Transplantation: How it's Done

• Preparation
  
• Induction therapy
  
• Patient's harvest
  
• Donor's harvest
  
• Purging marrow or stem cells
  
• Consolidation (high-dose therapy, conditioning, mobilization)
  
• Reinfusion of marrow
  
• Isolation
  
• Common side effects
  
• Engraftment
  
• Failure to engraft
  
• Outpatient follow-up
  
• Pets after transplant
  
• Long-term effects
  

Preparation

Before you can undergo the high doses of chemotherapy and radiation therapy used in transplantation, you must be tested to determine if you're healthy enough to withstand this treatment, and to establish base lines against which organ function can be measured later. In an outpatient setting, your heart, lungs, kidneys, and liver will be assessed, and a dental examination will be done. If one or more of your body systems is weak, the drug regimen used for the transplant may be modified to spare that organ more damage.

A venous catheter will be inserted under your skin, most likely in your upper chest, to deliver chemotherapy directly into the large veins near your heart instead of using arm veins. Having a catheter in place will benefit you in these ways:

• Using a catheter for blood draws will spare you repeated punctures with IVs and needles.
• It can save your arm veins from damage, as the veins near the heart are of much wider diameter than arm veins, and so are less affected by drugs.
• The catheter's location near the heart will assure that drugs are pumped evenly and quickly to all parts of the body.
• Apheresis, the collection of various blood cells such as platelets and stem cells from blood, is easier and more comfortable when a catheter is used. When arms veins must be used, one vein in each arm must be used simultaneously: the first to withdraw blood, and the other to return the blood to your body.
• A central venous catheter might be used as access to the vein in which it resides to measure important body functions such as central venous pressure (CVP), which help your doctor determine the amount of IV fluids a patient needs.
• If mouth sores become severe and you cannot eat, parenteral nutrition will be necessary. Due to the thickness of these feeding solutions, they will cause arm veins to become terribly sore if infused into an arm vein. Having access to a larger vein via a catheter will be an asset.

Several kinds of catheters are available.

An NHL survivor describes how having a catheter inserted turned out to be a much easier experience than she had imagined:

My doctor had planned to send me to a well-known cancer center for the stem cell harvest. I would not have had so much trouble with this had he not also told me I would need a catheter for that procedure, since it would involve higher pressure in the lines. I was weak, exhausted, and suffering from horrific headaches, which the doctor attributed to stress and I did not. I dreaded the thought of a five-minute, much less a two-hour car ride. Every movement or sound seemed torturous, and I had never had any history of migraines or similar ailments.

More than that, I was viscerally repulsed by the thought of the surgery given my experience with the insertion of the Groshong catheter. I seriously considered not undergoing any apheresis. I don't know how I finally talked myself into going ahead with the catheter insertion, but I may have reacted to my husband's appeals to my sense of what was the right thing to do.

My reward was to find that the surgery was a magical thing...both my husband and I told anyone who would listen what my fears were. It seemed to be a routine matter for the staff to respond. It is amazing what a pinch of anesthesia will do--just enough to put you to sleep while the local is administered, yet allow you to be awake for the rest of the procedure.

In general, you'll feel best if your room is like home, and if you have your own comfortable clothing to wear. Transplant units sometimes limit the kinds of materials, including gifts, that can enter your room. Some allow only what can be autoclaved: cotton clothing, books, and so on. Their rules are geared to the period of time during which you'll have no functioning white blood cells and will be vulnerable to infection.

If your child is being transplanted, see Nancy Keene's book Childhood Leukemia, which contains an excellent chapter on transplantation for children. This book is particularly suitable if you have a child with NHL being treated on an ALL protocol.

Induction therapy

For lymphomas and leukemias, an induction phase may be used first to try to induce a remission before transplantation. Induction resembles standard chemotherapy, although the doses may be somewhat higher than you've had in the past, or the drugs used may differ. Because it's so much like first-line chemotherapy, the induction phase may be done in your hometown by your local oncologist, even if your transplant is to be done out of town.

Some people do not achieve remission in the induction phase before going ahead with the transplant. Often this is of some, but not of overwhelming concern to the medical team, because the high-dose treatment you'll receive soon after will destroy any remaining NHL. For some subtypes of NHL, being in remission first may improve your chances of survival, but keep in mind that prognoses and survival are very much a function of treatment, that new treatments are always being devised, and that the subtypes of NHL vary too widely to generalize.

Patient's harvest

If you're having an autologous transplant, the harvest will be done now, before high-dose treatments are started, and kept frozen (cryopreserved) until your high-dose treatment has ended.

Marrow

If stem cells from marrow will be used, you'll be given a general anesthetic for the procedure, and you may have an overnight stay in the hospital. Four to six very small cuts that do not require stitches are made in the skin over your hipbones, and many punctures through the bone, into the dozens, are made to withdraw about a quart of marrow. About twice as much marrow is withdrawn from a patient than from a donor to compensate for the possibility of damaged, unproductive, or cancerous marrow, and to freeze extra against the possibility that the first infusion does not engraft.

You may have a sore derriere for a few days to a week after this procedure. You may feel as if you slipped on ice and landed on your bottom. You may also feel tired and lightheaded for a day or two. Anesthesia alone can cause these feelings of fatigue.

Peripheral stem cells

Many transplant centers now use stem cells collected from your arm veins or your catheter (depending on type) in place of bone marrow drawn from the hipbone. The collecting of stem cells in this way is called apheresis. The blood is drawn from one arm vein or from one catheter lumen, passes through sterile equipment used one time only, and is returned to your body via the other arm vein or second catheter lumen after stem cells have been separated from your blood.

There are fewer stem cells in circulating blood than there are in marrow, but the number of circulating stem cells can be boosted if drugs known as colony stimulating factors, natural body products that can be replicated in the pharmaceutical lab, are first administered. Granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) is administered by injection under the skin several times in the week before harvesting. G-CSF or GM-CSF may make your bones and joints feel sore. Ice packs and Tylenol should relieve this pain. GM-CSF may also cause fever, lung or heart inflammation. Call your doctor if you have fever, chest pain, or difficulty breathing.

The apheresis session will probably last several hours. The nursing staff will have movies you can watch and blankets to warm you, because the blood that is returned to your body will have cooled and will make you feel chilled.

Very rarely, an allergic reaction to the anticlotting agent used in the apheresis equipment may occur. If you feel shortness of breath or hives, let the nurse know. Generally, they're at your side throughout the entire procedure.

The anticlotting agent may reduce the calcium supply in your blood. If you sense an unusual heartbeat, feel numbness around the mouth, tingling sensations, or weakness, tell the nursing staff immediately. Intravenous calcium will be given to you.

It's not unusual for an NHL survivor to have to undergo repeated hemaphereses, perhaps up to six times, until enough stem cells are collected, because NHL or its previous treatment sometimes compromises the marrow's ability to produce stem cells.

The calculation based on my body weight did not require a long series of attempts to harvest enough stem cells. It only took four days. The catheter presented a few problems in terms of balky access, but it was nursed along.

Donor's harvest

The harvesting of marrow or stem cells from a donor is very much like that for the patient, described above in "Patient's harvest," with a few exceptions:

• The marrow is usually not frozen. Instead, it is collected and used immediately. If the donor is an unrelated donor found through the NMDP, the marrow is collected locally, then chilled and flown to the transplant center. It's no longer the case that the donor must be flown to the transplant center.
• Much less marrow--only about a pint or two--is taken because donor marrow is presumed to be healthy.
• If peripheral stem cells are used, usually fewer apheresis sessions are needed to collect an adequate supply from a healthy person.
• The donor's body will replace marrow and stem cells in three to four weeks.
• Side effects from either procedure and recovery time are likely to be less pronounced for the donor than for the patient whose own marrow is used.

Purging marrow or stem cells

Before the collected marrow or stem cells are put into your body, they are cleaned and sorted. Healthy blood precursor cells from marrow must be separated from pieces of bone, fat globules, red cells, mature white cells, platelets, and, most importantly, from cancerous cells. Stem cells that have been apheresed must be separated from mature white blood cells and from cancerous cells.

Although purging cancerous cells from marrow or stem cells is not always done, many researchers feel that it's wise to purge marrow, because small amounts of NHL may have lodged there. If your marrow was found to contain NHL, it's likely that marrow purging will be performed.

Marrow or stem cells that have been purged of all mature white blood cells may take longer to engraft. Some transplant centers prefer to leave certain types of some mature white blood cells in the mix to facilitate a good engraftment, but their presence may increase the chances of graft-versus-host disease (GVHD). Most transplant physicians strive for a balance of good engraftment versus GVHD.

Purging can be done using several techniques, but these techniques fall into two categories: destroying cancerous cells, or separating and saving healthy stem cells.

Much research is underway on selecting only healthy cells. Healthy stem cells, for instance, express a surface antigen identified as CD34 that cancerous cells do not express. CD34+ (CD34 positive) selection techniques also permit a one-step method to separate stem cells from mature white blood cells.

Consolidation (high-dose therapy, conditioning, mobilization)

For an autologous transplant, high-dose therapy follows the harvesting of marrow. If donor marrow is to be used, high-dose treatment of the patient may coincide with donor marrow harvesting. This high-dose therapy is called consolidation or consolidation of remission, and is also referred to as high-dose therapy, conditioning, or mobilization.

The purpose of high-dose conditioning is threefold: to kill all cancer cells; to vacate the marrow, leaving space for inbound stem cells to engraft and grow; and to reduce the chance of a host-versus-graft attack that your body will mount against incoming donated stem cells.

Many different chemotherapeutic regimens are used for high-dose treatment of NHL, and new combinations are always being tried. Your oncologic team will choose a combination of drugs that will best preserve your organ function while optimizing the killing of all remaining cancer cells. Some drugs being used in various combinations as of this writing are cyclophosphamide, busulfan, etoposide, carmustine, cytarabine, melphalan, and cisplatin, but other drugs and new combinations are always being assessed for superiority. Usually, high-dose chemotherapy is administered over two or three days.

Radiotherapy may also be used, and in several ways. Irradiation of only the tumor may be done to reduce its bulk, either during the consolidation phase or at the original site of the tumor after the transplant. Total body irradiation (TBI), which if used in sufficiently high doses destroys all bone marrow, is used when marrow is diseased, when donor marrow is going to be used, or when the subtype of NHL is such that a relapse in the marrow is likely if TBI is not used as a preventive treatment.

When TBI is used as part of consolidation, the dosage is spread over several days. This spreading, called fractionating the dose, permits more radiation to be given than the body would be able to withstand were it given in one large dose.

Reinfusion of marrow

Reinfusion, which is done in your room using your catheter, takes thirty minutes to several hours. Marrow and stem cells are reinfused using an IV line, much like any IV drug. Although the marrow is warmed before it's given to you, you may still feel cold as it's being infused.

Some NHL survivors consider the reinfusion of marrow an anticlimax after high-dose treatment. Others have a celebration while it's being infused, especially if they searched long and hard for a donor.

Marrow or stem cells are not reinfused until one or two days after high-dose consolidation treatment has ended in order to allow chemotherapy and radiotherapy time to have maximum effect against cancer, and to allow these and other toxins to exit the body. Too lengthy a delay would endanger the patient, though, because reinfused marrow takes two to four weeks to engraft. During that time, the patient must be protected from all pathogens because he is incapable of mounting an immune response.

During reinfusion, you may experience fever, chills, hives, shortness of breath, or chest pains. If so, tell the nursing staff immediately. They'll give you antihistamines to curb the allergic reaction.

Isolation

Within five to ten days following your high-dose therapy, you will experience a profound drop in white blood cell counts as your marrow dies. At this point, you have no immune system to protect you from bacteria, fungi, or viral agents until the reinfused marrow engrafts and begins producing new white blood cells. This process takes from eighteen to thirty-six days, or, in rare instances, longer.

To avoid infection, you will be kept in isolation until your new marrow engrafts and becomes productive. Isolation requirements differ among transplant centers, with some having rigorous curtailment of visitors and confinement in laminar airflow rooms. Others simply require visitors to wear masks and wash hands upon entry. Check with your treatment center about visitors, and gifts that are considered sterile or sterilizable, before your transplant begins.

Some transplantation protocols require administration of colony stimulating factors after reinfusion to encourage the new marrow to produce white cells more quickly.

Common side effects

Most side effects of high-dose treatment begin to appear several days after treatment ends. This means you may have just a bit of time to enjoy your new marrow, and then you may feel poorly for a few days or weeks.

In general, those receiving an allogeneic transplant are likely to feel worse and to have a longer recovery period than those receiving an autologous transplant, especially if an acute case of graft-versus-host disease develops.

Many patients who receive their own marrow have no side effects or minimal side effects that are easily controlled with medication. One autologous transplant recipient reports the ease with which she dealt with the procedure:

I am feeling so, so great. I sailed through the transplant with no nausea, vomiting, or diarrhea. The only side effects I experienced were throat and anal pain due to sores from the chemotherapy, and the skin peeled off those areas. I am feeling just about back to my precancer self, except for being tired and still needing to lose the forty pounds that I gained. I have to return for tests in a few weeks, including CT scans and gallium scans. Then I will be restaged, although I think that I am in complete remission. After that I will be getting low-dose "mop-up" radiation followed by four rounds of chemotherapy (once every three months for one year).

Many of the side effects experienced during and after transplantation resemble those of standard-dose treatment. Listed here are the side effects specific to transplant recipients, and how they're managed:

• Fungal infection. Although neutropenia and infection are discussed in the chapter on the side effects of treatment, fungal infection is of particular concern to transplant recipients because these infections can spread widely throughout the body and can be difficult to eradicate. If your transplant team suspects a fungal infection, cultures to confirm this will be done, and you may be placed on antifungal medication such as amphotericin.
• Veno-occlusive disease. (VOD) The high-dose treatment you're given may cause blood vessels in your liver to swell shut, a potentially fatal reaction. There is a higher risk of VOD if you first develop a fever, or are receiving an allogeneic transplant or a second transplant. If VOD develops, it's most likely to happen one to four weeks after the transplant. You may have pain in the upper right abdomen, swelling, jaundice, or fluid in the chest or abdomen. Supportive care is given for VOD, which usually goes away on its own. Cessation of drugs that stress the liver helps to ease the condition.
• Viral hepatitis. Many viruses that are latent in our bodies are able to take advantage of an immune-suppressed state, and can settle in the liver. There's no cure for a viral infection except time and good supportive care, although immunoglobulins and antiviral drugs can shorten the duration of some infections if they're given soon enough.
• Acute graft-versus-host disease. If you receive donor marrow, you may develop acute graft-versus-host disease (GVHD). Caused by white blood cells attacking liver, blood vessels, skin, the gastrointestinal tract, and other tissues, it can be controlled by immunosuppressive drugs. Earliest signs of GVHD appear as a rash or peeling on the skin of the hands and feet. At its most severe, GVHD can be fatal if it is not controlled.
• Drowsiness, mental confusion. Many transplant recipients report undesirable cognitive effects, particularly from TBI or cranial irradiation. This condition cannot be treated directly, but good nutrition, rest, and time may improve cognitive skills within a few weeks, although some transplant recipients report lingering effects years afterward.
• Pneumonia, pneumonitis, adult respiratory distress syndrome (ARDS). If you develop a dry cough or difficult, painful, rapid breathing within about two months after your transplant, you may have pneumonia, pneumonitis, or ARDS. Viruses such as cytomegalovirus (CMV) can cause pneumonia; radiation therapy can cause pneumonitis or pulmonary fibrosis; some chemotherapies can cause pneumonitis. Treatment depends on the diagnosis.

Engraftment

Everyone eagerly awaits engraftment. As time passes, many transplant recipients begin to worry a bit.

It takes about fourteen to twenty-eight days for marrow to engraft, but sometimes longer. Engraftment is presumed to have occurred when the patient's absolute neutrophil count or ANC--the number of mature white blood cells--begins to rise, as tracked by daily blood tests. Sometimes the rise is not steady. The counts may waver back and forth over several days, but the overall trend should be upward. It may be months or even years for the new marrow to produce enough cells to equal the amounts usually found among the general population, values called the normal range, although this is a somewhat arbitrary range that changes with age.

In general, stem cells will engraft more quickly than marrow. Those who have received an autologous transplant will engraft more quickly and produce adequate numbers of cells sooner than those who have received an allogeneic transplant.

Failure to engraft

Marrow sometimes fails to engraft well or at all. This can be detected in several ways:

• For an allogeneic transplant, genetic testing reveals that the marrow being produced is still the patient's marrow, not the donor's. This may pose a risk of relapse if the patient's marrow was found to contain NHL before the transplant.
• For an allogeneic transplant, the marrow is chimeric: a mixture of donor and patient marrow. This phenomenon is not well understood, but it is thought that a risk of relapse may be present if the patient's marrow was found to contain NHL before the transplant.
• For either an allogeneic or autologous transplant, the numbers of cells produced never reach normal levels. This is a poor engraftment rather than a failure to engraft.

A failure to engraft can be addressed with a second transplant, an infusion of additional donor white blood cells, a second infusion of more of the patient's own saved marrow or stem cells--or time, because sometimes very late engraftments occur. Failures to engraft are seen more often with marrow or stem cells purged of all mature lymphocytes than with unpurged products.

Outpatient follow-up

Many transplant centers are shifting their aftercare procedures to the outpatient setting. You may be released from the inpatient unit when your absolute neutrophil count in blood exceeds 500 on two consecutive days. If so, you will be expected to stay nearby for several weeks to facilitate care during possible medical emergencies, and for blood testing several times a week. Other tests will be performed from time to time, such as bone marrow biopsies to verify the productivity of marrow and the continued absence of NHL. You may be placed temporarily on antibiotic, antifungal, or antiviral medications as a precaution if your blood counts remain low.

The high-dose drugs used during a transplant can cause a form of depression known as chemical depression. Antidepressants are recommended, if needed.

It will take several months or more, perhaps up to a year, to recover from a transplant, although there is tremendous variability in individual recovery times. You may need to stay away from work for most or all of this time, depending on the health risks your job poses. Contact with small children or hard manual labor, for instance, might be considered large risks.

Pets after transplant

Transplant centers differ in their recommendations about being near family pets after transplantation. Some recommend complete avoidance; others recommend that the patient and the pets stay in separate parts of the house for the first few months; still others recommend avoiding handling the pet's bedding, smooching, and being licked or scratched. You should ask your discharge staff and your doctor what's best, but many post-transplant patients find that their veterinarians are better informed than human doctors about diseases that are contagious from animals, called zoonotic diseases.

In general, hand washing after handling pets is recommended, as well as delegating the task of cleaning waste from the kitty pan, the birdcage, and backyard dog droppings to someone else.

Toxoplasmosis frequently is mentioned as a special concern. Most cases of human toxoplasmosis are traced to eating undercooked meat, but there is a possible risk from contact with the feces of an infected cat. The risk of toxoplasmosis from cat feces is limited to those who come in direct contact with feces that are more than twenty-four hours old, as the eggs of T. gondii take twenty-four hours to hatch. Only those patients with cats that have an active case are at risk--usually those with kittens, as older cats have developed immunity long since. Outdoor cats, and indoor cats who catch mice, are potentially exposed to Toxoplasma gondii.

If you are told you must remove your pets from your home, you don't need to "get rid of them." You can find a temporary caretaker, a friend or relative, perhaps, or someone your veterinarian recommends. Your veterinarian may agree to board your pets at a reduced rate.

Long-term effects

Most long-term effects are discussed in Chapter 16, Late Effects, Late Complications; only those specific to transplantation are discussed here.

Chronic GVHD

If you have had an allogeneic transplant, there exists an ongoing risk of graft-versus-host disease.

(It is rare, but not impossible, to develop any form of GVHD, acute or chronic, after an autologous or syngeneic transplant. Researchers have experimented with deliberately creating GVHD in those who have had an autologous transplant for its graft-versus-lymphoma effect by administering and abruptly withdrawing immunosuppressive drugs.)

Unlike acute graft-versus-host disease, which appears soon after the transplant, chronic graft-versus-host disease (GVHD) appears three or more months afterward. It's less serious than acute GVHD, emerges less abruptly, can be controlled more easily, and is seldom fatal. Usually the skin is affected first, exhibiting itching, scaliness, or rash, although any organ can be affected, such as glands in the eyes or mouth. Often liver enzyme values in blood will become elevated, signaling the beginning of chronic GVHD. Graft-versus-host disease can affect connective tissue, tightening tendons and making movement painful.

Alexandre Azevedo, M.D., transplantation specialist, says:

Chronic GVHD impairs the immune system, rendering the patient highly susceptible to recurrent bacterial infections. Most of these infections are caused by bacteria such as Haemophilus influenzae and Streptococcus pneumoniae. Most often, patients have recurrent upper respiratory infections of the sinuses and throat. These infections should always be regarded as potentially dangerous in patients with chronic GVHD, in whom the risk of disseminated infection (sepsis) is always a concern. Most often, these patients receive long (sometimes lifelong) courses of prophylactic antibiotics such as penicillin or erythromycin. Post-transplant immunization against common pathogens is not reliable in the presence of chronic GVHD because of the severe immunologic dysfunction that is associated with the disease, as well as with its treatment with immunosuppressants.

Some researchers believe that a small amount of GVHD is beneficial against NHL. For this reason, the immunosuppressive medications you will be given may be carefully titrated to allow some GVHD to develop, but not enough to cause serious health problems.

Chronic graft-versus-host disease may eventually burn itself out, but usually not for five or more years.

Complications of immunosuppressive medication

Immunosuppressive drugs given to control GVHD pose their own risks.

Chief among these is the increased risk of infection. Those taking immunosuppressive drugs should take care to avoid breaking the skin, avoid crowds, thoroughly wash and cook all foods, postpone receipt of live vaccines, and avoid those who have had live vaccines. Check with your doctor about avoiding other risks, such as bacteria and fungi in soil that you may contact while gardening. Most transplant centers provide extensive information about such precautions.

Long-term use of immunosuppressive drugs such as cyclosporine may raise blood levels of lipids and cholesterol in some people, increasing the risk of blocked arteries. Different immunosuppressives can be substituted, cyclosporine levels can be adjusted, or cholesterol-lowering drugs can be prescribed.

Cyclosporine acts chiefly on T cells, disturbing the upward cascade of the immune response to threat by interfering with the action of interleukin-2 (IL-2). Certain cancers are known to be more likely among those whose T-cell function is suppressed, and many of these cancers are virally induced:

• NHL is about one hundred times more likely to develop among those with lowered levels of T cells than among the general population. It's usually a type of polyclonal NHL associated with Epstein-Barr virus (EBV) that usually regresses if T-cell function is restored by lowering the dosage of immunosuppressive drugs.
• Kaposi's sarcoma, a cancer induced by a human herpesvirus, may appear on the skin or in other organs, and is more prevalent among those whose T-cell function is suppressed.
• Melanomas are more likely among those with suppressed T-cell function.

Other late complications

Shingles, cataracts, peripheral neuropathy, kidney and liver function, infertility, weakness, fatigue, and cognitive and emotional problems as well as other problems may appear following a transplant.