This soreness can be relieved with medications like Tylenol® (acetaminophen, McNeil Consumer & SpecialtyPharmaceuticals). The catheter can also be used to give chemotherapy or other drugs and to obtain blood samples, and may be kept in place for several weeks.
Once the needle or catheter is in place, the donor can undergo aphaeresis. He or she sits in a comfortable chair, and the needle or catheter is connected to the aphaeresis machine with special tubing. Blood circulates through the apheresis machine, Which removes a portion of the blood containing the mobilized stem cells and returns other blood cells back to the donor.(24) Donors usually do not need to be hospitalized for apheresis, but must come in for one to three sessions, lasting 2 to 4 hours each, in order to ensure that enough stem cells are collected.(24)

B.(b) Collecting stem cells from bone marrow

Collecting, or “harvesting,” bone marrow is usually done in a hospital operating room under general anesthesia. Using a needle and syringe, a surgeon will draw bone marrow from several different areas of the hipbone (pelvis). The bone marrow, which appears as a thick red liquid, is typically frozen and stored until high-dose chemotherapy is completed. However, allogeneic bone marrow transplants need not be frozen if they will be used right away.(24)

C. Processing

After collection, the peripheral blood or bone marrow is taken to the processing laboratory, which is usually located within the hospital or local blood bank. The blood or bone marrow stem cells are prepared for freezing (cryopreservation) if they are not to be used right away, as is the case with autologous transplants.(24)

D. Cryopreservation

Following collection and processing, the blood or bone marrow (now referred to as the stem cell transplant) must be preserved to keep the stem cells alive until it is time to infuse the cells into the patient’s bloodstream. To preserve the cells, they are frozen and stored in liquid nitrogen or a special freezer. A chemical called DMSO (dimethyl sulfoxide) is mixed with the blood or bone marrow before freezing. DMSO keeps the water in the cells from forming ice crystals that would damage the cells during the freezing process. The blood or bone marrow can be stored in a frozen state as long as necessary. If donor (allogeneic or syngeneic) stem cells are collected at the time they are needed, this step is omitted.(13)

E. Chemotherapy

After the stem cells are frozen and stored, the patient is ready to receive high-dose chemotherapy. Sometimes called dose-intensive chemotherapy, this treatment is designed to destroy cancer cells more effectively than standard chemotherapy by giving patients higher doses of anticancer medicines. Depending on the type of cancer and other factors, some patients may receive one or more treatments of high-dose chemotherapy over a period of several days. The most common type of high-dose chemotherapy used to treat myeloma is melphalan, administered at a dose of 200 mg/mg2. However, the kind of high-dose chemotherapy a patient receives depends on a number of things, such as the type of cancer and how far advanced it is. Some patients may need only one cycle of treatment,while others may require several cycles with rest periods in between. In some cases,radiation may also be administered.(24)

F. Infusion

Within a few days of completing the high-dose chemotherapy, the stored blood or bone marrow is transplanted, or infused, into the patient’s bloodstream. The infusion process is similar to a blood transfusion. The frozen bags of stem cells are thawed in a warm water bath and infused through the catheter over a period of 2 to 4 hours. The infused stem cells travel through the bloodstream and settle in the bone marrow, where they begin to produce new white blood cells, red blood cells, and platelets.(24) Engraftment and recovery During the first few days after transplantation, the reinfused stem cells migrate to the bone marrow and begin the process of producing replacement blood cells. This process is called engraftment. The stem cells start to produce new blood cells within 10 to 14 days following infusion. Colony-stimulating factors may be administered during this time to stimulate the process of blood cell production. Until engraftment is complete, a transplant recipient is susceptible to infection, anemia, and bleeding caused by low blood cell counts. Therefore, special precautions are necessary during recovery. Patients may be given red blood cell and platelet transfusions during the recovery period to help prevent anemia and bleeding.(12)


4. Types of Stem Cell Transplants: Overview



There are many types of stem cell transplants. This section defines each of the various types of transplants.(23)

4.1 First, stem cell transplants are defined by the source of the stem cells.(24)

§ Bone marrow transplants are those that are obtained from the bone marrow. However, they are rarely performed today in myeloma because of the ability to collect stem cells from the peripheral blood (see below). Bone marrow transplants are sometimes used if insufficient numbers of stem cells can be obtained from the peripheral blood.

§ Peripheral blood stem cell (PBSC) transplants are obtained from the peripheral blood. PBSC transplants are now performed much more often than bone marrow transplants because they are easier to collect, they provide a more reliable number of stem cells, the procedure puts less strain on the donor's system, and the patient recovers more quickly.

§ Cord blood transplants refer to transplants where the stem cells are obtained from umbilical cord blood. Historically they have not been used frequently due to limited numbers of stem cells that can be collected from each umbilical cord. Recently, however, exciting new data have been generated using multiple cord blood units from more than one donor.

4.2 Stem cell transplants are further categorized based on the donor who provides the stem cells.(4)
§ Autologous stem cell transplants (autografts) refer to stem cells that are collected from an individual and given back to that same individual. Most stem cell transplants in myeloma are autologous transplants.

§ Allogeneic stem cell transplants (allografts) refer to stem cells that are taken from one person and given to another. Currently, these types of transplant are performed much less frequently in myeloma in the US and are usually performed in the context of clinical trials.

§ Syngeneic stem cell transplants refer to stem cells that are taken from an identical twin of the recipient. These types of transplants are quite rare



4.3 Lastly, there are also several types of transplants under investigation in clinical trials.(24)

A tandem autologous transplant, also known as a double autologous transplant, requires the patient to undergo two autologous stem cell transplants within 6 months.

§ A mini (nonmyeloablative) allogeneic transplant involves the use of moderately high-dose chemotherapy in combination with an allogeneic stem cell transplant.



5 .GENERAL DISCUSSION OF STEM CELL TRANSPLANTS


5.1 Allogeneic Stem Cell Transplants

For patients undergoing allogeneic stem cell transplantation, hematopoietic stem cells are collected from a donor who is another person. A donor who is a relative undergoes a pretransplant evaluation and hematopoietic stem cell collection at St. Jude. When a relative is unable to donate stem cells.

The transplant coordinator is the primary contact with the donor registry and is responsible for arranging the timing and type of hematopoietic stem cell product collected. All donors undergo an evaluation by an independent physician who is not a member of the Transplant Service. This independent examination assures that the donors are objectively evaluated before the stem cells are collected. In addition, donors undergo routine screening for infectious disease screening before stem cell collection; this screening is standard for all persons who donate blood products. If any abnormality is identified by the pre-transplant screening, the results will be discussed with and provided to the donor for review.

In some cases, stem cells from bone marrow rather than from peripheral blood are collected. Patients or donors generally undergo their pre-evaluation during the week before the bone marrow harvest. They are also seen in the Transplant Clinic on the day before the scheduled bone marrow harvest. At that time, a transplant physician reviews the donors’ blood work and the donor is asked to sign a consent document for the harvest procedure. On the morning of the procedure, the donor is taken to the pre-operative area where he or she is evaluated by anesthesiologist. If no problems are found during the evaluation, then the bone marrow is harvested while the donor is under general anesthesia in the operating room. In general, the bone marrow harvest lasts approximately one hour and is done on an outpatient basis. A donor may require oral pain medication for three to four days after the harvest. The donor returns to Transplant Clinic the day after the harvest to have the dressing removed, and, in some cases, to have blood drawn for additional tests. Adult donors (older than 25 years) may go to an adult institution for harvest.

Patients and donors from whom peripheral blood stems are to be collected will undergo a pre-transplant evaluation approximately one week before the patients or donors start taking growth factor medication (G-CSF). G-CSF is administered as a shot under the skin by staff members in the Medicine Room. The growth factor is given once each day for six consecutive days. On the fifth and sixth days of G-CSF administration, patients or donors will undergo apheresis in the Donor Room. During the apheresis procedure, which lasts approximately four to six hours, patients will have a venous access line placed for collection of peripheral blood stem cells.

In some circumstances, blood from an umbilical cord, i.e., “cord blood,” is used as a source of stem cells. Cord blood can be obtained from appropriate blood banks.(23)

5.2 Autologous transplants.

High-dose chemotherapy and autologous stem cell transplant are considered to be the current standard of care for patients who meet specific criteria. Several studies have shown that compared with conventional chemotherapy, high-dose chemotherapy with autologous stem cell transplantation offers a higher rate of complete response (undetectable disease; also referred to as complete remission) in patients under the age of 65 that is associated with improved survival.
Following high-dose chemotherapy and autologous transplant, approximately 20% to 40% of patients achieve a complete response. Since there’s no known cure for
myeloma, patients will eventually have recurrence or progression (also referred to as relapse) of their disease. Individual patient factors play a role in the duration of response.

5.3 Syngeneic transplants

The rarest type of transplants—syngeneic transplants—are considered to be the safest type. This is because the transplant is taken from a patient’s twin, who is genetically identical to the recipient. In addition, a syngeneic transplant does not contain any potentially contaminating myeloma cells, as an autologous transplant might. Thus, one is less likely to give anything back to the patient that might adversely affect him or her. The survival rates for syngeneic transplants are similar to those seen with autografts.
The rate of disease recurrence/progression following syngeneic transplants has been reported to be equal to or lower than autologous procedures.(24)




5.4 Tandem autologous transplant



A tandem autologous transplant, also known as a double autologous transplant, requires the patient to undergo two planned autologous stem cell transplants within 6 months. Stem cells are collected once before the initial transplant and half are used for each procedure. The second transplant is performed after recovery from the first procedure.
Although the relative merit of double transplantation has yet to be definitively determined, several studies have shown improved response rates and survival with the highly-demanding tandem regimen compared with single transplantation. However, it has yet to be determined which patients benefit most from a tandem transplant, and strategies to improve survival rates are still needed. Various strategies are being evaluated to improve the outcome of tandem transplants. One such strategy is intensification of therapy, such as that implemented in the Total Therapy program (see below), which is showing promising results. Another strategy is the incorporation of novel agents, such as thalidomide, Velcade, or Revlimid, into the treatment regimen either before or after transplant.

One of the first published reports of the use of tandem transplants in a large number of patients showed that the procedure was feasible and that the complete response (CR) rate increased from 24% after the first transplant to 43% after the second transplant. (Vesole et al. Blood. 1994;84:950-956.) Results of several tandem therapy trials are described below. Total Therapy I. One of the first studies to show that a tandem autologous transplant can improve response rates and survival over that seen with standard therapy or a single transplant was Total Therapy I. (Barlogie et al. Blood. 1997;89(3):789-793; Barlogie et al. Blood. 1999;93:55-65.) Two hundred thirty-one patients with symptomatic myeloma were enrolled in Total Therapy I between 1990 and 1995.



The Total Therapy I regimen included induction therapy with 3 cycles of VAD (vincristine, doxorubicin, dexamethasone). High-dose cyclophosphamide plus granulocyte-macrophage colony-stimulating factor (GM-CSF) was then used to mobilize stem cells prior to peripheral blood stem cell (PBSC) collection. After stem cell collection, EDAP (etoposide, dexamethasone, cytarabine, cisplatin) was given to enhance reduction of tumor cells prior to high-dose therapy (melphalan 200 mg/m²) and autologous transplant. The second course of high-dose therapy and transplant was performed 3 to 6 months later. Patients then received interferon maintenance until diseases. In the study, 71% of patients completed the treatment through the second transplant. Mortality rates were 3% during induction, 1% with the first transplant, and 4% with the second transplant. There was a progressive increase in response rates after each treatment phase. The complete response rate was 5% after VAD, 26% after the first transplant, and 41% after the second transplant. In comparison with matched historical controls receiving standard chemotherapy, patients receiving the Total Therapy regimen had a significantly higher response rate and survival. Ten-year data presented at ASH 2003 show that in comparison to standard chemotherapy, the tandem transplant regimen used in the Total Therapy I trial offered superior 10-year event-free and overall survival. (Barlogie et al. Blood. 2003;102(11). Abstract 136.) An important observation made from this trial and the various single autologous transplant studies noted earlier is that achieving a complete response-by whatever means-is associated with longer overall survival. Other randomized trials.Preliminary results of several randomized trials comparing tandem and single autologous transplants, which have not been followed as long, have also shown superior event-free survival with the tandem regimen in most studies (see table). In one study (Bologna 96), significantly improved event-free survival with double transplants was seen among patients <60 years of age, particularly those who had not achieved a near CR after the first transplant. However, only the IFM-94 study has demonstrated improvement in overall survival with the tandem approach. The designs of these studies vary, so comparisons are difficult. In addition, it has yet to be determined which patients benefit most from a tandem transplant. It appears that in patients with poor prognostic features, outcome is not improved with tandem transplants, so additional strategies need to be evaluated in this patient population.Total Therapy II. The ongoing Total Therapy II trial is evaluating a double transplant regimen that incorporates a more intensive chemotherapy regimen than Total Therapy I and includes thalidomide.Second salvage transplants. A second autologous stem cell transplant is sometimes performed in patients who have relapsed after an initial stem cell transplant. Some myeloma centers automatically collect enough stem cells for two transplants and reserve them for a possible second transplant. Analysis of data on 96 myeloma patients who received a second transplant following relapse, which was presented at the IXth International Workshop on Myeloma, showed that a second (salvage) transplant is a feasible option for refractory/relapsed disease. (Powles et al. Hematology J. 2003;4(suppl 1):S62. Abstract P10.3.1.) The median survival in patients receiving the salvage transplant (6.4 years) was equivalent to that typically seen with a planned tandem transplant. However, these patients represent a select subgroup of patients with relatively good prognosis.(23)

 5.5 Mini-transplants.

 Conventional allogeneic transplants have largely been replaced by allogeneic mini transplants, a type of transplant being evaluated in clinical trials. With a mini-transplant, patients receive lower doses of chemotherapy than those used with a conventional allograft. Patients may also receive radiation. Because these doses of chemotherapyand/or radiation do not destroy the bone marrow completely, mini-transplants are also referred to as non-myeloablative transplants.Because it is a result of allografts, the graft-versu myeloma effect helps destroy tumor cells. However, mini-transplants are associated with lower transplant-related mortality than conventional allografts (approximately 10% to 15% within the first year post-transplant). Patients receive immunosuppressive drugs to prevent GVHD, which can still occur, and may receive an additional infusion of white blood cells from the donor to enhance the graft-versus-myeloma effect. Mini-transplants can be used alone, but are generally not very effective due to limited graft-versus-myeloma effects. They appear to be more effective when used in combination with an autologous stem cell transplant. In this type of tandem transplant, patients first undergo an autologous stem cell transplant, which may provide substantial antitumor effects. This is followed by a mini-transplant, using peripheral blood stem cells from a matched donor, 2 to 4 months later. This strategy is designed to provide a sequential antitumor effect from the two transplants and a potential graft-versusmyeloma effect from the allogeneic mini-transplant.Mortality with this tandem approach is approximately 20%. Mini-transplants can be used alone, but are generally not very effective due to limited graft-versus-myeloma effects. They appear to be more effective when used in combination with an autologous stem cell transplant. In this type of tandem transplant, patients first undergo an autologous stem cell transplant, which may provide substantial anti-tumor effects. This is followed by a mini-transplant from a matched donor two to four months later. This strategy is designed to provide a sequential anti-tumor effect from the two transplants and a potential graft-versus-myeloma effect from the allogeneic mini-transplant.(24)





6. Stem Cell Transplant Works: MECHANISM


Allogeneic stem cell transplantation is more complex than autologous transplantation because of the interaction between the donor’s immune cells and the immune system of the recipient. Potentially fatal complications include graft failure and graft-versus-host disease (GvHD). Graft failure occurs when the recipient’s immune system recognizes the donor’s stem cells as foreign; the signs and symptoms of GvHD include rashes, liver problems, vomiting and diarrhea.

1. Stem cells are harvested from the bone marrow, umbilical cord blood or peripheral blood of the donor, who may or may not be related to the patient.

2. The patient receives high doses of chemotherapy with or without radiation. In addition, immunosuppressive agents that destroy the patient’s immune (or infection-fighting) system may be given.

3. Stem cells from donor marrow, cord blood or peripheral blood are administered intravenously; this infusion is much like a blood transfusion. The stem cells find their way through the bloodstream to the center of the long bones.

4. Supportive care with blood products, antibiotics, anti-viral drugs, and, in some cases, immuno suppressive medications to prevent GvHD allows many patients to recover from the stem cell transplant process. Stem cells are harvested from the bone marrow, umbilical cord blood or peripheral blood of the donor, who may or may not be related to the patient.(15)

7. Advantages and Disadvantages

Advantages and disadvantages of the various types of stem cell transplants :

7.1 Autologous transplant

Advantages • Considered to be the standard of care for certain eligible patients
• Safer than allogeneic; high survival rate
• Lower complication rate
• Less infection
• No need for immunosuppressive drugs
Disadvantages Disease recurrence/progression than allogeneic
• Prior treatment with certain chemotherapy drugs or radiation may impair ability to collect
• No graft-versus-myeloma effect; higher rate of stem cells
• Potential contamination of graft with tumor cells. (23)

7.2 Allogeneic transplant

Advantages
• Lower rate of disease recurrence/ progression; attributable in part to graft-versus-myeloma effect
• Contains no tumor cells
Disadvantages
• Higher mortality rates
• Need matched donor
• Graft-versus-host disease

• Need immunosuppressive drugs
• Takes longer to recover immune function higher risk of infection
• Limited to younger and healthier patients
• Most performed in the context of a clinical trial.(20)

7.3 Syngeneic transplant

Advantages
• Safest procedure
• Contains no tumor cells
• Survival rate similar to autologous
• Disease recurrence/progression rate equal to or lower than autologous

Disadvantages
• Twins are rare
• No graft-versus-myeloma effect.(11)

8. Diseases Treated by Stem Cell Transplant


Many malignant and non-malignant disorders can be treated with hematopoietic stem cell transplant. High-dose chemotherapy and subsequent autologous hematopoietic stem cell transplant is typically used for patients with high-risk solid tumors, lymphomas, and acute myeloid leukemia. Stem cell collection for these patients is ideally performed when bone marrow has minimal or no involvement by malignancy.(1)

8.1 Diseases treated by autologous stem cell transplant include:
acute myeloid leukemia (AML)
brain tumors
Ewing sarcoma
germ cell tumors
Hodgkin disease
neuroblastoma
non-Hodgkin lymphoma (NHL)
retinoblastoma
rhabdomyosarcoma
Wilms tumor(1)

8.2Allogeneic hematopoietic stem cell transplant has been successful as a treatment for various malignant and non-malignant disorders.(2)

A)Malignant disorders treated by this method include:
acute lymphoblastic leukemia (ALL)
acute myeloid leukemia (AML)


juvenile myelomonocytic leukemia (JMML)
myelodysplastic syndrome (MDS)
non-Hodgkin lymphoma (NHL)
high-risk solid tumors, under certain circumstances.(2)

B)Non-malignant disorders treated with this method include:
bone marrow failure syndromes
chronic granulomatous disease
Fanconi anemia
metabolic storage disorders
osteogenesis imperfecta
osteopetrosis
severe aplastic anemia
severe combined immunodeficiency syndrome (SCID)
sickle cell anemia
thalassemia
Wiskott-Aldrich syndrome.(5)

9. Conditioning Regimens


Conditioning regimens, also referred to as preparative regimens, are combinations of chemotherapy or radiation therapy designed to prepare the patient’s body to receive the donor’s bone marrow. The purpose of the conditioning regimen varies according to the type of stem cell transplant to be received by the patient. For autologous transplants, the conditioning regimen is designed so that increasing doses of chemotherapy with or without irradiation are administered to destroy more malignant cells. For allogeneic transplants, the conditioning regimen is designed not only to destroy residual malignant cells, but also to provide immunosuppression to prevent the patient’s body from rejecting the donor’s stem cells. Historically, the most common types of conditioning regimens for patients receiving allogeneic stem cell transplants have been cyclophosphamide with total body irradiation or busulfan and cyclophosphamide. The conditioning regimens for those receiving autologous stem cell transplantation vary markedly among centers and, to some extent, on the basis of tumor type. Today cyclophosphamide, cytarabine (Ara-C) and etoposide (VP-16) are chemotherapeutic drugs commonly used in conditioning regiments for patients receiving allogeneic transplants. Total body irradiation (TBI) is also commonly used in most of these regimens. Sometimes busulfan is used instead of TBI when patients cannot receive additional radiation therapy. In some cases, antibodies such as OKT3 or anti-thymocyte globulin (ATG) are administered to prevent graft rejection. These antibody preparations are designed to recognize T-cells, which are part of the immune system, and destroy them so that they cannot cause graft rejection. For patients receiving autologous stem cell transplants, the conditioning regimens may consist of cyclophosphamide, etoposide (VP-16), carmustine (BCNU), cytarabine (Ara-C), melphalan, cisplatin, carboplatin, and busulfan. In many cases, total body irradiation before transplantation is not administered; instead, radiation to localized sites of disease is administered after autologous transplantation. This approach allows higher doses of radiation to be given to specific sites where most tumor cells were found before transplantation. As part of conditioning regimens, chemotherapeutic drugs are usually administered in doses that are 3 to 8 times higher than standard doses given without stem cell support. The increases in doses are permissible because the initial toxicity (destruction of the patient’s marrow) will be overcome by the transplantation of stem cells. The side effects resulting from a conditioning regimen typically vary and depend on the chemotherapeutic drugs used, and whether radiation therapy is administered.(23)

9.1 Before the Stem Cell Transplant
All patients must have double or triple lumen central lines placed before the start of stem cell transplant. This placement is necessary to allow adequate venous access for drawing blood samples and administering intravenous medications required during the transplantation process. Occasionally blood samples must be drawn from peripheral veins. Specific instances where peripheral blood samples are required include the development of a new fever and coagulation (blood clotting) studies. Patients are admitted to the Stem Cell Transplantation Unit at St. Jude the day before the conditioning regimen begins. The conditioning regimen, also known as the preparative regimen, is designed to prepare the recipient’s body to receive the autologous or allogeneic hematopoietic stem cell graft. The graft is the stem cell source. This conditioning regimen may consist of chemotherapy alone or in combination with total body irradiation and typically lasts five to10 days. After the conditioning regimen has been completed, stem cells are administered to the patient in the patient’s room. The stem cell infusion is administered through the patient’s central line. On this day, the patient typically receives medications designed to prevent allergic reactions to the stem cell product. The patient’s heart rate, respiratory rate, oxygen levels and temperature are monitored for several hours after the stem cell infusion. During the two to three weeks after the infusion of stem cells, the patient is neutropenic. Recipients of autologous stem cell transplantation will receive granulocyte colony-stimulating factor (G-CSF), whereas recipients of allogeneic transplant typically do not.(24)

9.1 A)Preparation for a stem cell transplant.

Usually you remain at home until your transplant is actually scheduled. During that time, your health care team may recommend that you work on building up your strength and maintaining a healthy diet.

9.1 B)Pre-Stem Cell Transplant Evaluation

The pre-stem cell transplant evaluation is conducted to assess the patient’s clinical condition and eligibility for protocol enrollment before transplantation. Typically, the pre-evaluation requires re-staging studies that may include bone marrow studies, diagnostic imaging, and organ function studies to be performed within 30 days of enrollment on a research protocol. In addition, blood work to assess blood counts, liver and kidney function, electrolyte concentrations, infectious disease markers and HLA-typing are typically performed. Specific studies of heart, lung, kidney and liver function are also included. These tests are necessary to determine that the patient is able to undergo the stem cell transplant process.
At the time of the pre-evaluation, patients are seen by specialists in ophthalmology, clinical nutrition, social work and physical therapy. All patients must have a double or triple lumen central line placed before the stem cell transplant is undertaken. The central line is needed to allow efficient administration of chemotherapy, medications and blood product transfusions the patient requires.

9.1 C)plant tests and procedures
Once donor stem cells become available, you undergo many tests and procedures to assess your health and the status of your condition, and to ensure that you're physically prepared for the transplant. In addition, an intravenous (IV) catheter is typically surgically implanted, usually in your chest near your neck. This is often called a central line, and it usually remains in place for the duration of your treatment. It's through the central line that the transplanted stem cells will be infused. The central line is also used to collect blood samples, give chemotherapy, provide blood transfusions and even supply nutrition when necessary.(24)

9.2 Conditioning process

After completion of pretransplant tests and procedures, you begin a process known as conditioning. During conditioning, you undergo chemotherapy and possibly radiation in order to:

§ Destroy cancer cells

§ Suppress your immune system so that your body doesn't reject the transplanted stem cells

The type of conditioning process you undergo depends on a number of factors, including your disease, overall health and the type of transplant planned — whether you get stem cells donated from someone else (allogeneic transplant) or whether the stem cells come from your own body (autologous transplant). Conditioning generally occurs in the week leading up to your stem cell transplant. In some cases, you receive high doses of chemotherapy and total body irradiation (TBI). On the other hand, you may receive only high doses of chemotherapy and no radiation at all. The type of conditioning you undergo depends on your unique circumstances. The conditioning process may be done in the hospital or on an outpatient basis. It can cause numerous side effects and complications because your bone marrow and stem cells are destroyed in anticipation of the transplant, and even if your conditioning process is outpatient, you may need hospitalization for side effects.(24)

Efects of the conditioning process can include:

§ Nausea and vomiting

§ Diarrhea

§ Hair loss

§ Mouth sores or ulcers

§ Infections, such as pneumonia

§ Bleeding

§ Infertility or sterility

§ Premature menopause

§ Anemia

§ Fatigue

§ Cataracts

9.3 During the Stem Cell Transplant

In general, patients are hospitalized on the Stem Cell Transplant Unit a minimum of four to eight weeks. Depending upon the complications the patient experiences, the length of hospitalization is sometimes greater. Patients who receive stem cell transplants typically stay in Memphis a minimum of 100 days. During the time that the patient must remain in Memphis, St. Jude provides housing at the Target House. During the stem cell transplant process, patients undergoing autologous transplantation are at lower risk of infectious complications than are those receiving allogeneic transplants. Therefore, recipients of allogeneic transplants are placed on a low-bacteria diet, whereas recipients of autologous transplants are maintained on a regular diet. The clinical nutritionist will meet with the patient and family before the stem cell transplant to explain the diet and review any food preferences. Every effort is made to encourage patients to continue eating and drinking throughout the transplantation process and each patient’s nutritional status is closely monitored on a regular basis. The hospital has room service that allows patients to call the cafeteria to request food that is on their approved diet. However, if the number of calories that a patient consumes orally each day decreases below 50 percent of their daily requirements, the clinical nutritionist, in consultation with the clinical pharmacist and transplant physician, will consider placing the patient on total parenteral nutrition (TPN). Recipients of autologous stem cell transplants are maintained on a regular diet; however, they often need TPN as well. In all circumstances, patients must wear specially designed masks when they are outside the hospital room - in the hospital hallways, clinic areas or other crowded areas. These masks reduce the patient’s risk of inhaling infectious organisms. In addition, patients are instructed to wear the masks when they are in any public place. Hand washing is crucial and is the primary means of infection control. The Transplant Clinic is open from 8 am to 5 pm, Monday through Friday. Two nurses, one unit clerk, one nursing assistant, and a nurse scheduler staff the clinic. Each day, nurse practitioners, physician assistants, and physicians see patients in the clinic. Medications and transfusions are administered in the Medicine Room, which is open from 7:30 am to 11:30 pm every day. An on-call physician is available at all times and can be contacted through the hospital operator at (901) 495-3300.(10)

9.4 After the Stem Cell Transplant.

 Discharge planning begins at the earliest time of engraftment, which is typically defined as the point at which an absolute neutrophil count (ANC) greater than or equal to 500/mm3 has been achieved. To be discharged from the Transplant Unit a patient must have no fever, be able to receive intravenous and oral medications as an outpatient, have no pain or have pain that is well controlled, and have no significant infectious or treatment-related complications. A clinical nurse specialist, clinical dietitian, and clinical pharmacist will meet with the family to assess the patient’s discharge needs and to educate the patient and family about the procedures necessary for the patient’s outpatient care. Once a patient is able to return home after their initial stem cell transplant, the attending physician will send a letter summarizing the patient’s course to the referring physician. Recipients of autologous stem cell transplants will return only for protocol-required tests; the referring physicians are expected to provide routine tests and clinical care. During the first year, patients who have received an allogeneic stem cell transplant will return monthly to our institution. During the second year, these patients are seen every two to three months at St. Jude; during the third year, patients are seen approximately every four months; during the fourth year, every six months. After that point, these patients are seen once a year until they are 18 years old or until 10 years after the transplant has passed, whichever is longer. At that time, patients are discharged permanently from the hospital and given a summary of their entire treatment.(24)

10. Complications and Side Effects after Stem Cell Transplant

Hematopoietic stem cell transplants may not be successful because of disease recurrence or regimen-related toxicity. Regimen-related toxicity refers to side effects that patients may experience during the course of transplantation. These side effects include graft-vs-host disease (GvHD), graft rejection, bacterial infections, fungal infections, viral infections, gastrointestinal and hepatic complications, neurologic complications, pulmonary complications, and late effects after stem cell transplant.(5)

10.1 Gastrointestinal or Liver Complications after Stem Cell Transplant.

 Gastric or hepatic diseases are frequent complications that occur after stem cell transplant. All conditioning regimens consisting of high-dose chemotherapy, radiation therapy, or both cause in mucositis. Mucositis is the presence of sores throughout the gastrointestinal tract; signs and symptoms include mouth sores, esophagitis (soreness when swallowing), stomach ulcers, or diarrhea with stomach cramps. Patients sometimes require intravenous narcotic medications and total parenteral nutrition (TPN) until the mucositis has resolved.

The most common hepatic complication that occurs after stem cell transplantation is veno-occlusive disease (VOD) of the liver. Patients with prior liver injury, a history of hepatitis or a high-risk disorder are at greatest risk of VOD, although the disease can develop in any patient after transplantation. VOD is characterized by the elevated concentration of bilirubin (which results in the yellow appearance of the skin and eyes), an enlarged liver and fluid retention or weight gain. VOD is frequently treated by fluid restriction. Preventive measures include the administration of heparin and daily monitoring of weights and fluid balance while the patient is hospitalized while the patient is staying in Memphis. VOD can be severe and, in such instances, can even result in death.(5)

10.2 Graft Rejection after Stem Cell Transplant.

 Graft rejection occurs when the infection-fighting system of the patient recognizes the infused donor stem cells as being different and destroys them. High-dose chemotherapy destroys the patient’s bone marrow and it cannot regenerate on its own. Therefore, patients who experience graft rejection can become quite ill and, in some instances, die of complications from the treatment. To prevent graft rejection, the patient receives medications, chemotherapy, total body irradiation, and other antibody medications before the donor stem cell is infused. The chances of graft rejection are related to the match between the donor and recipient HLA antigens, the overall genetic relationship between donor and recipient, and the type of disease for which the transplantation is being performed.(4)

10.3 Graft-vs-host disease

 Graft-vs-host disease (GvHD) is a complication that is observed after allogeneic stem cell transplant. GvHD occurs when infection-fighting cells from the donor recognize the patient’s body as being different or foreign. These infection-fighting cells then attack tissues in the patient’s body just as if they were attacking an infection. GvHD is categorized as acute when it occurs within the first 100 days after transplantation and chronic if it occurs more than 100 days after transplantation. Tissues typically involved include the liver, gastrointestinal tract and skin.Symptoms of acute GvHD include rash, yellow skin and eyes due to elevated concentrations of bilirubin, and diarrhea. Acute GvHD is graded on a scale of 1 to 4; grade 4 is the most severe. In some severe instances, GvHD can be fatal. GvHD is more easily prevented than treated. Preventive measures typically include the administration of cyclosporin with or without methotrexate or steroids after stem cell transplant. Alternatively, T lymphocytes are removed from the stem cell graft before it is transplanted.
First-line treatment of GvHD is steroid therapy. Alternative therapies are considered for patients whose GvHD does not respond to steroids. Chronic GvHD occurs approximately in 10-40 percent of patients after stem cell transplant. Symptoms vary more widely than those of acute GvHD and are similar to various autoimmune disorders. Some symptoms include dry eyes, dry mouth, rash, ulcers of the skin and mouth, joint contractures (inability to move joints easily), abnormal test results of blood obtained from the liver, stiffening of the lungs (difficulty in breathing), inflammation in the eyes, difficulty in swallowing, muscle weakness, or a white film in the mouth.

The incidence of GvHD increases with increasing degree of mismatch between donor and recipient HLA antigens, increasing donor age and increasing patient age.(6)

10.4 Infections after Stem Cell Transplant.

 Infection complications are one of the most serious side effects of stem cell transplant. Life-threatening infections can occur in approximately 30 percent of patients receiving allogeneic transplants; the incidence is lower for recipients of autologous transplants. Because the Transplant Program at St. Jude is concerned about infectious complications, recipients of allogeneic stem cell transplants undergo weekly screening for the presence of infectious organisms during their stay in the Transplant Unit while they reside in Memphis. In addition, patients are placed on prophylactic or preventive medications to reduce chances of infections. Recipients of allogeneic stem cell transplants are placed on a restricted or low-bacteria diet to minimize the chance of infection. Because patients who receive autologous transplants have an immune system that is not as weakened by conditioning regimen and post-transplantation therapy, these patients have no dietary restrictions in place. Bacterial, fungal and viral infections can make patients quite ill. Prompt investigation and, in some instances, surgical procedures are required to diagnose and treat these complications.(6)

10.5 Neurologic Side Effects after Stem Cell Transplant.

 Neurologic complications associated with stem cell transplantation are significant problems. Certain chemotherapeutic drugs can cause seizures. Therefore, patients who receive chemotherapeutic drugs that are associated with seizures can be given medication to prevent seizures. In addition, patients may experience infection resulting in meningitis or encephalitis. Pain is another complication. Cyclosporin and other medications given to prevent or treat GvHD can cause nerve or neuropathic pain that can be controlled by medications.(6)

10.6 Pulmonary Side Effects of Stem Cell Transplant

Pulmonary or lung complications are significant causes of morbidity and mortality after stem cell transplant. Infectious and non-infectious causes of pneumonitis or lung inflammation after transplantation are well characterized. Pathogens that cause lung infections include bacterial, fungal and viral organisms. Weekly screening measures can be done to monitor patients for early reactivation of certain infectious agents, such as cytomegalovirus (CMV). Prophylactic medication is administered to recipients of allogeneic stem cell transplants at many centers along with weekly monitoring.(4)

10.7 Late Effects after Stem Cell Transplant

Patients who receive allogeneic or autologous stem cell transplants are usually observed for a long time after transplantation to determine whether side effects are present. Recipients of conditioning regimens in which total body irradiation was used are at risk of endocrine (gland) problems that include hypothyroidism, adrenal insufficiency or growth hormone insufficiency. Therefore, it is important that the patient’s height and weight be serially evaluated, when necessary, monitored by an endocrinologist.

Survivors of stem cell transplantation are at increased risk of osteoporosis or weakening of the bones. This complication is largely due to the treatment required during the transplant process, and the use of corticosteroids, which are used to treat graft-vs-host disease (GvHD). Pulmonary and cardiac abnormalities should be followed by routine screening examinations. In addition, survivors of transplantation have been shown to be at high risk of second malignancies, which include leukemia, brain tumors and skin cancers. The type of late effects for which a patient is at risk vary according to the type of conditioning regimen administered.(15)

10.8 Graft-vs-Tumor Effect In allogeneic stem cell transplantation.

 the infusion of donor marrow into the patient’s body allows cells from two immune systems the opportunity to interact. Conditioning regimens for patients receiving allogeneic transplants allow the donor stem cells to engraft in the patient by suppressing the immune system. Once the donor’s infection-fighting cells are established in the patient’s body, they may recognize the patient’s tissue and cells, including any residual cancer cells, as being different or foreign. The immune system may then cause damage to certain organs such the liver, gastrointestinal tract or skin; this effect is known as graft-vs-host disease (GvHD). In other ways, the donor’s immune cells may recognize residual leukemia, lymphoma or cancer cells as being different and destroy them. Retrospective studies have demonstrated that patients in whom acute or chronic GvHD develops have lower disease recurrence rates than patients who do not develop GvHD. This finding is an indirect indication of a graft-vs-tumor effect. Infusion of certain types of the donor’s blood cells such T-lymphocytes can also stimulate a graft-vs-leukemia effect. This effect has been best observed in patients with chronic myeloid leukemia (CML). In CML, 75 percent of patients relapsing after transplant re-enter remission. For other disorders such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), the effect is less pronounced; AML and MDS in approximately 20 percent of patients enter remission. For patients with acute lymphoblastic leukemia (ALL), the presence of graft-vs-leukemia effect is unclear, although small numbers of patients have reportedly benefited, at least transiently, from the effect.(15)


11. Future Aspects

As mentioned earlier, high-dose chemotherapy destroys not only myeloma cells, but also stem cells in the bone marrow. When this happens, the reduced supply of blood cells can cause severe problems, including:

• Fatigue and difficulty breathing from the lack of red blood cells carrying oxygen through the body
• Infection from the lack of white blood cells attacking invading germs
• Bleeding from the lack of platelets that help the blood to clot Fortunately, a stem cell transplant replenishes stem cells that arelost during high-dose chemotherapy. Thus, astem cell transplant restores the production of blood cells, including immune cells, in patients who have received high-dose chemotherapy.

Stem cell transplants, performed as support for high-dose chemotherapy,offer hope to many patients with myeloma. There is much ongoing research to makestem cell transplants safer and more effective. One very promising strategy is the integration of novel therapies with stem cell transplantation. Incorporation of various novel therapies, such as thalidomide and Velcade, into the transplant induction regimen appears to improve the outcome prior to transplant, which may lead to greater benefit following the transplant. Novel therapies are also being investigated for use in maintaining a response following transplantation.
In addition, high-dose chemotherapy and stem cell transplantation can significantly reduce the tumor burden, providing a platform upon which new immune therapies against myeloma can be tested. It is in this context that such immune therapies are most likely to be successful.(7)

12. Reference

1)Palmer, T., Schwartz, P.H., Taupin, P., Kaspar, B., Stein, S.A., and Gage, F.H. (2001). "Progenitor cells from human brain after death." Nature 411: 42-43.

2) Galli, R., Borello, U., Gritti, A., Minasi, M.G., Bjornson, C., Coletta, M., Mora, M., Cusella De Angelis, M.G., Fiocco, R., Cossu, G., and Vescovi, A. (2000). Nature Neuroscience 3: 986-991.
3) Jahoda, C. and Reynolds, A. (2000). "Skin stem cells -- a hairy issue." Nature Medicine 6:1095-1097.
4) Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W-Y., DuMoucel, W., Kao, R., Dillon, S., Winfield, H., Culver, S., Trojanowski, J.Q., Eidelberg, D., and Fahn, S. (2000) "Transplantation of embryonic dopamine neurons for severe Parkinson's disease." New England J. of Med. 344: 710-719.
5) Lumelsky, N., Blondel, O., Laeng, P., Velasco, I., Ravin, R., McKay, R. (2001) "Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets." Science 292: 1389-1394.
6) Magavi, S.S., Leavitt, B.R., and macklis, J.D. (2000). "Induction of neurogenesis in the necortex of adult mice." Nature 405: 951-955
7) "Public backs stem cell research." An analysis by Gary Langer for ABCnews.com on June 16, 2001, using results from their survey conducted by TNS Intersearch between June 20-24, 2001. Accessed 6/01. http://www.abcnews.go.com/sections/pol

8)Bellos, Alesandra. "Can Religion Trump the Bioethics Debate?" hybrid vigor: a discussion of bioethics, Issue 3. http://www.emory.edu/college/HYBRIDVIGOR/issue4/religion.htm
9)Bush, President George W. "Remarks by the President on Stem Cell Research" made on August 9, 2001. http://www.whitehouse.gov/news/releases/2001/08/20010809-2.html

10)Chapman, Audrey R., Mark S. Frankel, and Michele S. Garfinkel. "Stem Cell

Research and Applications Monitoring the Frontiers of Biomedical Research." American Association for the Advancement of Science and the Institute for Civil Society, November 1999. http://www.aaas.org/spp/dspp/sfrl/projects/stem/main.htm
11)Human Embryonic Stem Cells: An Introduction to the Science and Therapeutic Potential Ann Kiessling and Scott C. Anderson Jones and Bartlett Publish

12)Methods in Molecular Biology: Basic Cell Culture Protocols Editors: Cheryl D. Helgason and Cindy L. Miller Humana Press; Totowa NJ, USA; Oct. 2004ers, Boston MA, USA; 2003

13)CORD BLOOD, Biology, Immunology, Banking and Clinical Transplantation
Editor: Hal E. Broxmeyer AABB Press, Bethesda , MA , USA; Jan. 2004

14)Adult Stem Cells Editor: Kursad Turksen Humana Press; Totowa NJ, TheraVitae, Ltd.

15)student textbook Molecular Biology of Cancer Mechanisms, Targets, and Therapeutics (Oxford University Press, 2005).
16)Dr. Lauren Pecorino received her Ph.D. in Cellular and Developmental Biology from the State University of New York at Stony Brook. http://www.gre.ac.uk/scho ) results from their survey conducted by TNS Intersearch between June 20-24, 2001.

17)Primer on Ethics and Human Cloning"Glenn McGee, Ph.D., examines the social and ethical implications of human cloning.
18). Bellos, Alesandra. "Can Religion Trump the Bioethics Debate?" hybrid vigor: a discussion of bioethics, Issue 3.
20).Chapman, Audrey R., Mark S. Frankel, and Michele S. Garfinkel. "Stem Cell Research and Applications Monitoring the Frontiers of Biomedical Research." American Association for the Advancement of Science and the Institute for Civil Society, November 1999.
21).Langer, Gary. "Public Backs Stem Cell Research: Most Say Government Should Fund Use of Embryos."ABCNews.com 26 June 2001. http://www.abcnews.go.com/sections/politics/DailyNews/poll010626.html
22).National Academy of Sciences Committee on the Biological and Biomedical



Applications of Stem Cell Research, Board on Life Sciences National Research Council, and Board on Neuroscience and Behavioral Health Institute of Medicine. "Stem Cells and the Future of Regenerative Medicine." Washington, D.C.: National Academy Press, 2001. http://www.nap.edu/books/0309076307/html/
23).Stem cell transplantation, performed as support for high-dose chemotherapy, is a... for the use of stem cell transplantation as an effective therapy for myeloma.

www.multiplemyeloma.org/treatments/3.03.html.

24). The idea of "stem cell transplantation" is more foreign and and difficult to grasp ... Transplantation.

www.cancernews.com/data/Article/258.asp