January 5, 2003
The New Bone Marrow Transplants
Today's Bone Marrow
Transplants are saving the lives of cancer patients in unexpected
By Scott C. Anderson
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
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
"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.
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
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.
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
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.
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.
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
"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
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
Leukemia & Lymphoma Society
National Association of Hospital Hospitality Houses, Inc.
Ronald McDonald House Charities
BMT TREATMENT CENTERS
City of Hope National Medical Center
Department of Hematology & Bone Marrow Transplantation
1500 East Duarte Road
Duarte, CA 91010-3000
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
San Francisco, CA 941143-0128
H. Lee Moffitt Cancer Center
12902 Magnolia Drive
Tampa, FL 33612-9497
Johns Hopkins Kimmel Cancer Center
401 North Broadway
Baltimore, MD 21231-2410
National Cancer Institute
Public Inquiries Office
6116 Executive Boulevard, MSC8322
Bethesda, MD 20892-8322
Dana-Farber Cancer Institute
44 Binney Street
Boston, MA 02115
Mayo Clinic Transplant Center
200 First Street, SW
Rochester, MN 55905
University of Minnesota Cancer Center
Mayo Mail Code 806
420 Delaware Street SE
Minneapolis, MN 55455
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, NY 10021
The University of Texas M. D. Anderson Cancer Center
1515 Holcombe Blvd
Houston, TX 77030
Fred Hutchinson Cancer
1100 Fairview Avenue North
P. O. Box 19024
Seattle, WA 98109
Copyright © 2000-2014 by Scott Anderson
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