Spring 1994 Volume 1, Number 1

BONE MARROW TRANSPLANTATION

Peripheral Blood Progenitor Cell Transplantation

Peripheral blood progenitor cells (PBPC) are used with increasing frequency to reconstitute hematopoiesis following myeloablative therapy in cancer patients. The first trials of PBPC transplants were performed in the 1970s in patients with chronic myeloid leukemia. These patients underwent a small number of leukophereses during the chronic phase of the disease, and their leukocytes were cryopreserved for use at the time of disease progression. Upon disease acceleration or during blast crisis, patients received myeloablative therapy followed by PBPC reinfusion. Although a second chronic phase was achieved in most patients, it was generally of short duration, and no patient was cured. In the mid 1980s, trials of PBPC transplants began in patients with acute leukemia or lymphoma in whom autologous bone marrow harvest was not feasible because of hypocellularity or tumor involvement. Eight or more aphereses were required to obtain sufficient progenitor cells for transplant. Although occasional engraftment failures were reported, these trials established that PBPCs can support full hematologic recovery following myeloablative therapy.

Observations of increased numbers of circulating stem cells following dose-intensive cyclophosphamide therapy led investigators to explore methods to expand the pool of PBPCs. Numbers of circulating progenitor cells increase significantly after treatment with hematopoietic growth factors or at the time of marrow recovery following moderately intensive chemotherapy (eg, cyclophosphamide 4 gm²) with or without growth factors. Following mobilization, only one to three aphereses are needed to obtain sufficient cells for a transplant. The PBPCs are collected by standard apheresis techniques and cryopreserved in liquid nitrogen. Compared to bone marrow harvest, PBPC collection can be done in the outpatient setting, requires no anesthesia, and can be repeated as often as needed to obtain sufficient progenitor cells for multiple transplants.

Experience with PBPC transplants demonstrated that both neutrophil and platelet recovery was more rapid than recovery following bone marrow transplants. Faster hematologic recovery resulted in reduced transplant complications, decreased transfusion requirements, shorter hospitalizations, and less costly treatments. Reduced transplant toxicity has permitted further intensification of cytotoxic therapy in patients with solid tumors by administration of two or more courses of high-dose chemotherapy with PBPC support. PBPC transplant trials are currently underway in the treatment of hematologic malignancies, lymphomas, and a variety of solid tumors. In these studies, PBPCs are used either in conjunction with bone marrow cells or as an alternative to bone marrow transplantation. Longer follow-up is needed to determine whether these dose-intensive treatments will increase complete response rates and improve long-term disease-free survival.

Several important questions about PBPC transplants require further investigation:

• The risk of tumor cell contamination is presumed lower with PBPC than with bone marrow transplantation, but this has yet to be proved. Furthermore, PBPC purging has not been studied sufficiently.
• One report of high-dose chemoradiotherapy conducted in patients with lymphoma showed decreased relapse rates in patients receiving PBPC transplants compared to bone marrow transplants. It was suggested that the improved disease-free survival resulted from cytotoxic T cells that were present in the PBPC product. Further studies are needed to characterize immune reconstitution following PBPC transplant.
• The number of PBPCs required to achieve sustained engraftment is not established. Early trials employed mononuclear cells and CFU-GM as a measure of the efficiency of PBPC collection. Current investigations focus on assessing cells expressing the CD34 antigen, a marker of early progenitor cells. Measuring CD34+ cells has the double advantage of rapid turnaround time and strong correlation with the rate of engraftment.
• Very few studies have employed PBPC in allogeneic transplants. Although the use of mobilization techniques in healthy donors raises ethical concerns, PBPCs may be advantageous because large numbers of stem cells can be collected. This is particularly useful in the context of T-cell depleted transplants in which the risk of rejection is high.
• Ongoing trials are attempting to exploit the large number of stem cells obtained after mobilization to achieve tumor purging by positive selection of CD34+ cells. Also, PBPCs can be used for ex vivo stem cell expansion and genetic engineering.

In conclusion, mobilized PBPC can accelerate hematologic recovery after myeloablative therapy in cancer patients. Further studies are needed to determine whether dose-intensive treatments significantly improve treatment outcomes. Until this is established, high-dose therapy and PBPC transplant should be limited to carefully designed clinical trials.

Richard Ghalie, MD
Rush-Presbyterian-St. Luke's Medical Center
Chicago, Illinois

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