Combination of umbilical cord mesenchymal stem cells and standard immunosuppressive regimen for pediatric patients with severe aplastic anemia

Yang Lan, Fang Liu, Lixian Chang, Lipeng Liu, Yingchi Zhang, Meihui Yi, Yuli Cai, Jing Feng, Zhibo Han, Zhongchao Han, Xiaofan Zhu, Yang Lan, Fang Liu, Lixian Chang, Lipeng Liu, Yingchi Zhang, Meihui Yi, Yuli Cai, Jing Feng, Zhibo Han, Zhongchao Han, Xiaofan Zhu

Abstract

Background: Defects of bone marrow mesenchymal stem cells (BM-MSCs) in proliferation and differentiation are involved in the pathophysiology of aplastic anemia (AA). Infusion of umbilical cord mesenchymal stem cells (UC-MSCs) may improve the efficacy of immunosuppressive therapy (IST) in childhood severe aplastic anemia (SAA).

Methods: We conducted an investigator-initiated, open-label, and prospective phase IV trial to evaluate the safety and efficacy of combination of allogenic UC-MSCs and standard IST for pediatric patients with newly diagnosed SAA. In mesenchymal stem cells (MSC) group, UC-MSCs were injected intravenously at a dose of 1 × 106/kg per week starting on the 14th day after administration of rabbit antithymocyte globulin (ATG), for a total of 3 weeks. The clinical outcomes and adverse events of patients with UC-MSCs infusion were assessed when compared with a concurrent control group in which patients received standard IST alone.

Results: Nine patients with a median age of 4 years were enrolled as the group with MSC, while the data of another 9 childhood SAA were analysed as the controls. Four (44%) patients in MSC group developed anaphylactic reactions which were associated with rabbit ATG. When compared with the controls, neither the improvement of blood cell counts, nor the change of T-lymphocytes after IST reached statistical significance in MSC group (both p > 0.05) and there were one (11%) patient in MSC group and two (22%) patients in the controls achieved partial response (PR) at 90 days after IST. After a median follow-up of 48 months, there was no clone evolution occurring in both groups. The 4-year estimated overall survival (OS) rate in two groups were both 88.9% ± 10.5%, while the 4-year estimated failure-free survival (FFS) rate in MSC group was lower than that in the controls (38.1% ± 17.2% vs. 66.7% ± 15.7%, p = 0.153).

Conclusions: Concomitant use of IST and UC-MSCs in SAA children is safe but may not necessarily improve the early response rate and long-term outcomes. This clinical trial was registered at ClinicalTrials.gov, identifier: NCT02218437 (registered October 2013).

Keywords: Child; Immunosuppressive therapy; Mesenchymal stem cell; Severe aplastic anemia; Umbilical cord.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Peripheral blood cells were quantified at baseline, at 40 days and 90 days after rabbit ATG in two treatment groups. a-d show the changes of absolute neutrophil count, hemoglobin, platelet count and absolute reticulocyte count, respectively
Fig. 2
Fig. 2
The percentage of CD3 + CD4+ T-cell lymphocytes (a), CD3 + CD8+ T-cell lymphocytes (b), and CD4 + CD25 + CD127dim regulatory T cells (c) in the peripheral blood of patients performed by means of flow cytometry at baseline and after treatment
Fig. 3
Fig. 3
The estimated failure-free survival (FFS) curves of patients between two groups

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