Cord Blood Cell Fucosylation Bolsters Transplant Capabilities

Although cord blood transplantation (CBT) is a viable alternative for patients lacking an HLA-matched donor, using cord blood as a source of stem cells for allogeneic transplantation has several drawbacks including the potential for delayed engraftment and poor immune reconstitution. Strategies are being investigated to overcome these limitations, and, in a first-in-human clinical trial published in Blood, researchers at the University of Texas MD Anderson Cancer Center in Houston may have found a quick and safe method to mitigate these issues.

Cord blood cells have a reduced capacity for homing to bone marrow, which appears to be related to low levels of fucosylation (process of adding fucose sugar units to a molecule) of cell surface molecules that are responsible for binding to P- and E-selectins in bone marrow, the researchers, led by Uday Popat, MD, explained. Therefore, the authors hypothesized that conducting ex vivo fucosylation of cord blood cells would lead to faster neutrophil and platelet engraftments.

To test this hypothesis, Dr. Popat and colleagues analyzed time to neutrophil and platelet engraftment in 22 patients with high-risk hematologic malignancies (and no HLA-matched donor) who had received myeloablative therapy followed by transplantation with two cord blood units. Red blood cell–depleted cord blood units were thawed, washed, and infused on the first day of treatment. A second unit was treated ex vivo for 30 minutes with the enzyme fucosyltransferase-VI (FTVI) and guanosine diphosphate fucose to enhance the interaction of CD34+ stem and early progenitor cells with microvessels. Results from these 22 patients were compared with results from 31 historical controls who had undergone double unmanipulated CBT at the same center.

FTVI treatment led to maximal fucosylation of CD34+ cells: Expression was only 36.5 percent (95% CI 31.5-41.5%) before FTVI treatment, but it increased to 98.9 percent (95% CI 98.2-99.6%) post-treatment. “FTVI treatment also led to substantial fucosylation of CD61+ megakaryocytes, CD14+ monocytes, and CD56+CD3- NK cells,” the authors wrote, “while CD3+ T cells and CD19+ B cells were not fucosylated at all following this treatment.”

All cord blood cell infusions were well tolerated, with no serious infusion-related toxicity during a median follow-up of 8 months, the researchers reported. Incidence of graft-versus-host disease (GVHD) at 100 days were not significantly different between groups:

  • Acute grade II-IV: 40.91 percent (95% CI 20.18-60.71%) in the study group versus 38.71 percent (95% CI 21.67-55.49%) in controls
  • Acute grade III-IV: 9.1 percent (95% CI 1.5-25.6%) in the study group versus 12.9 percent (95% CI 3.97-27.26%) in controls
  • Chronic GVHD overall: 5 percent (95% CI 0.30-19.55%) in the study group versus 22.51 percent (95% CI 8.48-40.61%) in controls

One patient died from bacterial sepsis on day 23 without engrafting neutrophils or platelets, the authors reported. Another patient developed secondary graft failure on the day after initial engraftment (day 14 post-transplantation), and was rescued with previously stored autologous peripheral blood progenitor cells.

Among the 20 remaining patients, the median time to neutrophil engraftment was 17 days, compared with 26 days for controls (p=0.0023). Platelet engraftment was also improved with a median 35 days for the fucosylated group, compared with 45 days for controls (p=0.052). At the end of follow-up (range, 3-20 months), 12 of these 22 high-risk patients had died due to infection, chemotherapy-related organ toxicities, relapse, or GVHD.

Based on their results, the researchers commented, “Ex vivo fucosylation of CB cells is a rapid, logistically straightforward and safe procedure that appears to improve times to neutrophil and platelet engraftment in high-risk patients with hematologic malignancies who have undergone double CBT.”

However, as co-author Elizabeth Shpall, MD, pointed out to ASH Clinical News, this technique is currently not approved by the U.S. Food and Drug Administration. A randomized trial to confirm the safety and feasibility of this technique is in the works.

Future research will include looking at specific patient characteristics, such as high-risk disease, to determine if some patients are better suited for fucosylated CB treatment than others, Dr. Shpall added.

“As of now, any cord blood transplant patient might benefit from faster engraftment; [however], this needs to be confirmed in larger prospective randomized trials,” she emphasized.


Reference

Popat U, Mehta R, Rezvani K, et al. Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation. Blood. 2015 March 16. [Epub ahead of print.]

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