INTRODUCTION

Tremendous interest has been generated in the use of peripheral blood stem cells (PBSC) as a means of restoring hematopoiesis after intensive cyto-reductive therapy.  It has been conclusively shown that these cells can serve e as the sole source of progenitors and thus are capable of “rescuing” patients after “lethal” irradiation or chemotherapy.  PBSC has been used for marrow reconstitution in the treatment of both hematological and non-hematological malignancies including acute leukemia, CML, non-Hodgkin’s lymphoma, breast cancer, ovarian cancer, and childhood neuroblastoma.  One of the most striking differences between PBSC and conventional marrow transplantation is in the rate of hematological recovery: PBSC transplants have briefer periods of aplasia.  This results in fewer complications, shorter periods of hospitalization, and ultimately, in lower costs associated with transplant.

For many years, it has been known that stem cells, the progenitor cells for both the myeloid and the lymphoid series, are present in small numbers in the blood.  In the mid-1980’s, clinical studies showed that mononuclear cells obtained by leukapheresis, contained sufficient numbers of these cells to restore hematopoiesis.  However, a large number of collections were required to obtain a sufficient number for transplant.  More recently, it has been found that the numbers of these stem cells can be markedly augmented by either collecting cells shortly after a course of chemotherapy or by administering myeloid growth factors.  This has greatly reduced the number of apheresis procedures needed to obtain the required number of cells.

ADVANTAGES OF PBSC

PBSC transplantation offers practical and theoretical advantages over conventional autologous bone marrow transplants.  These include: 1) the ability to harvest stem cells in an outpatient setting, thereby avoiding hospitalization and the risks of general anesthesia; 2) a reduced potential for malignant cell contamination of blood derived vs. marrow stem cells, especially in patients with overt bone marrow involvement; 3) the capabilities to obtain sufficient numbers of stem cells in patients with prior marrow damage, such as that due to irradiation, chemotherapy, or fibrosis; and 4) more rapid hemato-logical recovery than with conventional marrow transplants.

stem cell mobilization

The most useful and best-studied methods for mobilizing PBSC have involved two approaches, which may be used alone or in combination.  One approach involves using post-chemotherapy rebound.  The early post-chemotherapy recovery period is associated with a 3-20 fold increase in the number of circulating hematopoietic progenitors.  Since this effect persists for only a few days, the timing of leukapheresis to collect these cells is critical.  Another effective approach employs myeloid growth factors, such as G-CSF or GM-CSF, to mobilize PBSC.  For example, administration of granulocyte-macrophage colony stimulating factor (GM-CSF) results in a 10-20 fold increase in granulocyte-macrophage colony forming units, a measure of hematopoietic stem cells.  Granulocyte colony stimulating factor (G-CSF) has also been shown to increase by 10-fold the number of CD34+ cells in the circulation.  Measurement of CD34+ cells by flow cytometry is a sensitive and rapid means of quantitating stem cells and results can be correlated with colony assays, the other measure of stem cells.  An important advantage of using growth factors is that stem cell levels appear to be maintained for the duration of their administration.

Over the past several years, Central Blood Bank, in collaboration with local transplant centers, has collected PBSC primarily using two protocols: eligible patients (including advanced Hodgkin’s or non-Hodgkin’s lymphoma, breast or ovarian cancer) in a stable state receive the hematopoietic growth factor G-CSF starting five days prior to the initial apheresis procedure, or G-CSF follows 24-48 hours after cytoreductive chemotherapy, with apheresis commencing when the patient’s leukocytes begin to recover.  Daily collections (usually 3-5) with an automated cell separator are performed until a sufficient number of mononuclear cells are obtained.  The collected cells are cryopreserved, then reinfused after completion of myeloablative chemotherapy. 

HEMATOLOGIC RECONSTITUTION

Our experience has shown engraftment after myeloablative therapy using G-CSF primed PBSC to be remarkably rapid.  In a group of 25 patients, the median time to ³ 500 neutrophils/ml was 10 days and for ³20,000 platelets/ml, in 12 days.  In one study performed in conjunction with the Adult Bone Marrow Transplant Program of the Pittsburgh Cancer Institute, it was found that neutrophil recovery was 4.5 days faster than a comparable group of patients reconstituted with autologous marrow stem cells.  Most striking was the recovery of platelets, which occurred at a median of 7.5 days earlier using PBSC.  As might be expected, reconstitution using PBSC was associated with marked decrease in the number of red cell and platelet transfusions required during the period of aplasia.  Most patients receiving PBSC show sufficient hematopoietic recovery to leave the hospital within 14 to 17 days after transplant.

PBSC grafts have been reported to maintain adequate function for more than five years post-transplant.  There is little reason to believe they will not be as durable as grafts using marrow.  The rapid development of new recombinant growth factors that act at differing points in hematopoietic differentiation (e.g., stem cell factor), promises to further enhance our ability to provide rapid and durable hematologic engraftment after intensive conditioning therapy.

Copies of the Transfusion Medicine Update can be obtained by contacting Deborah Small at (412) 209-7320 or
by e-mail:  dsmall@itxm.org.