Improvement in Poor Graft Function After Allogeneic Hematopoietic Stem Cell Transplantation Upon Administration of Mesenchymal Stem Cells From Third-Party Donors: A Pilot Prospective Study
Authors: Liu Qifa , Liu Xiaodan , Wu Meiqing , Peng Yanwen , Chen Xiaoyong , Sun Jing , Huang Fen , Fan Zhiping , Zhou Hongsheng , Wu Xiuli , Yu Guopan , Zhang Xian , Li Yonghua , Xiao Yang , Song Chaoyang , Xiang Peng 
Published: October 2019

Abstract
Abstract 1904

Background
Poor graft function (PGF) is a refractory complication that occurs in 5–27% patients, and is associated with considerable morbidity and mortality related to infections or hemorrhagic complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mesenchymal stem cells (MSCs) possess the capacity to differentiate into several types of mesenchymal tissues, to suppress immunological responses, and to support hematopoiesis. Clinical applications of MSCs are evolving rapidly with goals of improving hematopoietic engraftment, preventing and treating graft-versus-host disease (GVHD) after allo-HSCT and so on. In the present study, we prospectively evaluated the efficacy and safety of MSCs expanded from the bone marrow of a third-party donor to patients with PGF after allo-HSCT.

Methods
Twenty patients, including primary PGF in 7 and secondary in 13, were enrolled in this prospective multicenter trial. Bone marrow-derived MSCs were obtained from HLA-unrelated third-party donors. MSCs were cultured and expanded with human MSCs growth medium (low-glucose Dulbecco's modified Eagle's medium [L-DMEM], Hyclone, Logan and UT) with 10% (v/v) fetal bovine serum. MSCs were harvested after 4–5 passages for clinical administration. MSCs were given at 4 weeks intervals at the dose of 1×106 cells/kg. If ANC counts did not achieve >1.5×109/L and PLT counts not >50×109/L within 28 d after MSCs treatment, a second course of MSCs treatment was given. Flow cytometry was used to examine the lymphocyte subsets in peripheral blood pre- and post-MSCs treatment.

Results
Seventeen patients were responsive and 3 (primary PGF in 2 and secondary in 1) were not to 1–3 cycles of MSCs treatment. Within the first 100 d after MSCs treatment, 13 patients developed 20 episodes of infections. Moreover, 5 patients experienced cytomegalovirus-DNA viremia and 7 experienced Epstein-Barr virus (EBV)-DNA viremia within the first 100 d after MSCs treatment. Within a median follow-up of 125 d (range 11–579 d) after MSCs treatment, 6 patients (primary PGF in 3 and secondary in 3) experienced CMV-DNA viremia, and 8 (primary PGF in 2 and secondary in 6) developed EBV-DNA viremia, including 3 with EBV-associated post-transplant lymphoproliferative disorders (PTLD). One patient developed gradeII acute GVHD and 2 developed local chronic GVHD after MSCs treatment; 2 developed acute GVHD and chronic GVHD, respectively, after donor lymphocyte infusion because of PTLD. The proportions of CD3+ T cells and CD3+CD4+ T cells at 56 d after MSCs treatment were higher than those prior to MSCs treatment (88.05 ± 1.26% vs 79.05 ± 3.23%, P=0.015 and 24.09 ± 1.95% vs 17.40 ± 1.57%, P=0.012, respectively). The proportion of CD3+CD8+ T cells at 56 d after MSCs treatment was lower than that prior to MSCs treatment (51.91 ± 2.86% vs 61.39 ± 3.43%, P=0.043), and the ratio of CD3+CD4+ to CD3+CD8+ T cells was higher after MSCs treatment (0.31 ± 0.04 vs 0.51 ± 0.06, P=0.01). The proportions of CD4+CD25+ FoxP3 regulatory T cells, CD19+ B cells, and NK cells did not change significantly after MSCs treatment. With a median follow-up time of 508 d (range, 166–904 d) post-transplantation, 9 patients were alive and 11 died. No short-term toxic side effects were observed after MSCs treatment. Two patients experienced leukemic relapse. With the exception of 3 patients with PTLD, no secondary tumors occurred.

Conclusions
MSCs derived from the bone marrow of a third-party donor are effective to both primary and secondary PGF after allo-HSCT. However, whether such treatment might increase the risks of EBV infection and reactivation or the development of EBV-associated PTLD should be studied further.

Disclosures:
No relevant conflicts of interest to declare.