UNIVERSITY OF MICHIGAN MEDICAL CENTER

PATIENT'S INFORMED CONSENT

ALLOGENEIC OR UNRELATED STEM CELL TRANSPLANTATION AFTER MARROW ABLATIVE OR REDUCED INTENSITY CHEMOTHERAPY AND/OR RADIATION THERAPY FOR THE TREATMENT OF HEMATOLOGIC DISORDERS

INTRODUCTION: The following consent form describes the purpose, procedures, benefits, risks (side effects), discomforts and precautions that go along with your treatment for your disease. In addition, this consent form outlines your rights as a patient in this treatment. You are urged to ask your doctor or other medical staff who are taking part in your care any questions you may have about this treatment. This will keep you fully informed of the nature of this treatment, and what your part is in it. They will answer your questions. You will then be asked to sign this consent form if you agree to participate.

PURPOSE: This treatment is recommended because you have been diagnosed with a hematologic problem. Your physician feels the best chance for a cure of your underlying disease is through an allogeneic or unrelated stem cell transplant.

TREATMENT/BENEFITS: To undergo this treatment, you must have a biopsy which has confirmed diagnosis of a hematologic problem that may be cured by a bone marrow transplant. Allogeneic bone marrow or peripheral stem cell transplantation is often thought to be the only potentially curative therapy for these diseases. This procedure is proposed in an attempt to achieve a more permanent remission of the disease process than one could ordinarily expect from conventional forms of therapy. Other options are available to me which may have fewer side effects than allogeneic or unrelated stem cell transplant. The odds of remaining in remission with each treatment depend on a number of factors, and are best discussed with your treating hematologist.

The donor for your allogeneic bone marrow or peripheral stem cell transplant is either a family member with an identical or near identical tissue type or an unrelated donor. Each brother or sister has a 25% chance of having the same tissue type as you. If you do not have a family member who matches your doctor may recommend a transplant using an unrelated donor. If you need an unrelated donor you will be have that process explained by a coordinator who is familiar with that procedure. 

Although the purpose of this treatment is to put your disease into remission, there is no guarantee that this treatment will directly benefit you. The potential benefits to you may be a longer control of your disease, causing it to temporarily disappear, and/or to prolong your life, and/or improve the quality of your life.

Between 10-60% of individuals that receive a transplant will be alive and disease-free 5 years after the procedure. The large range depends on your disease status at the time of transplant and the type of donor used with the transplant. Patients transplanted at the end stage of their disease or if their disease is refractory have a higher risk of relapse and fewer can be expected to be alive and disease-free 5 years later. The principal causes of treatment failure are complications of the transplant and the recurrence of the underlying disease. The mortality rate for patients in your situation may be as high as 20%-30% during the first 100 days

PATIENT INTAKE AND PRE-PROGRAM EVALUATION: You will be given a program calendar that lists your schedule of appointments, tests and treatments that you will have during the program. Additional appointments, tests and treatments will be scheduled if clinically indicated or requested by your doctor. During this period, you will be screened to make sure that you are eligible to undergo the transplant. This pretreatment evaluation may include a bone marrow biopsy, blood labs, a dental evaluation which may lead to repair or extraction of your teeth, an electrocardiogram, urine collections, PFT (pulmonary function test), MUGA (heart function test), chest and skeletal x-rays and possibly CAT scans and spinal taps. Approximately 100cc or about 1/2 cup of blood will be drawn during the course of the work-up. As part of this evaluation, you will have an HIV test to confirm that you have not been infected with the AIDS virus and a hepatitis test to determine that you do not have infectious hepatitis (liver disease). If you are found to have HIV or hepatitis antibodies in your blood stream, you may not be able to participate. Prior to this testing, Michigan law requires that you be given an information booklet and a separate informed consent describing the HIV test. The risks of simple blood drawing include, commonly, the occurrence of discomfort and/or bruise at the site of puncture, and less commonly, the formation of a small blood clot (black and blue mark) or swelling of the vein and surrounding area, and bleeding from the puncture site. Once these tests are completed and if you agree with the procedure you will be admitted for the transplant.

HIGH DOSE CHEMOTHERAPY AND RADIATION THERAPY: This treatment attempts to cure your disease with very high doses of chemotherapy and/or radiation therapy followed by allogeneic bone marrow or peripheral stem cell rescue. The chemotherapy/radiation therapies given prior to allogeneic bone marrow or peripheral stem cell transplantation are high enough to severely damage the bone marrow. To avoid this likely fatal toxicity, stem cells from a sibling or unrelated donor must be infused following high dose therapy to allow recovery to occur.

The type of chemotherapy and radiation therapy you will receive will depend on your underlying disease. The toxicities of these agents will be stated below. In addition prior to your admission, a central venous catheter known as a Hickman catheter will be inserted. The catheter will be used for your chemotherapy infusion, stem cell infusions, blood transfusions, IV fluids, and other medications and blood draws while you are in the hospital. We may keep it in you for a long time after you have been discharged from the hospital for infusions of various medications you may need post-transplant. This catheter can become infected or form a blood clot in your vein, however we will monitor you for these complications very closely.

Cyclophosphamide (Cytoxan) can cause hair loss, nausea and vomiting, mouth sores, sterility, bleeding into the heart muscle, decreased hormone production, bleeding from the bladder wall, and scarring of the bladder.

The combination of these drugs will cause your bone marrow to stop making the blood cells it normally makes. Without the white blood cells from the marrow, you will likely develop fevers and infections making it necessary for you to receive multiple antibiotics and blood transfusions. The infections may be severe and even life threatening. The high dose chemotherapy can result in damage to your gastrointestinal tract which may be so severe that you will not be able to eat, making it necessary to receive intravenous feedings. It may also cause bleeding from your gastrointestinal tract. The chemotherapy may also damage your kidneys and affect their ability to filter the blood severely enough so that you may even require dialysis. The combination of drugs can also cause a condition in the liver known as veno-occlusive disease. This condition makes it difficult or impossible for blood to leave the liver, leading to liver swelling and pain, jaundice, and possibly liver failure resulting in death. The drug combination can also result in damage to the lungs that may require the use of a mechanical ventilator and could result in permanent failure of your lungs. The drugs will cause permanent damage to your ovaries/testicles, making it very unlikely that you would be able to have children following the bone marrow or peripheral stem cell transplant.

STEM CELL TRANSPLANTATION: Approximately 24-48 hours after completion of the chemotherapy/radiation therapy you will receive the infusion of your donor's stem cells. You will continue to be hospitalized following your transplant as you are at risk for infection and bleeding complications, which could be severe or even fatal. The average length of time you will be hospitalized is 15-20 days after the transplant. However the time you are in the hospital may vary greatly. You will have daily routine blood tests done while you are here in the hospital. All patients are at risk for infection and you may receive multiple antibiotics to control infection. Tests will be done to determine if your fever is the result of an infection or a side effect of the treatment. In addition, while the stem cells are re-growing after infusion, you will also be receiving transfusions of platelets and red cells. There also may be a need to receive fresh frozen plasma or even white cells. Every transfusion of donated blood carries with it a risk of AIDS and hepatitis. Every unit of blood is screened for the AIDS virus antibodies and hepatitis antibodies. The chances of contracting viral infections are lowered by this testing. It is understood that a small risk of viral transmission does remain. Once you are discharged home you will be followed quite closely in the Bone Marrow Transplant Clinic for 2-3 months after the transplant.

The reason you will be followed so closely is so that we can quickly treat any of the complications that may occur after transplant. Typically patients are seen 2-3 times per week after the transplant in our clinic. If you live longer than a one-hour car ride we will expect you to make arrangements to stay closer to the hospital after your transplant. You may stay with friends or relatives. If no friends are available we will aid you in making those arrangements.

GRAFT-YERSUS-HOST DISEASE: Graft-versus-host disease (GYHD) is the leading cause of death after an allogeneic bone marrow or peripheral stem cell transplant. Patients undergoing a transplant using a related donor with an identical tissue type have a 30%-40% chance of having significant GYHD. If a transplant is done using a non-related donor with an identical tissue type then the risk of significant GVHD becomes 70%-80%. The bone marrow or peripheral stem cells from your donor may see your body as foreign tissue. These bone marrow or peripheral stem cells may try to reject your body in much the same way that a kidney transplant patient may try to reject the transplanted kidney. The transplanted bone marrow or peripheral stem cells tend to go to certain tissues. The most common sites of rejection are the skin, liver, and gut. Skin problems may range from a mild rash to a sloughing of the entire skin. Liver problems can result in jaundice and liver failure. Involvement of the gut can result in anything from a mild diarrhea to sloughing of the lining of the gut with massive watery diarrhea. Severe GVHD can be fatal. Acute GVHD may resolve with treatment or may persist throughout the life of the patient. Drugs will be given to suppress your immune system in an attempt to prevent GVHD. Usually the drugs are given for at least 6 months. If GVHD does occur despite these drugs, more drugs will be given in an attempt to suppress the immune system even further. In these cases you may be on these drugs for longer than 6 months.

Cyclosporine and Tacrolimus(FK506) are two of the most common drugs used to prevent GVHD. Drugs such as these are effective at suppressing the immune system. However these drugs used to treat or prevent GVHD have side effects. Since they suppress the immune system they also make you more susceptible to various, and often unusual infections. These drugs can also cause depressed kidney and liver function, excessive hair growth, hypertension and tremors, swollen gums, pain or tingling in the palms and soles of the feet, and weakness. Less common side effects are loss of appetite, sleep disturbances, vivid dreams, hallucinations, agitation, tremors, irritability, slurred speech, weakness, and abnormal blood cell levels. All of these side effects are reversible by reducing the dose or discontinuing the drug. Rare fatal cases of severe allergic reactions have been reported in patients receiving Cyclosporine or Tacrolimus

Methotrexate is the other medication used to prevent GVHD. You will be scheduled to receive it four times after the transplant. Its major toxicities include mucositis and esophagitis, which involve inflammation of the mouth and esophagus. It can also cause lung problems and some delay in the recovery of your white blood cell count.

Steroids may be given for the treatment of GVHD. They can have many side effects. The most common side effect is that it increases susceptibility to infections that may, in certain cases, be life threatening. In addition they can cause fluid retention, diabetes, and weakening of the bones. If you do require steroids, you will be monitored for these complications very closely.

INFECTIONS: Infections are the second major risk of allogeneic transplantation. These infections that would ordinarily present little threat to a normal healthy person can be fatal in the allogeneic transplant patients. The virus responsible for the majority of fatal viral illnesses is called cytomegalovirus (CMV). CMV is the most common fatal viral infection but by no means the only one. Other viruses called adenovirus, herpes virus, respiratory syncytial virus, and others can also be fatal after an allogeneic transplant. Other infections such as fungal infections can also be quite severe after a bone marrow or peripheral stem cell transplant. A number of medications are used to prevent these infections but even with these medications you may become infected and there is a small chance that you may die from these infections.

Other side effects that may occur after transplant may be life threatening. One example of such delayed side effects may be secondary cancers. This can occur as a result of the treatment given. Just as the potential benefit to you of higher dose therapy compared to standard therapy is not known, the precise increase of these secondary cancers and secondary malignancies is also not known. Although the risk is small, it is present and also something for which you will be monitored.

If you should die from transplant related complications your physician will ask your nearest relative or legally responsible adult about the possibility of obtaining an autopsy. The autopsy would be helpful in determining the cause of death. Your family has the right to refuse this request but we ask that you discuss this with your family before you begin the transplant.

NEW INFORMATION: If there are any significant new findings developed over the course of this treatment which may affect your willingness to participate, you will be told of these findings so that you may decide if you want to continue this treatment. Your physician may stop your participation in this program if your disease comes back or if you have excessive or severe side effects. However, information will continue to be collected on your condition unless you withdraw your consent to do so.

ALTERNATIVE THERAPIES: Your physician has discussed other treatments for your condition with you as well as the complications and consequences of these choices. These include other chemotherapy drugs, alone or in combination, or no additional treatment. 

COST OF PARTICIPATION: All the drugs used in this program are commercially available. Every attempt will be made to arrange for payment from your insurance carrier prior to the peripheral stem cell transplant. If your insurance carrier denies payment for the bone marrow or peripheral stem cell transplant, you may decide to pay for the procedure yourself. The average cost of hospitalization for an uncomplicated allogeneic bone marrow or stem cell transplant is $90,000 - however, this cost could range between $60,000 to $250,000. Other fees (i.e., professional fees, clinic visits, outpatient laboratory evaluations, scans and/or x-rays) associated with your participation in this program will be billed to you in the usual manner. It has been suggested that you contact your insurance carrier to determine its policy on payment of cost for your participation in this program. You will not be compensated for your participation.

COMPENSATION FOR ILLNESS OR IN.JURY: In the event of a physical injury, which may result from these procedures, the University of Michigan will provide first aid medical treatment. The University of Michigan, in accordance with its determination of its responsibility to provide such treatment will provide additional medical treatment. However, the University of Michigan does not provide compensation or monetary reimbursement to a person who is injured while participating as a patient. You understand that you will receive no payment for your participation in this program.

RIGHT TO WITHDRAW: Your participation in this treatment is voluntary. You may later change your mind and stop at any time without jeopardizing any future treatment. However, you understand that there may be serious consequences if you decide to withdraw from treatment after you receive the. high dose chemotherapy but before you receive the stem cell transplant. If this occurs, the high dose chemotherapy will lower your blood counts, causing risk of fatigue, infection, and bleeding. It is possible that, without the transplant, your bone marrow may not ever recover its normal function.

Your physician may stop treatment if 1) you have not followed the program schedules and procedures as required, 2) if you have any adverse effects that in the opinion of your doctor would endanger your welfare with the continued use of the medication/treatment, 3) if your cancer progresses significantly in spite of treatment, 4) if you should become pregnant, or 5) if you develop a non-cancer related illness that prevents continuation of this program treatment or regular follow-up care.