Expanded Umbilical Cord Blood Units Speed Engraftment During transplantation
By Roxanne Nelson
Medscape Medical News
January 25, 2010 — Although these results are early and continue to evolve, researchers have found a way to optimize umbilical cord blood for use in stem cell transplantation. According to data published online January?17 in Nature Medicine, the use of ex?vivo expanded stem cells from umbilical cord blood led to rapid engraftment in patients with high-risk acute leukemias who were in morphologic remission at the time of transplantation.
Researchers from the Fred Hutchinson Cancer Research Center in Seattle, Washington, developed a clinically relevant Notch-mediated ex?vivo expansion system for human CD34+ cord blood progenitors. The resulting cord blood progenitors expanded ex?vivo in the presence of Notch ligands, and when they were infused after a myeloablative preparative regimen for stem cell transplantation, the time to neutrophil recovery was substantially reduced.
After an average follow-up time of 1 year, 7 of the 10 patients who underwent transplantation were alive, with no evidence of disease and with sustained complete donor engraftment.
This is the first demonstration of rapid hematopoietic engraftment derived from ex?vivo expanded hematopoietic progenitors, the researchers note. Preliminary results from the study were first presented at the 2008 annual meeting of the American Society of Hematology, and were reported at that time by Medscape Oncology.
Research Early But Encouraging
Although this is still early research with a very small cohort, the results are encouraging, explained lead author Colleen Delaney, MD, MSc, director of the Cord Blood Transplant Program at Fred Hutchinson.
However, even though rapid neutrophil engraftment has been shown in the patients treated to date, more data are needed. "We are planning a phase?2/3 trial that will involve a much larger group of patients in a randomized fashion," she told Medscape Oncology. "We have definitively shown that ex?vivo expanded hematopoietic stem/progenitor cells can rapidly engraft."
The next step, she added, is to demonstrate these same findings in a larger trial. They are also planning on using this technique in more patients at their institution.
Cord blood is an effective and widely used source of stem cells for patients needing hematopoietic stem cell transplantation, the authors note, but the time to donor engraftment is relatively slow. On average, it takes more than 3 weeks to achieve an adequate number of myeloid cells, leaving the patient susceptible to infection.
Investigations aimed at improving the rate of engraftment using ex?vivo cytokine-mediated expansion methods to generate increased numbers of cells have been less than successful, and have not demonstrated significant clinical effects, they write.
Dr. Delaney and her team examined the role of the Notch signaling pathway in the regulation of ex?vivo expansion of hematopoietic stem/progenitor cells, with the goal of developing a method of increasing cell numbers that is capable of providing rapid myeloid engraftment.
In 3 previous experimental trials, the researchers observed measurable human cell engraftment (defined as ?0.5% human CD45+ cells) 10 days after transplantation in the marrow of mice who had received cultured cells. This was compared with no engraftment in mice who received noncultured cord blood cells. This engraftment consisted of more than 95% myeloid cells, and indicated to the researchers the ability of Notch-expanded cord blood progenitors to substantially accelerate hematopoietic repopulation in an experimental setting.
Faster Engraftment Observed
In the current phase?1 trial, each patient received 2 units of cord blood after a myeloablative preparative regimen. One unit was unmanipulated cord blood cells, and the second contained cord blood progenitors that had undergone Notch-mediated ex?vivo expansion.
The cohort consisted of 10 patients with high-risk leukemias who had a median age of 27.5 years (range, 3 to 43 years). Among this group, the median time to achieve an absolute neutrophil count of more than 100 cells/μL was 9 days, compared with 19 days in patients undergoing a double unmanipulated cord blood transplant (P?= .006).
Although 1 patient experienced primary graft rejection, the authors did not observe any toxic effects related to the infusion or other safety concerns.
They did observe substantially enhanced rates of myeloid engraftment, and the median time to neutrophil recovery was decreased by more than 1 week, compared with neutrophil recovery after infusion of 2 unmanipulated units, as reported in published literature. The expanded cells contributed almost exclusively to the initial myeloid engraftment that was observed at 1 week. This demonstrated "an enhanced capacity of the expanded cell graft to provide rapid myeloid recovery," they write.
Of the evaluable 8 patients, 7 of whom were engrafted before day?21, this was independent of whether the expanded cell graft persisted in?vivo. Conversely, the average time to engraftment is approximately 4 weeks in a double unmanipulated cord blood transplant. These results, note the authors, are "highly suggestive of a facilitating effect of the cultured cells in promoting engraftment from the unmanipulated cord blood unit."
All evaluable patients experienced acute grade?2 graft-vs-host disease (GVHD); acute grade?3 GVHD was observed in 1 patient. All responded to treatment and, at this time, 3 patients have been diagnosed with chronic limited GVHD.
Next Step Forward?
Whether or not this technique will be the next leap forward in advancing stem cell transplantation largely depends on longer-term patient outcomes in larger populations. However, Dr. Delaney is optimistic that their technique will eventually become more mainstream and widely used; it does appear to cut down on the engraftment time. "That is the hope," she said, "that the use of this methodology will provide clinical benefit and will be more widely available."
The study was supported by the National Institutes of Health. The researchers have disclosed no relevant financial relationships.
