From Jones and Bartlett, a book on Stem Cells from Dr. Ann A. Kiessling and Scott C. Anderson:


Selected Articles:

January 5, 2003

The New Bone Marrow Transplants

Today's Bone Marrow Transplants are saving the lives of cancer patients in unexpected ways.

By the time he was diagnosed with chronic lymphocytic leukemia, (CLL) Michael Billig's cancer had already taken over 90 percent of his blood. His doctors lost no time in getting the 43-year-old into chemotherapy. After several grueling rounds of chemotherapy, Billig's cancer went into remission and he felt good enough to start running again.

His doctors told him that, good as he felt, chemo alone would not cure his cancer. A treatment involving a new kind of bone marrow transplant (BMT) offered a glimmer of hope for a complete cure, but at a cost: he would have to forgo his hard-won remission.

"That's the irony," says Billig, an anthropology professor at Franklin & Marshall College in Lancaster, Pennsylvania. "I was  in remission and feeling great. Then I had to decide to go through hell and risk dying from the procedure, rather than just the disease." But when one of his doctors said she would recommend the transplant for her own son, Billig's mind was made up.

The idea behind the treatment was simple: harvest some of Billig's marrow cells, use high-dose chemo to blast any remaining cancer in his body, then "reboot" his immune system by injecting the harvested cells in a process called reinfusion.

But that blasting part is a killer - literally. Any cell that is dividing is killed. Cancer cells are notorious for uncontrolled division - that's how they had managed to take over so much of Billig's blood and lymph system. But a few other cells are similarly prolific, like skin, hair, gut, and marrow cells. In the indiscriminate battle of chemotherapy, many good cells are caught in the crossfire. One of these "friendly-fire" victims is the immune system, fueled by cells produced in the bone marrow.

The innovative treatment described by Billig's doctor was a BMT with a twist, using some unusual new drugs, including rituximab, a monoclonal antibody (a man-made antibody that can target tumor cells), and growth factors (substances that regulate the rate at which cells divide).

That was in 1999, and although scientists are still analyzing the data, it appears that the monoclonal treatment has great promise. Michael Billig is back into his running routine and has celebrated three healthy birthdays since the transplant.

His procedure took place at the Johns Hopkins Kimmel Cancer Center in Baltimore, overseen by Ian Flinn, MD. Dr. Flinn is working to improve the treatment with another new monoclonal antibody called Campath. Based on what he saw in Billig's case, he says he has high expectations for treatments that combine monoclonals and growth factors.

"Combination treatments are likely to extend remission significantly," says Dr. Flinn. The scientists who have been working with Campath are extremely excited by it. It is an unbelievably effective way of clearing the bone marrow, which is where all the leukemia cells begin."

Dr. Flinn sees even more hopeful treatments on the horizon. Instead of relying on high-dose chemo to kill cancer cells in the bone marrow, a so-called "mini" BMT uses lower doses of chemo and focuses on allowing the cells from a BMT donor to prompt an immune response. In the mini procedure, bone marrow from the donor identifies the cancer cells as being foreign and destroys them.

Mini transplants also have the benefit of being easier on the patients, as opposed to high-dose chemo, which can be deadly to very weak or older patients. That's why autologous transplants (where the transplanted cells came from the patient's own marrow, and typically involve heavy chemo) are rarely recommended for people over 55. But, by minimizing the chemo dose, mini transplants promise to help the approximately 60,000 older people who need transplants each year but cannot tolerate the side effects.

NEW TREATMENTS

Better Purging

Researchers are learning how to purge cancer cells from the marrow without damaging the good cells, leading to faster and better treatments. At Johns Hopkins they are finding new uses for a drug called granulocyte macrophage colony stimulating factor (GM-CSF), the same growth factor that Michael Billig received. Typically used to boost the production of stem cells (the building blocks for all the major tissues as well as the immune system), GM-CSF can also cause certain cancer cells to die prematurely. This unexpected benefit is proving to be valuable for purging cancer from the bone marrow before it is returned to the patient.

Purging typically involves killing or filtering out the bad cells. But a new technique called "positive selection" filters out healthy stem cells from the bone marrow. One of these new techniques depends on a cell marker called CD34, which is only found on normal, non-cancerous stem cells. Although there are fewer reinfused cells with this technique, the results look promising.

New Monoclonal Antibodies (MAbs)

New and better-targeted MAbs are on the horizon. Like the rituximab that Michael Billig received, these drugs promise to home in on just the cancerous cells, leaving the rest of the immune system intact.

This precision means they have far fewer side effects than traditional chemo. They seek the bad cells out and tag them for destruction in the immune system by natural killer cells that target and kill tumor cells on contact. Since antibodies depend on the killer cells to do much of the work, MAbs are typically administered first. That's because subsequent chemo seriously damages the immune system, including the killer cells.

The first MAbs were produced using mice antibodies, but that sometimes led to rejection by the patient's immune system. Newer techniques aim to "humanize" the treatments. One approach splices human and mouse proteins to reduce rejection. Another uses a specially bred mouse line with human antibody genes. Still another technique involves bacteria engineered to produce human antibodies.

Another promising line of research attaches a radioactive atom to each antibody molecule. When the antibody finds its cancerous target, the radiation helps to kill it. And antibodies are also being used to target and remove certain cells (like B-cells) that aren't cancerous, but could lead to rejection of the bone marrow transplant.

Better Matching

Human leukocyte antigens, or HLAs, have been the key to tracking down a compatible bone marrow donor. HLAs are protein molecules that mark the body's cells. Ideally, a patient and donor have six matching antigens. But now a new technique - DNA matching - can produce even better results with fewer side effects such as graft vs. host disease (GvHD). That's when the transplanted marrow, which contains immune cells, perceives the patient's organs and tissues as foreign and then attacks the patient. DNA testing has shown that certain HLA markers - thought to be matches, in the past - turn out to have several variants. This could explain the occasional case of GvHD even with properly matched antigens.

There is a type of graft vs. host disease that turns out to be helpful, called graft vs. leukemia (GvL). Instead of attacking healthy cells, GvL mounts an attack on the patient's cancer cells, keeping them in check. Researchers are examining the delicate balance between GvHD and GvL at the DNA level. So far the research indicates that DNA matching may help determine which "near misses" - where the DNA is close but not identical - will actually prove to be beneficial.

Stem Cell Magic

Researchers are trying to culture stem cells and beef up their numbers in the lab. The idea is to reduce the number of cells that need to be harvested, and thus reduce the number of needle punctures. Although this is a promising line of research, adult stem cells are still difficult to culture.

On the other hand, embryonic stem cells can be cultured indefinitely. Research on these cells is still controversial, but new treatments promise to be less ethically troublesome and even more powerful.

One of these techniques creates embryonic stem cells by extracting the DNA from a donated human egg and replacing it with DNA from the patient. This hybrid egg can divide and grow into embryonic stem cells, which - unlike adult cells - are immortal. That means scientists can grow a few million cells, enough for treatment. Since these cells are genetically identical to the patient, there is no chance they'll be rejected. Another advantage: These cells are grown from scratch in a petri dish, so they're guaranteed to be free of any cancer cells.

Since embryonic stem cells can be derived from a tiny snippet of skin, they may ultimately replace the traditional BMT, which extracts stem cells from the bone marrow. Government-funded research on this awaits a political decision.

GETTING HELP

Bone marrow transplants are expensive. The procedure varies widely in cost, depending on the treatment, ranging from $50,000 to $250,000 or more.

For Omer Whittington, who had been diagnosed with a lymphoma in his chest wall, that kind of money was out of reach. "There was a time between the end of my disability payments and when my Social Security benefits started that I didn't have any income," says Whittington, For many, the answer is financial support from one of the foundations set up to help patients who need a transplant.

One of the best known is the Bone Marrow Foundation, started in 1992 by Christina Merrill. While employed as a social worker at Mount Sinai Medical Center in New York, Merrill saw firsthand how BMTs could extend a person's life - and devastate their finances. She was determined to help. Merrill started by raising money from her friends and family. In 1993, the Bone Marrow Foundation held its first fundraiser, collecting $100,000. Ever since, Merrill has expanded the foundation to include hundreds of donors and a panel of doctors.

"Our goal is to provide desperately needed information to patients and families in a crisis situation," she says. "We also provide money to help with the many direct and indirect costs that come up, such as medicines, accommodations, travel, home care and donor searches."  The Bone Marrow Foundation also offers emotional assistance in the form of support groups and a service called SupportLine where newly diagnosed patients and their family members can talk with BMT veterans to soothe their anxieties. Another popular online service: "Ask the Expert," where patients can ask questions of the foundation's network of doctors, who provide a confidential answers.

The Bone Marrow Foundation helps hundreds of patients each year; last year their website received over a million hits. It's a sobering testimonial to how many people need financial or emotional help with their BMT.

Another major player in fundraising is Harry Pearce. As the vice chairman of General Motors, he was used to holding the reins. But in 1998 Pearce was diagnosed with acute myelogenous leukemia and his life turned upside down. Suddenly he was dependent on others. When faced with a devastating disease, he says, "you realize how the support of others contributes to your still being around."

Pearce went to the Fred Hutchinson Cancer Center in Seattle for a marrow transplant from his brother. After his recovery, he became a one-man money-raising machine, helping to set up and fund dozens of groups, including the Bone Marrow Foundation where he serves as a member of the board. With his impressive business connections, he has convinced many large companies and their executives to donate money to the cause.

"I am very grateful to The Bone Marrow Foundation and their donors for all the help they have given me," says Whittington, whose treatment was a success. "My life is back to normal. I'm surrounded by my four children and six grandchildren. I even went back to work. I hope someone reading my story will be inspired, and will get the courage to go on."

HOW BMT WORKS

When most people think of transplants, they think of hearts or kidneys - surgical procedures with donated organs. But bone marrow transplants (BMTs) are different in two ways: they aren't surgical procedures, and they may be "autologous," involving the patient's own marrow and not a donor's. Over two-thirds of transplants today are autologous.

The active ingredients in bone marrow are stem cells, which are the body's "generic" cells. Although marrow contains more stem cells than any other body tissue, even here they are rare, comprising less than one in a thousand cells. There are stem cells for each of the major tissues, like nerves, blood, bone, and muscle. Stem cells for blood have the capacity to become every type of blood cell, including disease-fighting cells of the immune system, such as T cells, B cells, and macrophages.

BMTs can effectively treat patients whose marrow is diseased, as it is in blood-related cancers such as leukemia. In these cases, it may be preferable to use donated marrow. When the patient's own marrow is used, it's first treated by a special purging technique to eliminate as many cancer cells as possible.

Doctors may also prescribe a BMT when a patient's immune system is weakened by radiation or chemotherapy for cancers not related to the blood, such as breast or testicular cancer. In such cases, the patient's own marrow - harvested, frozen, and saved - may be perfectly suitable for restarting the immune system.

Michael Billig, a professor of anthropology in Lancaster, Pennsylvania, had such a transplant. Although doctors tried to find a donor among his relatives, none of them matched Billig's HLAs, or human leukocyte antigens. These antigens are markers on the cells of the immune system that help distinguish friend from foe. A foreign cell will carry different HLA markers and will be destroyed. So if the HLAs of a donor don't properly match those of the patient, there can be two different outcomes, both of them potentially bad. In one case, the patient will reject the transplant. In the other case, the transplant will attack the patient. This is called graft vs. host disease and it can be deadly.

Without a matching relative to donate marrow, Billig's doctors turned to the bone marrow registry that lists over 4.6 million potential donors. There still was not a good match, so Billig's doctors settled on an autologous transplant. That solution, however, is not without peril. According to Ian Flinn, MD, who oversaw Billig's care at Johns Hopkins, "One of the problems with autologous transplantation is that without an effective purging technique, we're very likely to reintroduce cancer cells back into the patient and probably contribute to their ultimate relapse."

In a traditional BMT, marrow can be harvested from the bone, usually the hip. The area is anesthetized and then a needle is pushed into the bone and some marrow is extracted. It can take several of these "aspirations" to retrieve a sufficient number of cells. The advantage of this technique is that it's quick, inexpensive, and straightforward.

Good results are now being obtained from peripheral blood stem cell transplants - stem cells harvested from blood circulating in the bloodstream. This treatment uses growth factors (substances that regulate the rate at which cells divide) to prompt marrow cells to spill out of the bone and into the bloodstream. The cells are then collected from the blood using a process called apheresis. It's less painful than a typical BMT, but slower, since it takes a while to build up sufficient stem cells in the blood. If time is of the essence, doctors often recommend traditional BMT.

FOR MORE INFORMATION

Some of the organizations that provide financial aid and support for patients undergoing bone marrow transplant:

The Bone Marrow Foundation
1-800-365-1336

Leukemia & Lymphoma Society
1-800-955-4572

National Association of Hospital Hospitality Houses, Inc.
1-800-542-9730

Ronald McDonald House Charities
630-623-7048

BMT TREATMENT CENTERS

California

City of Hope National Medical Center
Department of Hematology & Bone Marrow Transplantation
1500 East Duarte Road
Duarte, CA 91010-3000
1-800-826-HOPE (4673)

University of California, San Diego
UCSD Cancer Center
9500 Gilman Drive
La Jolla, CA 92093-0658
858-657-7053 or 6790

University of California, San Francisco
UCSF Comprehensive Cancer Center
Box 0128
San Francisco, CA 941143-0128
1-800-888-8664

Florida

H. Lee Moffitt Cancer Center
12902 Magnolia Drive
Tampa, FL 33612-9497
1-888-663-3488

Maryland

Johns Hopkins Kimmel Cancer Center
401 North Broadway
Baltimore, MD 21231-2410
410-502-1033
1-800-507-9952

National Cancer Institute
Public Inquiries Office
Suite 3036A
6116 Executive Boulevard, MSC8322
Bethesda, MD 20892-8322
1-800-4-CANCER (1-800-422-6237)

Massachusetts

Dana-Farber Cancer Institute
44 Binney Street
Boston, MA 02115
1-866-408-3324

Minnesota

Mayo Clinic Transplant Center
200 First Street, SW
Rochester, MN 55905
507-284-2511

University of Minnesota Cancer Center
Mayo Mail Code 806
420 Delaware Street SE
Minneapolis, MN 55455
612-624-8484
1-888-226-2376

New York

Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, NY 10021
212-639-2000
1-800-525-2225

Texas

The University of Texas M. D. Anderson Cancer Center
1515 Holcombe Blvd
Houston, TX 77030
713-792-6161
1-800-392-1611

Washington

Fred Hutchinson Cancer Research Center
1100 Fairview Avenue North
P. O. Box 19024
Seattle, WA 98109
206-667-5000

 


Copyright © 2000-2013 by Scott Anderson
For reprint rights, email the author: Scott_Anderson@ScienceForPeople.com

Here are some other suggested readings about Bone Marrow Transplants: