Clinical Newswire, Jan 20 - A new method to greatly expand the number of hematopoietic stem/progentior cells (HSPCs) ex vivo in umbilical cord blood that was then infused into leukemia patients undergoing hematopoietic stem cell transplantation, has resulted in rapid and successful engraftment for the first time, according to a study published in the January 17 edition of Nature Medicine by Colleen Delaney, MD, and colleagues.
Umbilical cord blood is widely used as a source of stem cells in patients undergoing hematopoietic stem cell transplantation, as the donated cells don’t require perfect matching with the patient. However, the number of stem cells in cord blood units is relatively small, which causes the time to donor engraftment to be delayed, averaging more than 3 weeks to achieve adequate numbers of myeloid cells. Delayed myeloid engraftment leaves the patients susceptible to infections and is therefore associated with greater morbidity and mortality among transplant recipients.
Researchers at Fred Hutchinson Cancer Research Center investigated the role of the Notch signaling pathway in regulating ex vivo expansion of HSPCs and developed a Notch-mediated expansion system for human cord blood that resulted in a marked increase in the absolute number of HSPCs. The expanded cord blood was then tested in a phase I clinical trial in patients undergoing stem cell transplantation.
The Notch signaling pathway has a key regulatory role in hematopoiesis. Delaney and colleagues engineered a Notch ligand protein that stimulated a more than 100-fold increase in hematopoietic CD34+ cells in an ex vivo culture of cord blood stem/progenitor cells.
“The real ground-breaking aspect of this research is that we have shown that you can manipulate stem/progenitor cells in the lab with the goal of increasing their numbers. When given to a person, these cells can rapidly give rise to white blood cells and other components of the blood system,” said Dr Delaney.
The researchers also describe the outcomes of 10 high-risk acute leukemia patients in an ongoing phase I clinical trial involving transplantation of two units of cord blood. The patients (age range 3 to 43 years) were in morphologic remission at the time of transplantation and each received one unit of unmanipulated cord blood and one in which the cells had undergone Notch-mediated ex vivo expansion. Evaluation of the safety of infusing the expanded cord blood cells is the primary objective of the study, while secondary objectives include the evaluation of kinetics and durability of hematopoietic reconstitution and the relative contribution of the expanded and unmanipulated units to engraftment.
The results to date show that average engraftment time was 14 days, while it took an average of 4 weeks for the transplanted cells to engraft when non-expanded cord blood units were used. Seven of the 10 patients are still alive with sustained, complete donor engraftment and no evidence of disease. Tests showed that the recovery of leukocytes early post transplantation came predominantly from the expanded cord blood unit.
Researchers conclude that these results are the first to demonstrate rapid hematopoietic engraftment derived from ex vivo-expanded hematopoietic cells. However, larger phase II and III studies will be necessary to verify whether expanded cord blood transplants will improve patient outcomes, such as overall survival, incidence of infections and time spent in the hospital.
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