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.
A new technique for enriching progenitor blood cells and purgingtumor cells before reinfusing the progentitor cells into cancerpatients offers significant advantages over bone marrow for transplantation,according to investigators at Stanford University.
Cancer patients who receive the enriched and purged blood cellsrecover from the high-dose chemotherapy and transplantation proceduresignificantly faster and require fewer blood cell transfusionsthan patients who undergo transplantation with bone marrow, theresearchers report in the journal of Blood. By creatinga high concentration of the desired progenitor cells, the enrich/purgetechnique replaces the several-hour transfusion of unprocessedblood progenitor cells with a 15-minute procedure to transfusethe processed cells.
The new technique is a refinement of standard stem- cell reinfusionin which blood progenitor-cell (stem- cell) transplants are substitutedfor autologous bone marrow transplants. Researchers at Stanfordand elsewhere discovered in the 1980s that stem cells can be enticedto leave the bone marrow and enter the bloodstream when patientsare given high-dose chemotherapy and blood growth factors. Theyfound that harvesting cells from the blood instead of the marrownot only spared patients the somewhat painful bone marrow harvestbut also enabled patients to recover faster after the procedurethan they would after transplants of bone marrow.
However, as these blood cell transplants have become commonplace,some key questions have remained unanswered. First, researchershave wondered how to get rid of tumor cells that are frequentlypresent in the blood they transplant back into the patient. Anyremaining tumor cells may leave the patient vulnerable to a relapseof the cancer. In addition, researchers have wondered how manyblood cells to give a patient to be sure enough stem cells aretransplanted to quickly replenish blood cells.
In a clinical trial using autologous blood stem-cell transplantsin 21 patients with non-Hodgkin's lymphoma, the Stanford teamused a technique for separating high- and low-density portionsof the blood to maximize the number of stem cells. Stem cellsare 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 about80% of the stem cells, yet deplete the white blood cells we don'tneed or want," said hematologist Robert Negrin, MD, an assistantprofessor of medicine in Stanford's bone marrow transplant division.
Stem cells regenerate blood cells and platelets significantlyfaster than autologous bone marrow following the transplant. Patientswho received blood stem cells required an average of four platelettransfusions to prevent bleeding while waiting for their stemcells to replenish other blood cells, compared to 13 transfusionsfor patients transplanted with bone marrow. Also, patients whoreceived blood stem cells were released from the hospital a weekearlier on average.
The Stanford research group said that the blood stem- cell transplantprocedure is much less traumatic for patients than bone marrowtransplantation. A single round of chemotherapy and daily dosesof growth factors stimulate some of the patient's stem cells toleave the marrow for the blood. When the white blood cell countrecovers after this treatment and the stem-cell level in the bloodstreampeaks, the patient undergoes apheresis to collect white bloodcells from the blood. The rest of the blood is returned to thepatient. The cells collected during apheresis are processed throughthe enriching and purging steps and frozen. Then, after the patientgoes 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 onlya small amount of blood to be returned. Autologous blood progenitor-celltransplants normally require up to 10 or 12 bags of blood productto be administered--a procedure that takes about 15 minutes perbag. But Negrin and his collaborators have found that with theirtechnique, the result of a single apheresis collection--a singlebag of blood product--contains enough stem cells to replenishthe 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 studyhas died after the transplant procedure. Analysis of the studyresults indicate that the patient who died hadn't received enoughprogenitor cells, noted postdoctoral fellow Dr. Claus Kusnierz-Glaz,an author of the study and one of the originators of the conceptof the enrich/purge technique. "Since we have found the thresholdfor how many progenitor cells we need to administer, we are nowable to select patients who are likely to have a more favorableresponse to the treatment," he said.
Bone marrow transplantation generally carries a regimen-relatedmortality of 7% to 10%, Negrin noted, and transplantation of unprocessedblood 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 treat50 additional patients with non-Hodgkin's lymphoma. The resultscontinue to be extremely encouraging, Negrin said.
The first 21 patients to receive this treatment all had relapsedcases of non-Hodgkin's lymphoma. But because the initial resultshave been so promising, Negrin and his colleagues are collaboratingwith Stanford oncologist Sandra Horning, MD, associate professorof medicine, to start using the technique for primary treatmentof patients with lymphoma who are deemed at high risk of relapsing.
"We estimate that the lack of operating room expenses forbone marrow removal, fewer platelet transfusions, and earlierdischarges for autologous blood stem- cell transplant patientsresult in a $30,000 to $40,000 cost savings per procedure overbone marrow transplantation," said Samuel Strober, MD, professorof immunology and rheumatology and a member of the study team.
The improved outcome, reduced patient morbidity, and significantcost savings are boosting the use of auto-logous blood progenitorcell transplants.
"At least 9 out of 10 autologous transplants [at Stanford]are done with peripheral blood," noted Dr. Karl Blume, directorof Stanford's bone marrow transplant division. "We hardlytake the patient to the operating room any more."