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Meeting Reports |
(summarized by Margaret Stull and Rachata Lumkul)
The use of umbilical cord blood (UCB) for hematopoietic stem cell transplantation has recently received great attention due to the possibility of increased engraftment potential and decreased incidence of graft versus host disease (GVHD) for UCB, as compared to bone marrow (BM). Indeed, several studies have suggested that UCB may be an enriched source of hematopoietic stem cells. In 1992, the New York Blood Center initiated the Placental Blood Project, through which UCB units are collected from healthy newborns at Mt. Sinai Hospital. The phase I trial using the banked UCB for transplant grafts began five years ago as a collaboration between Dr. Kurtzberg's group at Duke University and Dr. John Wagner's group at The University of Minnesota. In this trial, researchers are attempting to determine the efficacy of banked partially mismatched UCB in hematopoietic stem cell transplants. Concerns in performing unrelated UCB transplants include the number of cells that can be harvested and the feasibility of using this procedure in adults, the limits of HLA mismatch, GVHD incidence and severity, and graft versus leukemia (GVL) effects.
The 167 consecutively transplanted patients included in Kurtzberg's report suffered from hematological malignancies, congenital and acquired bone marrow failure conditions, and genetic diseases. They ranged from 0.4 to 58 years of age, with the median age being 7.1 years. At the time this information was presented, data were updated through October 1998, and all patients had been observed following transplant for at least 100 days and up to 66 months. In these UCB transplants, UCB cell dose is typically 10-fold lower than that given with BM, averaging approximately 3 x 107 nucleated cells/kg, with 5 x 105 CD34+ cells/kg. Infants may receive a cell dose equal to that given with BM (3 x 108 nucleated cells/kg).
Of the 167 patients, 124 were treated at Duke and 43 at Minnesota; some differences exist between the two centers' approaches. All patients at Minnesota received total body irradiation (TBI), whereas only one-half of the Duke patients had TBI; patients at Minnesota had a lower dose of steroid regimen with cyclosporin than one-half of those at Duke. Researchers at Duke gave more mismatched grafts than those at Minnesota, so they have a greater number of patients with <5/6 HLA match, and only 8% of their patients received a 6/6 match. Similarities include the provision of standard supportive care to all patients and the administration of G-CSF, IVIG, GVHD prophylaxis. In both centers, the preparative regimen was busulfan and cytoxan for all patients with non-neoplastic diseases. Duke patients with malignancies received melphalan with TBI and/or busulfan while Minnesota patients received cyclophosphamide.
The matching strategy used by Dr. Kurtzberg's group has evolved during this study. Initially, matching was prioritized in the following order: best HLA matched unit, Class I serology, and DRß-1. Later, data from BM transplants showed the advantage of DRß-1 matching over Class I serology. Currently, cell dose is prioritized over DRß-1 and Class I serology matching. In other words, the researchers would select a larger cell number (dose) with 4/6 HLA match and DRß-1 match over a smaller total cell number with 6/6 HLA match.
Results show 93% of the patients engrafted eventually. The engraftment, measured as the achievement of an absolute neutrophil count (ANC) of 500, was found to be correlated with the number of CD34+ cells transplanted, rather than the degree of HLA matching. In spite of the finding of Kurtzberg's group that cell dose overrides the HLA disparity, this effect may be due to the fact that there are few 6/6 matches in this study. Nonetheless, their study shows that a dose of CD34+ cells <2-3 x 105 CD34+ cells/kg results in diminished and delayed engraftment of platelets and neutrophils. Multivariate analysis shows that any dose >3 x 105 CD34+ cells/kg results in fairly consistent engraftment, which has led the Kurtzberg group to consider a dose of 2-3 x 105 CD34+ cells/kg the lower threshold for a positively engrafting transplant. Patients who received G-CSF had a nine-day advantage in achieving an ANC of 500 over those who did not receive G-CSF; G-CSF had no affect on platelet engraftment or overall survival.
Forty percent of patients experienced levels II-IV GVHD, while 14% reached levels III-IV. These proportions are less than what would be expected from a comparable (historical) transplant with BM, and even those with levels III-IV GVHD following UCB transplant had a higher percent survival than patients with levels III-IV GVHD following historical BM transplant. Additionally, there was no difference in acute GVHD between patients with 1, 2, or 3/6 HLA mismatching. The occurrence of chronic GVHD was low (11%) compared to the historical incidence after BM transplant (70%) and was limited, rather than extensive, in severity.
GVHD prophylaxis continued for 9-12 months after transplant. Patients were given steroids for the first two to three months and cyclosporin for the first 9-12 months, and then they came off prophylaxis completely. Phytohemagglutinin and lymphocyte counts were normal and remain normal after this period, and blood levels of CD45RA T lymphocytes remained elevated for up to three to four years. Some transplants failed due to non-relapse mortality, which occurred in the first three months; half of these cases were due to viral, bacterial, and sepsis infections. Adults tended to suffer more infections than children, and there was a lag of approximately one year to reaching normal CD4+ counts in adults as compared to children.
Kurtzberg's group has also performed expansion studies using the Aastrom system, which is designed for BM cell expansion. Twenty-eight patients were given a portion of UCB cells on day 0 by a conventional transplant and were later boosted on day 12 with cells that had undergone expansion in Aastrom media containing FLT-3, PIXY, low dose erythropoietin (EPO), fetal calf and horse serum. Following expansion, there was a 4- to 10-fold increase in myeloid cells and a loss of lymphoid cells. In the patients, there was no advantage to myeloid, erythroid, or platelet engraftment, although a positive relationship was found between colony-forming unit-granulocyte/macrophage dose and platelet engraftment.
The Food and Drug Administration (FDA) has approved a randomized trial in which patients will receive either fresh or expanded/cultured UCB, but there will not be enough units banked to begin this experiment for one to two years. In the meantime, Kurtzberg's group continues to experiment with culture conditions. The standard Aastrom expansion media contains interleukin 3/GM-CSF, EPO, FLT-3, and stem cell factor (SCF). Current government regulations do not permit the use of SCF in clinical trials, so the Kurtzberg lab has instead made placental adherent cells from placental tissue that was frozen simultaneously with UCB. Without SCF but with placental stroma or BM stroma, Kurtzberg has found an increase in expansion when compared to Aastrom conditions. With the addition of SCF to the media, expansion increases even further. If SCF is not soon approved by the FDA for clinical use, Kurtzberg plans to obtain BM stromal cells from the patient before UCB transplant, expand UCB cells on the BM cell stroma, and harvest them together for the transplant.
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