Transplantation

• Terminology
  
• Autologous transplants (rescues)
  
• Donor transplants
  
• Who gets which transplant?
  
• Which type of transplant is better?
  
• Finding a donor--quickly
  
• Choosing a transplant center
  
• Getting insurance company approval
  
• Becoming a donor
  

Doctors have struggled for years against their inability to give some patients enough chemotherapy or radiation therapy to destroy all cancer cells. The barrier they face is that very large doses of radiation or chemotherapeutic drugs destroy other tissue along with cancerous cells, including the soft inner core of bone called bone marrow. Permanently destroying most or all marrow eventually results in death, because blood cells are made only within bone marrow. Bone marrow transplantation provides a solution to this problem.

Bone marrow transplantation was attempted in the 1930s and 1940s as a cure for aplastic anemia, but was abandoned after many failures later attributable to a lack of knowledge of tissue rejection factors. In the early 1950s, studies with mice revealed that bone marrow could regenerate itself following an ostensibly fatal dose of radiation if some of the marrow was saved before treatment and reinjected a few days after. By the late 1960s, some researchers, equipped with a somewhat better understanding of white blood cell compatibility and marrow regeneration, began once again to use marrow transplantation to treat some leukemias and lymphomas.

But suppose the marrow itself contains NHL cells, as is frequently the case for some subtypes? Reinserting one's own diseased marrow would seem risky--and it is. For these circumstances, either marrow purging or donor marrow is used.

At one time, transplantation was considered the last resort in treating cancers for which all other treatments had failed. This is no longer the case. Some highly reputable oncologists may recommend an immediate transplant at diagnosis for widely spread low-grade NHL, for patients with several bad-risk features, for lymphomas that are particularly aggressive, or at first relapse for other NHLs and many leukemias. Moreover, if the transplant fails, other options exist, such as boosting donor marrow to act against NHL or, if a transplant using your own marrow fails, retransplantation using donor marrow.

Terminology

Terminology about transplants can be confusing. Even medical personnel tend to interchange terms such as marrow and stem cells, transplantation and marrow rescue. The following sections clarify the terms we'll use.

Transplant versus rescue

Although many people use the word "transplant" to describe any procedure involving reinfusion of blood precursors after marrow-suppressing (nonmyeloablative) or marrow-destroying (myeloablative) treatment, a true transplant involves receiving marrow or blood products from a donor. When one's own blood products are used, the procedure is more correctly called a marrow or stem cell rescue. Nonetheless, many people, including many medical personnel, refer to both of these procedures as transplants.

Marrow versus peripheral stem cells

Stem cells are the young offspring of bone marrow, capable of becoming any kind of blood cell. They are found in the blood, but are found in greater abundance within bone marrow. They can be harvested from either, and when they are harvested from blood via a vein, a colony stimulating factor such as Neupogen, or certain chemotherapies such as cyclophosphamide and etoposide, or both in tandem, are sometimes used first to force more of them out of the marrow.

Using peripheral stem cells in place of marrow appears to make no difference in the success rate of the transplant with respect to freedom from relapse. Accordingly, many transplant centers now use stem cells collected from the donor's or the patient's arm veins in place of bone marrow drawn from the hipbone. Stem cells from peripheral blood engraft more quickly than marrow upon reinfusion, and are less painful and less risky to harvest than marrow, because no anesthetic is required and the hipbone (iliac crest) does not need to be punctured.

Autologous transplants (rescues)

Autologous transplantation is performed using the patient's own stem cells or marrow. This procedure is also called marrow or stem cell rescue, autologous transplantation, or abbreviated as autologous transplant, ABMT, PSCT, or APSCT. It is done to allow extremely high, cancer-killing doses of anticancer therapies to be used--doses that also destroy most or all marrow--as opposed to a true transplantation from a donor, which aims to replace diseased marrow with healthy marrow.

As long as bone marrow appears unaffected by NHL, it's generally considered safe to reinfuse the patient's own marrow after high-dose chemotherapy and radiotherapy. Often, though, the marrow still is subjected to a purging process, either to kill cancer cells or to select healthy cells, even if no cancer cells are detected in it.

Donor transplants

There are several kinds of transplants performed using donor tissue, each having advantages and disadvantages. First, though, it's wise to have an understanding of how donors and recipients are matched to each other.

Matching haplotypes

Before a recipient's body can accept donor marrow or stem cells, testing must be done to ensure that the donor and recipient tissues can tolerate each other. This acceptance or rejection is mediated by proteins that extend from the surface of white blood cells. These sensors recognize and accept similar tissue, but trigger an attack against foreign tissue, including foreign white blood cells.

A sound knowledge of genetics, expensive equipment, and time are required to locate and analyze these white blood cell proteins in order to match donors and recipients properly. Engraftment failure, graft rejection by the host, or a very serious illness called graft-versus-host disease in which the donor's white blood cells attack the recipient's body organs may result from immune system mismatches. A closer match of white blood cell characteristics is required for marrow or stem cell transplantation than for other organ transplants, because it's the immune system itself that's being transplanted.

Currently, donors and recipients are matched on white blood cell characteristics, called haplotypes, that are controlled by certain genes on chromosome 6. Haplotypes HLA-A, HLA-B, and HLA-DR are always tested, with the DR locus being the most critical, but HLA-C is emerging as an important genetic site, or locus, on which to match as well. Nonetheless, currently only the first three are routinely tested for matching. Red blood cell type, commonly known as ABO typing, has no major effect on marrow compatibility.

Within these haplotypes are subtypes of almost inestimable variation. For this reason, the older serological testing method that uses intact white blood cells in a cross-reaction with others, called major histocompatibility (MHC) testing, is being replaced by direct testing of the genes extracted from the nucleus of the white blood cell--high-resolution DNA typing--for the more subtle differences in genetic makeup.

To make matters even more complex, each of us has two copies of each of these haplotypes, owing to our having inherited one copy of chromosome 6 from each parent. This means that the sites that must match actually are double the number discussed in the paragraphs above.

You'll hear matching success referred to as a 6 out of 6 match, or a 4 out of 6 match, and so on, abbreviated as 6/6 or 4/6. (As other genes are discovered to have a bearing on tissue rejection, eventually you'll hear the match described as a 7/8 or 8/8 match, an 8/10 or 10/10 match, and so on.) As newer direct DNA typing techniques become more common, you'll hear of matches on alleles--slightly different versions of the same gene--as well as the older term, haplotype matching. It's likely the two techniques will coexist for a time.

You inherit half of your genes from each parent. As a result, the odds of matching one parent's haplotypes are usually only three out of the currently used six genes, unless your parents are from a closely related ethnic community within which coupling outside of the tribe is discouraged.

Matching other family members is to some extent a roll of Mother Nature's dice. It's more likely that you will match a sibling, because genetic material of sibs is drawn from the same two sources, the parents. The odds of having a sibling match increase with the number of siblings you have. Fortunately, on some occasions a match can be found among first cousins.

Least likely of all is the chance that you will find a good match among those not related by blood. Nonetheless, in spite of these reduced odds, the National Marrow Donor Program now contains well over three million volunteers, among whom many matches for those needing transplants have indeed been found.

When a donor outside the family must be sought, problems may arise. African Americans and Asian Americans have white blood cell characteristics that are quite distinct, whereas Caucasian Americans, Latin Americans, and Native Americans have more white blood cell characteristics in common. This means that the full three million NMDP pool is not equally useful to all applicants. It's important to increase awareness of the need for marrow donors among ethnic groups. Friends and loved ones may join the NMDP by calling (800) MARROW-2. A blood sample only--not marrow--is required for donor testing.

Most transplant centers aim for a 6/6 match if an unrelated donor is used, and a 5/6 or 6/6 match if a related donor is used. A few centers specialize in transplantation using partially matched 3/6 or 4/6 related donors, and others are conducting clinical trials to improve partial-mismatch transplants. But many transplant centers still view partial mismatches as too risky within the constraints of technology that exist today.

More detailed discussions of inheritance and the calculation of odds of inheriting genes can be found in any textbook on genetics.

Allogeneic transplants

Allogeneic transplants are transplants using marrow or stem cells from someone who may or may not be a relative, but who is genetically not identical to the recipient. Allogeneic transplants are also known as allo-BMTs.

If an unrelated donor is used, very careful matching of white blood cell characteristics is done first, as described above under "Haplotypes," to reduce the chance of graft failure, graft rejection, or of very serious illness called graft-versus-host disease that may result from immune system mismatches.

If a related donor is used, careful matching of haplotypes is performed, but in general, fewer problems arise with a related donor, no doubt owing to the serendipitous matching of immune-related antigens of which we're not yet aware.

Preparation for an allogeneic transplant may differ from that used for an autologous transplant, because many transplant centers attempt to destroy the existing capacity of the patient's marrow to regenerate, regardless of the presence or absence of NHL in the marrow. It is thought that any remaining active marrow within the recipient may cause donor marrow to fail to engraft, or fail to replicate.

There are some studies underway, however, to test the effect of chimerism--a mixture of donor marrow and residual patient marrow--on NHL, and other studies are being performed to test the feasibility of converting the patient's marrow to donor marrow slowly, via repeated donor leukocyte infusions, without first destroying all of the patient's marrow.

Mary Butler describes her satisfaction with having had an allogeneic transplant:

I had an allogeneic donor marrow transplant for (what my doctor now says was) intermediate-grade, mixed large- and small-cell, with sclerosis, follicular non-Hodgkin's lymphoma. I was in stage four by the time I was diagnosed, and also upon relapse after six rounds of CHOP.

It's true my quality of life is diminished from what it was prior to diagnosis, but it beats being dead. I got to see my son graduate from high school and I also saw him set off for college. I share wonderful quality time with friends and family that I otherwise would not have experienced. I have had to adjust to chronic fatigue, but it is manageable and I can still do the things that matter most to me. I get to laugh, cry, see the sunset, hug the people I love, see great movies, read good books, play on my computer, and so on.

I have come to accept that life is change. Everyone, whether there is a cancer diagnosis or not, has to adjust to some changes and to things that didn't go quite the way they had planned. I am a very happy person despite my limitations, and maybe in part because of them. It has taught me to let go, to stop wasting my time with things that don't really matter, because they are a waste of energy, and mostly to express my feelings and communicate with the people in my life.

I'm just delighted to be here, alive, still sucking in air. Without the transplant I would be dead. A choice between diminished and dead, for me, was clear.

Syngeneic transplants

Syngeneic transplants are transplants from an identical twin.

The earliest efforts at bone marrow transplantation for aplastic anemia in the 1930s succeeded most often when the donor was an identical twin. Until then, it was thought that the ABO red blood cell matching system was the important factor in successful transplantation. The likelihood that marrow donated by an identical twin would engraft where others failed gave a strong indication that other compatibility factors were at work.

With identical genes in marrow from both the donor and the recipient, no graft-versus-host problems are expected, but on rare occasions they do arise.

Transplants using an identical twin as a donor are slightly more likely to fail owing to relapse of NHL than transplants using matched related or matched unrelated donors. It appears that genetic makeup may play a role in the development of NHL; thus, receipt of marrow identical to one's own may provide a second hospitable environment for NHL. Another explanation might be that graft-versus-host disease, which usually arises following a transplant from a nonidentical donor but not from a twin, may also provide a graft-versus-lymphoma effect.

Umbilical cord blood transplants

Umbilical cord blood is rich in the precursor cells that develop into mature white cells, red cells, and platelets. More importantly, because the newborn child has had no opportunity to develop white blood cells that are trained to attack anything, including foreign tissue, the naive status of T-cells within umbilical cord blood makes it ideal for transplantation. While graft-versus-host disease may develop following an umbilical cord transplant from an unrelated donor, it's usually less pronounced than that which develops after using marrow from a mature donor.

In the last ten years, the public has been encouraged to donate or store umbilical cord blood, which is usually immediately discarded just after childbirth. Storage for one's own use or donation to a cord bank make these products available for future use by your family or others. To donate cord blood, call the National Cancer Institute at 1-800-4-CANCER or the International Cord Blood Foundation at (415) 635-1456.

At this time, cord blood from a single umbilical cord contains only enough material to transplant children or small adults. Research with combining cord blood from several donors to provide a larger volume is underway, as is research using technology to replicate cord blood stem cells.

Donor leukocyte infusion (buffy-coat infusion, adoptive immunotherapy)

Donor leukocyte infusion (DLI), also called adoptive immunotherapy or buffy-coat infusion, is usually done following an allogeneic transplant that has failed to engraft, following a relapse of NHL after allogeneic transplantation, or perhaps as part of a trial measuring the added success of following marrow infusion with leukocyte support. Mature white blood cells are collected from the donor in the same way stem cells or platelets are collected--several hours of apheresis, using two arm veins--and are infused into the NHL survivor.

Often, this boost of donor material will trigger engraftment or will cause an immune response to be mounted against the tumor. The price paid is an increase in the likelihood of graft-versus-host attacks against body organs, which can cause serious illness.

Who gets which transplant?

Several factors must enter into your decision to choose a transplant technique. Your general health, what kind of NHL you have, and whether any suitable marrow donors exist are a few of these factors.

Type of disease

The type of NHL you have can impact whether an autologous or allogeneic transplant is recommended.

Some researchers believe that certain NHLs are best treated with an allogeneic transplant, especially when NHL has invaded the marrow, but the different types of NHL vary widely in their response to high-dose treatment. This variation makes it impossible to say that all NHLs that involve bone marrow should be treated with an allogeneic transplant. In fact, Burkitt's lymphoma and the Burkitt-like lymphomas of adulthood respond well to brief-intensity, high-dose treatment without transplantation; in these instances, your marrow might be harvested and held in reserve for future autologous transplantation should you relapse.

Your doctor is your best source of information about how your specific subtype of NHL impacts the choice of allogeneic versus autologous transplants.

Age

In the past few years, the upper age limit for treatment with autologous transplantation techniques has climbed steadily from about age 40 in 1991 to age 60 and beyond.

Many transplant centers are reluctant to treat patients over age sixty with allogeneic techniques, however, owing to the severity of side effects following allogeneic transplant. There are isolated instances, though, of patients well beyond age sixty being transplanted with sibling marrow following high-dose therapy. Donor transplants are not yet commonly performed in this age group, however.

If you have Internet access, you can visit the National Cancer Institute's clinical trials database and read the entry criteria for clinical trials of transplants. You'll see that some trials specify the upper limit of age as "physiological age 65," or a similar phrase. This means that a patient older than sixty-five might be accepted if he or she is judged to be otherwise as physically sound as most people aged sixty-five.

In short, your state of health may be more important than your age in determining what treatment you can withstand.

Other health factors

In general, other health problems that existed before your diagnosis with NHL may cause your doctor to consider an autologous transplant instead of an allogeneic transplant, because the side effects and long-term effects of an autologous transplant are less severe than with allogeneic transplantation.

Availability of donors

Even if your doctor believes that your subtype of NHL is best treated with an allogeneic transplant, the lack of a suitable and willing donor may leave autologous transplant as the only choice.

Which type of transplant is better?

In general, autologous transplants are physically easier to sustain, and have better survival statistics associated with the treatment itself, while allogeneic transplants may be more effective in protecting against NHL relapse, but entail a higher risk of death associated with treatment alone. As marrow purging techniques improve, the success rate of autologous transplants against NHL may approach those of allogeneic transplants.

The NHL patient usually has a much easier time recovering and far fewer long-term side effects from an autologous transplant than from an allogeneic transplant using donor marrow. On the other hand, transplants with marrow or blood products from a related or unrelated donor who is not genetically identical to the recipient appear to have an antilymphoma effect, called graft-versus-lymphoma (GVL), suggesting that either genetic differences or graft-versus-host interactions are meaningful in controlling lymphomas.

As of this writing, the mortality rate associated with high-dose transplant-related treatment procedures alone, as opposed to mortality from NHL, is about 3 percent for autologous transplantation and about 20 percent for allogeneic transplantation.

Finding a donor--quickly

When your health team determines that your subtype of NHL is best treated with an allogeneic transplant, the search for a donor must begin. In some cases, if the NHL is transforming to a higher, more aggressive type, the search must move quickly.

The best place to start the search is within your own family, owing to the increased likelihood of finding a very good match among close relatives, as described above under "Matching haplotypes." In many of today's smaller families, however, a good match might not be found. It may be necessary to search among unrelated donors for a good match.

Some donor centers typically test about ten donor blood samples per patient per day, but if they are made aware of the need for haste, they may be able to test up to one hundred samples per day. Some cancer survivors have found that this is an area in which their direct and personal communication efforts make a real difference.

If you're aware of your ethnic heritage, you might consider publicizing your need for donor testing in your community or in similar ethnic communities around the country. Ask ethnic associations to spread the word to other cities and states. You might also try asking local radio and TV stations for air coverage. Most have a consumer advocate or goodwill officer who will be glad to listen to you.

It would be a mistake, though, to rely only on your ethnic group(s) for help, because some ethnic groups share white blood cell characteristics with many others. Europeans--in spite of ethnic pride and ongoing squabbles in some parts of Europe--are almost indistinguishable from each other with respect to haplotype, with a few exceptions such as the closed communities of Gypsies, originally from India. This means that a donor drive targeted only to a U.S. Lithuanian community will miss many potential matches in Scandinavian, German, Polish, Russian, or French U.S. communities.

It's also wise to ask what your haplotypes are, and research which ethnic groups have the highest percentage of these haplotypes so that you can better target your recruiting efforts:

After I volunteered to become a marrow donor, out of curiosity I asked the bone marrow coordinator at Johns Hopkins to read me my haplotypes. Using a few reference texts, I discovered that my haplotypes are not most often found in the ethnic groups my family lays claim to, but instead are much more common among Hispanics, American Indians, and Asians. One of my six haplotypes is found more often among Jewish people than among the groups our family claims as ancestors.

See the Resources section of this center for references you can use to verify which ethnic groups have the highest frequencies of your haplotypes. In particular, the 1996 text by Cavalli-Sforza is an excellent reference, and an abridged version now is available in paperback. The National Marrow Donor Program's recent research paper on the frequency of haplotypes in North America is available on the Web.

You should also make sure all donor registries are contacted. In addition to the NMDP, try:

• American Bone Marrow Donor Registry Search Coordinating Center, Patient Search Information: 1-800-7-A-MATCH (1-800-726-2824)
• International Bone Marrow Transplant Registry: (414) 456-8325

Choosing a transplant center

Bone marrow transplantation is a lengthy, serious procedure. It demands state-of-the-art medical expertise and a good deal of experience to succeed.

Your medical insurance carrier may constrain your ability to pick a transplant center if they have contracted for this service with a particular group. It may be possible for you to convince them you should have it done elsewhere if you can prove that another center is better at handling your particular circumstances.

The American Society of Clinical Oncology and the American Society of Hematology have drafted a joint standard that specifies that a transplant center must do ten or more transplants per year in order to be certified. This guideline may be too broad for your circumstances, though. You may believe that the center that has done the most transplants for NHL, or a center that specializes in autologous or allogeneic transplants for NHL, is the best choice.

A transplant center's experience reflects to some degree the areas of expertise of the researchers involved and the kind of research for which they've succeeded in getting funds. Some transplant centers specialize in transplantation from unrelated donors; others prefer to transplant only patients who have a related donor. A few centers specialize in doing mismatched transplants. Still others specialize in treating children.

You also need to assess the center for more practical aspects such as any nearby housing they may provide, and psychological, emotional, and educational support for your family. A center with a lengthy waiting list, for instance, will not be a good choice if your NHL is converting to a more aggressive grade.

Here are resources you can use to choose a transplant center:

• Every two years, the Oncology Nursing Society publishes an extensive guide to transplant centers. You may call them at (412) 921-7373.
• The Blood and Marrow Transplant Newsletter contains useful information for choosing a center. Their phone number is (847) 831-1913.
• The National Cancer Institute's Cancer Information Service (CIS) at (800) 4-CANCER can refer you to transplant centers that specialize in NHL.
• The National Marrow Donor Program has a booklet on transplantation using an unrelated donor. Call (800) 654-1247 or (800) 526-7809.

Getting insurance company approval

In 1998, the average cost of a transplant was $160,000, with prices ranging from $75,000 to $200,000. Costs for long-term follow-up care over the years can easily approach half a million dollars or more.

Owing to this extraordinary expense, some insurance companies scrutinize closely any medical plan that involves a marrow transplant. Staff with no medical training may use arbitrary means to deny approval, such as saying that transplantation for your disease is an experimental procedure, and thus not covered by your policy.

If your employer offers an open enrollment period annually--a period during which no previously existing medical conditions can be held against you--use this opportunity to upgrade your policy to the most liberal one offered.

Until legislation provides cancer survivors with fully reimbursed access to clinical trials, this battle is in your court. To overrule insurance company objections, you need to be familiar with state-of-the-art treatment for your subtype of NHL.

If you're not satisfied with your insurance company's decision, do challenge it. Ask your oncologist for a "letter of necessity," and ask your employer to intervene, a tactic that is surprisingly successful, especially for those working for companies that are self-insured.

Self-insured companies often have their plans administered by an independent health insurance firm, but always pay the cost of your treatment from their own pocket. This means that, if you're working for a self-insured company, your employer, not the insurance company, is denying you payment. This is a sensitive situation you can turn to your benefit by arguing that it's in the company's best interest to keep you healthy or, more frankly, to avoid your embarrassing them.

Only a fraction of an insurance company's clients ever challenge the insurance company's decisions. The funds saved on the majority who are silent easily pay the costs of the few who do challenge these rulings. The Blood and Marrow Transplant Newsletter has a list of lawyers who specialize in transplant approval problems.

You might want to consider using a facility that has few or no charges. Free treatment is provided at the National Cancer Institute in Bethesda, Maryland, but within clinical trials only. Treatment for children is free at the St. Jude Research Hospital in Memphis, Tennessee. Some transplant centers will work out a financial repayment agreement with you if you are left with an unusually high bill after health insurance reimbursement. In some states, state-funded hospitals must provide you with care if you are unable to pay.

Becoming a donor

Only 20 to 30 percent of patients needing allogeneic transplants are able to find a donor because there are too few donors in the marrow registries.

Family and friends of those with NHL should consider joining the National Marrow Donor Program. A blood sample only--not marrow--is used for testing.

Many who have donated marrow describe it as one of the most fulfilling experiences of their life, second only to becoming a parent. Most say they will do it again, eagerly and without hesitation, if called.

A decision to become a marrow or stem cell donor is a serious commitment. You must remain on call, be willing to undergo additional blood testing, and be willing to donate as soon as you're called, regardless of your other plans, including vacation plans or any minor illnesses. You will be responsible for saving a life. A donor should never back out of donating once treatment of the patient has begun, because often this treatment is intended to destroy all of the patient's marrow. Without donor marrow at this point, the patient will die. The process of harvesting marrow or stem cells is described above in the section called "Donor's harvest."

After you have donated, you may be asked to donate again later for the same patient if she relapses. Often the second donation is simply an apheresis of stem cells or mature white blood cells, even if marrow was used the first time.

Once you have donated for a patient, you will not be considered eligible to donate for a second patient for twelve months.

If you donated marrow or stem cells to an unrelated patient through the National Marrow Donor Program, you and the patient may contact each other after one year, if both agree.

You may join the NMDP by calling (800) MARROW-2.