MSC Infusions Promising for GVHD After Haploidentical Transplant

Still, many problems remain to be solved to optimize the procedure.

Infusions of mesenchymal stromal cells (MSCs) helped prevent chronic graft-versus-host disease (GVHD) in patients with blood malignancies who underwent HLA-haploidentical hematopoietic stem-cell transplantation (HSCT), according to the results of a randomized, controlled trial.

The 2-year cumulative incidence of chronic GVHD in the treatment group was 27.4% (95% CI 16.2%-38.6%) compared with 49% in the control group (95% CI 36.5%-61.5%), Xi Zhang, MD, PhD, of Xinqiao Hospital in Chongqing China, and colleagues reported in the Journal of Clinical Oncology.

 “We demonstrate for the first time, to our knowledge, that reduplicative infusion of MSCs after HLA-haplo HSCT can reduce the incidence of chronic GVHD, accompanied by changes in the number of Treg cells, memory B lymphocytes, and natural killer cells, as well as the Th1:Th2 cell ratio. Future studies to adjust the MSC infusion program and understand the underlying mechanism will enable us to elucidate the in vivo effects of MSCs and help facilitate their broad application.”

In an accompanying editorial, Hillard Lazarus, MD, of Case Western Reserve University in Cleveland, Ohio, and Steven Pavletic, MD, of the Experimental Transplantation and Immunology Branch, Graft-versus-Host and Autoimmunity Section, of the National Institutes of Health in Bethesda, Md., said that on the basis of the study, future investigations of chronic GVHD prophylaxis using MSCs should be explored.

“The permutations and combinations for using different cell sources for deriving the MSCs, 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,” they said. “Nonetheless, the results of the [Zhang et al] trial encourage us to further explore this approach.”

The phase II, randomized, double-blind, controlled trial included 124 patients with hematologic malignancies who underwent HLA-haploidentical hematopoietic stem-cell transplantation at five transplantation centers. Eligible patients met the following criteria: acute GVHD did not occur or was controlled for more than 100 days after transplantation; lack of chronic GVHD at 100 days after transplantation; and the absence of uncontrolled infections and severe liver, renal, lung, and heart diseases.

Patients were randomized 1:1 to receive either monthly infusions of umbilical cord-derived MSCs or saline. The infusions began 4 months after the transplant and continued for up to 4 months. Patients were enrolled from 2009 to 2013 and were followed until 2015.

 The primary endpoint was the development of chronic GVHD. Secondary endpoints included overall survival, disease-free survival, relapse, and changes in immune system cells.

Chronic GVD developed in 17 patients in the treatment group versus 30 in the control group. Seven patients in the control group developed severe lung GVHD, versus none in the treatment group.

The number of natural killer cells tended to be lower in the treatment group, but there were no significant changes in the proportions of T or B lymphocytes in the treatment versus the control group. However, an analysis of T lymphocyte subsets found that the numbers of CD4+, CD25+, and CD127- regulatory T-cells were significantly higher in the treatment group.

The investigators also found that the numbers of CD27+ B lymphocytes were significantly increased in the treatment group after the MSC infusions compared with pretreatment values.

Zhang and colleagues also reported that the ratio of type 1 to type 2 T-helper cells increased almost two-fold after four MSC infusions, from 1.37 to 2.86. “This result indicates that the Th0 cells developed a differentiation imbalance and tended to become Th2 cells before the treatment with MSCs. After four MSC infusions, the proportion of Th1 cells gradually increased, and the proportion of Th2 cells gradually decreased,” the investigators said.

 “Specifically, these results indicate that infusion with MSCs plays a role in downregulating excessive Th0-to-Th2 differentiation and increasing the proportion of Th1 cells, thereby reversing the Th1:Th2 cell imbalance in patients after HSCT. However, the increasing trend in the Th1:Th2 cell ratio disappeared after day 28.”

Two-year overall survival rates were not significantly different in the treatment versus the control group (66% versus 61%), and neither were the 2-year disease-free survival rates (65% versus 60%).

The rates of relapse were not significantly different between the treatment and control groups (31% versus 32%).

The infusions were well tolerated, with no acute infusional toxicity and no adverse events associated with them, Zhang and colleagues said.

Limitations of the study included that the investigators did not provide specific details of the MSC preparative steps, did not indicate if all centers received cells from the same batch of MSCs, and did not provide the protocol for cell infusion, Lazarus and Pavletic said in their editorial.

“In addition, the authors do not discuss blinding of subjects or observers, which, obviously, is critical in any GVHD study.”

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