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% to 4%.
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 cell transplants.
"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."