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Summer 1996Volume 3, Number 1 |
High-dose chemoradiotherapy plus allogeneic marrow transplantation has been established as a potentially curative therapy for patients with leukemia or lymphoma. Tremendous emphasis has been placed, appropriately, on the experience of the patient undergoing this procedure, but the process is also associated with temporary discomfort and inconvenience for the donor as a result of the multiple aspirations from the iliac crests while under general anesthesia (see figure 1). At many centers, the donor procedure requires an overnight stay for observation and recovery after the marrow harvest.
Recent experience demonstrates that peripheral blood stem cells collected from normal donors by apheresis, the same procedure routinely used to collect platelets, provides an adequate number of hematopoietic progenitor cells for full hematopoietic recovery in an allogeneic recipient without the disadvantages of a marrow harvest under general anesthesia for the donor. Hematologists have been aware for decades that hematopoietic progenitor cells circulate in peripheral blood and can be mobilized in large numbers from the marrow into the peripheral blood using hematopoietic growth factors such as filgrastim (rG-CSF). Hematopoietic stem cell mobilization and collection by apheresis is now a routine procedure for patients with malignancies who are about to undergo autologous transplantation. The same procedure can be applied to normal volunteer donors.
The peripheral blood stem cell donor receives subcutaneous injections of filgrastim twice daily for three or four days in preparation for apheresis. The apheresis procedure is performed on an outpatient basis and lasts approximately four hours. During apheresis, blood is removed from a vein in one arm, fractionated continuously on an automated cell separator to collect the stem cells, and the remaining cells are returned through a vein in the opposite arm (see figure 2). Donors remain awake and alert and can engage in sedentary activities during the procedure such as reading, watching television, or interacting with family members. The only discomfort for the donors other than the transient pain of the venipunctures is bone pain in response to the filgrastim injections which cause marrow expansion, but this pain is readily controlled with acetaminophen. Depending on the number of growth factor injections administered, one procedure yields a sufficient number of blood stem cells for allogeneic transplantation in 60-90% of donors.
Figure 1. Bone marrow is obtained from multiple aspirations of the donor's iliac crests. The marrow is then filtered and readied for intravenous infusion into the recipient.
To date, almost 500 normal donors have undergone this procedure, and its short-term safety appears to be at least equivalent to that of the standard marrow harvest. Concerns have been raised regarding the use of a hematopoietic growth factor in a normal individual. Studies in children with congenital neutropenia treated with filgrastim have demonstrated no excess in long-term adverse events, suggesting that there would be little if any late risk for normal donors. However, to address this concern, a registry is being established to follow blood stem cell donors long-term and to compare their experiences to those of marrow donors. In addition, preclinical studies are underway to develop new agents for mobilization with even fewer potential side effects.
Although peripheral blood stem cell collection has clear advantages for normal donors, questions have been raised regarding the safety and efficacy of these cells for allogeneic transplantation. Some have suggested that a marked increase in acute graft-versus-host disease (GVHD) in the allogeneic blood stem cell recipients might be encountered, since blood stem cell grafts contain more than ten times as many lymphocytes as marrow allografts. Such a large number of lymphocytes clearly has little or no consequence in an autologous recipient.
The international experience with allogeneic blood stem cell transplantation was reviewed at the first international symposium sponsored by the European Group for Blood and Marrow Transplantation in Geneva in October, 1995. The major allogeneic blood stem cell transplantation centers in North America include M.D. Anderson Cancer Center in Houston, Fred Hutchinson Cancer Research Center in Seattle, University of Nebraska in Omaha, and the University of Alberta in Calgary.
Extensive experience with autologous recipients has demonstrated that blood stem cells provide for durable engraftment with the advantage of far more rapid hematopoietic recovery than autologous marrow transplants, and the preliminary results presented at the symposium demonstrated that hematopoietic recovery was rapid and complete following transplantation of human leukocyte group A antigen- (HLA) matched allogeneic blood stem cells as well. In fact, several centers reported that recovery of platelets was far more rapid than with marrow transplants. For high-risk patients, this effect translated into a reduction in early morbidity and mortality.
Figure 2. Peripheral blood stem cell harvest by apheresis.
Many of the centers also reported no significant increase in acute GVHD despite the infusion of a large number of donor lymphocytes. Additional laboratory work suggested that the use of filgrastim in normal donors may have changed the type of lymphocytes collected so that the risk of GVHD was not proportional to the number of lymphocytes, as would be expected from animal studies of GVHD after peripheral blood infusions when filgrastim was not used. Additional meetings are planned to review long-term outcomes in order to evaluate the impact of blood stem cell transplantation on relapse and on chronic GVHD.
A number of investigators have also used blood stem cells from unrelated or mismatched related normal donors. Patients receiving allografts from these HLA-nonidentical donors would be expected to have an extraordinarily high incidence of acute GVHD even when marrow was used as the graft. It was reported at the symposium that engraftment was complete in recipients of blood stem cells from HLA-nonidentical donors, and toxicity was not considered excessive. Several centers are utilizing procedures to separate out only the hematopoietic progenitors from the apheresis product in order to reduce the number of lymphocytes infused and provide additional protection against acute GVHD. Preliminary experience demonstrated that the current selection procedures alone did not reliably provide for sufficient depletion of lymphocytes for complete protection against GVHD, and use of standard immunosuppressive drugs was required.
The overwhelming success of this initial experience has led to extensive interest in routine clinical application of allogeneic blood stem cell transplantation. However, issues regarding both patient and donor safety remain at the forefront. Several centers are currently engaged in assessments of new technologies in order to fine tune allogeneic blood stem cell collection and processing. Hopefully, the results of these investigations will provide clinicians with data on the optimal graft that will allow hematopoietic reconstitution and elimination of residual leukemia or lymphoma without the hazards of GVHD.
Donna Przepiorka, MD, PhD
Section of Bone Marrow Transplantation
M.D. Anderson Cancer Center
Houston, Texas
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