A new technique for enriching progenitor blood cells and purging
tumor cells before reinfusing the progentitor cells into cancer
patients offers significant advantages over bone marrow for transplantation,
according to investigators at Stanford University.
Cancer patients who receive the enriched and purged blood cells
recover from the high-dose chemotherapy and transplantation procedure
significantly faster and require fewer blood cell transfusions
than patients who undergo transplantation with bone marrow, the
researchers report in the journal of Blood. By creating
a high concentration of the desired progenitor cells, the enrich/purge
technique replaces the several-hour transfusion of unprocessed
blood progenitor cells with a 15-minute procedure to transfuse
the processed cells.
The new technique is a refinement of standard stem- cell reinfusion
in which blood progenitor-cell (stem- cell) transplants are substituted
for autologous bone marrow transplants. Researchers at Stanford
and elsewhere discovered in the 1980s that stem cells can be enticed
to leave the bone marrow and enter the bloodstream when patients
are given high-dose chemotherapy and blood growth factors. They
found that harvesting cells from the blood instead of the marrow
not only spared patients the somewhat painful bone marrow harvest
but also enabled patients to recover faster after the procedure
than they would after transplants of bone marrow.
However, as these blood cell transplants have become commonplace,
some key questions have remained unanswered. First, researchers
have wondered how to get rid of tumor cells that are frequently
present in the blood they transplant back into the patient. Any
remaining tumor cells may leave the patient vulnerable to a relapse
of the cancer. In addition, researchers have wondered how many
blood cells to give a patient to be sure enough stem cells are
transplanted to quickly replenish blood cells.
In a clinical trial using autologous blood stem-cell transplants
in 21 patients with non-Hodgkin's lymphoma, the Stanford team
used a technique for separating high- and low-density portions
of the blood to maximize the number of stem cells. Stem cells
are of low density, so the high-density portion is discarded.
Then, using antibodies and complement to target the tumor cells,
the low-density mixture is purged of malignant cells.
"The advantage of this technique is that we can retain about
80% of the stem cells, yet deplete the white blood cells we don't
need or want," said hematologist Robert Negrin, MD, an assistant
professor of medicine in Stanford's bone marrow transplant division.
Stem cells regenerate blood cells and platelets significantly
faster than autologous bone marrow following the transplant. Patients
who received blood stem cells required an average of four platelet
transfusions to prevent bleeding while waiting for their stem
cells to replenish other blood cells, compared to 13 transfusions
for patients transplanted with bone marrow. Also, patients who
received blood stem cells were released from the hospital a week
earlier on average.
The Stanford research group said that the blood stem- cell transplant
procedure is much less traumatic for patients than bone marrow
transplantation. A single round of chemotherapy and daily doses
of growth factors stimulate some of the patient's stem cells to
leave the marrow for the blood. When the white blood cell count
recovers after this treatment and the stem-cell level in the bloodstream
peaks, the patient undergoes apheresis to collect white blood
cells from the blood. The rest of the blood is returned to the
patient. The cells collected during apheresis are processed through
the enriching and purging steps and frozen. Then, after the patient
goes through treatment with high-dose chemotherapy or radiation,
the cells are thawed and returned to the bloodstream.
With the enriching and purging technique, patients require only
a small amount of blood to be returned. Autologous blood progenitor-cell
transplants normally require up to 10 or 12 bags of blood product
to be administered--a procedure that takes about 15 minutes per
bag. But Negrin and his collaborators have found that with their
technique, the result of a single apheresis collection--a single
bag of blood product--contains enough stem cells to replenish
the blood-forming system permanently.
Although it's too early to draw conclusions on improved survival,
said Negrin, only 1 of the 21 patients in the newly reported study
has died after the transplant procedure. Analysis of the study
results indicate that the patient who died hadn't received enough
progenitor cells, noted postdoctoral fellow Dr. Claus Kusnierz-Glaz,
an author of the study and one of the originators of the concept
of the enrich/purge technique. "Since we have found the threshold
for how many progenitor cells we need to administer, we are now
able to select patients who are likely to have a more favorable
response to the treatment," he said.
Bone marrow transplantation generally carries a regimen-related
mortality of 7% to 10%, Negrin noted, and transplantation of unprocessed
blood progenitor cells generally carries a regimen-related mortalityof2%
In the 6 months since these results were submitted for publication,
Negrin and his colleagues have used the new procedure to treat
50 additional patients with non-Hodgkin's lymphoma. The results
continue to be extremely encouraging, Negrin said.
The first 21 patients to receive this treatment all had relapsed
cases of non-Hodgkin's lymphoma. But because the initial results
have been so promising, Negrin and his colleagues are collaborating
with Stanford oncologist Sandra Horning, MD, associate professor
of medicine, to start using the technique for primary treatment
of patients with lymphoma who are deemed at high risk of relapsing.
"We estimate that the lack of operating room expenses for
bone marrow removal, fewer platelet transfusions, and earlier
discharges for autologous blood stem- cell transplant patients
result in a $30,000 to $40,000 cost savings per procedure over
bone marrow transplantation," said Samuel Strober, MD, professor
of immunology and rheumatology and a member of the study team.
The improved outcome, reduced patient morbidity, and significant
cost savings are boosting the use of auto-logous blood progenitor
"At least 9 out of 10 autologous transplants [at Stanford]
are done with peripheral blood," noted Dr. Karl Blume, director
of Stanford's bone marrow transplant division. "We hardly
take the patient to the operating room any more."