The efficacy and the safety of the administration of multipotent mesenchymal stromal cells (MMSCs) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic hematopoietic cell transplantation (HSCT) were studied. This prospective clinical trial was based on the random patient allocation to the following two groups receiving (1) standard GVHD prophylaxis and (2) standard GVHD prophylaxis combined with MMSCs infusion. Bone marrow MMSCs from hematopoietic stem cell donors were cultured and administered to the recipients at doses of 0.9–1.3 × 106/kg when the blood counts indicated recovery. aGVHD of stage II–IV developed in 38.9% and 5.3% of patients in group 1 and group 2, respectively, (P = 0.002). There were no differences in the graft rejection rates, chronic GVHD development, or infectious complications. Overall mortality was 16.7% for patients in group 1 and 5.3% for patients in group 2. The efficacy and the safety of MMSC administration for aGVHD prophylaxis were demonstrated in this study.

Allogeneic bone marrow transplantation (allo-BMT) is currently the only way to cure many hematoproliferative disorders. However, allo-BMT use is limited by severe complications, the foremost being graft-versus-host disease (GVHD). Due to the lack of efficiency of the existing methods of GVHD prophylaxis, new methods are being actively explored, including the use of donors' multipotent mesenchymal stromal cells (MMSC). In this work, we analyzed the results of acute GVHD (aGVHD) prophylaxis by means of MMSC injections after allo-BMT in patients with hematological malignancies. The study included 77 patients. They were randomized into two groups - those receiving standard prophylaxis of aGVHD and those who were additionally infused with MMSC derived from the bone marrow of hematopoietic stem cell donors. We found that the infusion of MMSC halves the incidence of aGVHD and increases the overall survival of patients. Four of 39 MMSC samples were ineffective for preventing aGVHD. Analysis of individual donor characteristics (gender, age, body mass index) and the MMSC properties of these donors (growth parameters, level of expression of 30 genes involved in proliferation, differentiation, and immunomodulation) revealed no significant difference between the MMSC that were effective or ineffective for preventing aGVHD. We used multiple logistic regression to establish a combination of features that characterize the most suitable MMSC samples for the prevention of aGVHD. A model predicting MMSC sample success for aGVHD prophylaxis was constructed. Significant model parameters were increased relative expression of the FGFR1 gene in combination with reduced expression levels of the PPARG and IGF1 genes. Depending on the chosen margin for probability of successful application of MMSC, this model correctly predicts the outcome of the use of MMSC in 82-94% of cases. The proposed model of prospective evaluation of the effectiveness of MMSC samples will enable prevention of the development of aGVHD in the maximal number of patients.

Background: Recent evidence suggests that MSCs might improve survival during sepsis in animal models. However, no study has investigated the effects of MSC therapy on the survival of pts with sepsis and SS, especially severe-neutropenic pts. Aim: The aim of this study was to investigate the efficacy of the administration of MSCs for the treatment of SS in neutropenic pts. Patients and Methods: This prospective, single-center, randomized Russian clinical trial of MSCs in severe neutropenic pts with SS (RUMCESS) (NCT 01849237) was approved by the local ethics committee and was begun in December 2012. Neutropenic pts (WBC < 0.5x109/l) with SS were enrolled on to the study. The pts were randomly assigned (1:1) to receive either conventional therapy (CT) of SS (CT group), or CT plus donor MSCs at a dose of 106/kg intravenously within the first 10 hours after SS onset (CT+MSCs group). Written informed consent was obtained for all pts. All pts were admitted and treated in the ICU of the National Research Center for Hematology (Moscow). The Acute Physiology and Chronic Health Evaluation (APACHE) II score and Sepsis-related Organ Failure Assessment (SOFA) score were employed to determine the severity of illness. Pts were followed up for 28 days after enrolment in the study, and 28-day all-cause mortality was assessed. Pts characteristics and complication rates were compared using Fisher's exact test. The Kaplan-Meier method with the log-rank test, and Cox proportional hazard regression model were used to determine the statistical significance of the relationship between overall survival (OS) and the treatment regimen. Statistical analyses were performed using SAS 9.1. Results: Of the 27 neutropenic pts with SS, 13 received CT and 14 received CT+MSCs. There were no statistically significant differences in the demographic variables between groups . The CT group included 7 males, 6 females, aged 33-81 yrs, median 55 yrs. The CT+MSCs group included 6 males, 8 females, aged 30-75 yrs, median 48 yrs. Hematological disorders were also similar in the two groups: AML (4), NHL (4), HL (1), MM (3), MDS (1) in the CT group, and AML (5), NHL (7), MM (1) in the CT+MSCs group. In all pts, except for one with MDS, neutropenia developed after chemotherapy. In 8/13 pts in the CT group and 9/14 pts in the CT+MSCs group blood cultures were found positive, mostly gram-negative. Baseline APACHE II scores (34.2 [95% CI 28.3-43.1] and 32.2 [95% CI 26.2-37.5] in the CT- and CT+MSC-groups, respectively), and SOFA scores (17.9 [95% CI 13.5-22.2] and 15.1 [95% CI 11.0-19.2] respectively), were similar in the two groups. 28-day survival rates were 15% (2 out of 13 pts) in the CT group and 57% (8 out of 14 pts) in the CT+MSCs group (P=0.04) (Figure 1). The significant increase in 28 days OS of the pts in CT+MCSs group was associated with SOFA score decrease, which was started in three days after onset of SS. Despite higher 28-day survival rates only 3 pts treated with CT+MSCs remained alive after 3 months, and 5 of 8 pts from the CT+MSCs-group who survived 28 days died later because of sepsis-related organ dysfunction. Conclusions: Administration of MSCs in the first hours of SS might improve short-term survival in neutropenic pts, but does not prevent death from sepsis-related organ dysfunction in the long term. Perhaps repeated administration of MSC is required. Figure 1. Comparison of OS rates between the two groups of pts in the ICU. There was a statistically significant increase of the 28-day OS rates (42% vs. 15%; P=0.04) and a statistically significant decrease of the risk of death (HR 0.35; 95% CI 0.13 - 0.91; P=0.04) in the CT+MCSs group vs. the CT group. Figure 1. Comparison of OS rates between the two groups of pts in the ICU. There was a statistically significant increase of the 28-day OS rates (42% vs. 15%; P=0.04) and a statistically significant decrease of the risk of death (HR 0.35; 95% CI 0.13 - 0.91; P=0.04) in the CT+MCSs group vs. the CT group. Disclosures No relevant conflicts of interest to declare.

Bone marrow (BM) derived adult multipotent mesenchymal stromal cells (MMSCs) and fibroblast colony-forming units (CFU-Fs) of 20 patients with acute myeloid leukemia (AML) and 15 patients with acute lymphoblastic leukemia (ALL) before and during 1 year after receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) were studied. The growth characteristics of MMSCs of all patients before allo-HSCT were not altered; however, relative expression level (REL) of some genes in MMSCs, but not in CFU-Fs, from AML and ALL patients significantly changed. After allo-HSCT, CFU-F concentration and MMSC production were significantly decreased for 1 year; REL of several genes in MMSCs and CFU-F-derived colonies were also significantly downregulated. Thus, chemotherapy that was used for induction of remission did not impair the function of stromal precursors, but gene expression levels were altered. Allo-HSCT conditioning regimens significantly damaged MMSCs and CFU-Fs, and the effect lasted for at least 1 year.