Mesenchymal stromal cell infusions reduce chronic GVHD risk after haploidentical HSCT

Repeated infusions of mesenchymal stromal cells reduced the incidence of chronic graft-versus-host disease in patients who underwent haploidentical hematopoietic stem cell transplantation, according to results of a double blind randomized controlled phase 2 study.

The infusions further created changes in the numbers and subtypes of T cells, B cells and natural killer cells, which appeared associated with immune tolerance, results showed.

Chronic graft-versus-host disease (GVHD) occurs in 28% to 60% of patients who survive more than 100 days after allogeneic HSCT, and it is the leading cause of long-term morbidity in this patient population.

Patients undergoing haploidentical HSCT have a higher risk for and incidence of chronic GVHD than those with matched donors.

Xi Chang, MD, PhD, hematologist at Third Military Medical University in Chongqing, China, and colleagues sought to determine whether umbilical cord–derived mesenchymal stromal cells — which have been previously shown to possess immunomodulatory functions — could be used prophylactically to reduce the incidence of chronic GVHD in patients undergoing haploidentical HSCT.

The analysis included data from 124 patients with acute myeloid leukemia, acute lymphoblastic leukemia or myelodysplastic syndrome who remained free of chronic GVHD 100 days after transplantation. If they experienced acute GVHD, it was controlled by more than 100 days.

The researchers randomly assigned 62 patients each to infusions of mesenchymal stromal cells (3 x 10⁷ cells/100 mL per month) or normal saline (100 mL per month), beginning more than 4 months after transplantation.

Prophylaxis continued for four cycles, or until chronic GVHD occurred or a patient’s disease relapsed.

The 2-year cumulative incidence of chronic GVHD was significantly lower among patients assigned mesenchymal stromal cell infusions (27.4% vs. 49%; P = .021). Patients in the active agent arm had a median of 3.7 infusions (range, 2-4).

More patients in the control group experienced mild or moderate chronic GVHD (35.5% vs. 22.6%) and severe GVHD (12.9% vs. 4.8%).

Severe lung GVHD developed in seven patients in the control group and no patients in the mesenchymal stromal cell infusions group (P = .047).

The researchers did not record significant changes to the proportion of T cells or B cells in either group; however, natural killer cells decreased at different points following mesenchymal stromal cell infusions.

Subset analyses showed a higher proportion of CD4–positive/CD25–positive/CD127–negative regulatory T cells and CD27–positive memory B-lymphocyte numbers among patients assigned mesenchymal stromal cell infusions (P < .05 for both).

The researchers also found mesenchymal stromal cell infusions increased the ratio of type 1 T helper to type 2 T helper cells from 1.37 to 2.68 (P < .05).

Both treatment groups had similar incidences of relapse (30.6% vs. 32.3%) and treatment-emergent adverse events (72.6% vs. 64.5%).

Forty-one patients in the active arm and 38 on the control arm remained alive at the median follow-up of 51 months (range, 24-70).

“Future studies to adjust the mesenchymal stromal cell infusion program and understand the underlying mechanism will enable us to elucidate the in vivo effects of mesenchymal stromal cells and help facilitate their broad application,” Zhang and colleagues wrote.

Despite promising initial results from this study, additional research is needed, Hillard Lazarus, MD, director of novel cell therapy at University Hospitals Case Medical Center and professor of medicine at Case Western Reserve University School of Medicine, and Steven Z. Pavletic, MD, MS, senior clinician and head of the GVHD and autoimmunity section at the NIH’s Experimental Transplantation and Immunology Branch, wrote in a related editorial.

“Approximately 90% of [the study’s] population was younger than age 40, and it will be interesting to observe if this strategy is effective in older adults,” Lazarus and Pavletic wrote. “The permutations and combinations for using different cell sources for deriving the mesenchymal stromal cells, and in the context of different neoplastic disease, type and stage, conditioning regimen intensity, GVHD prophylaxis, graft and donor source, among other variables, are daunting. Nonetheless, the results of this trial encourage us to further explore this approach.” – by Cameron Kelsall

Disclosure: The researchers, Lazarus and Pavletic report no relevant financial disclosures.