Infusion of Mesnchymal Stem Cells (MSC) in Patients with Poor Hematopoietic Recovery after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): A Pilot Study.
Authors: Meuleman Nathalie , Ahmad Imran , Tondreau Tatiana , Delforge Alain , Martiat Philippe , Lagneaux Laurence , Bron Dominique 
Published: October 2019

Abstract
Background: MSC are pluripotent cells capable of differentiation into various mesenchymal tissues. These cells can also reconstitute the bone marrow stroma, source of several hematopoietic growth factors. It has been reported that infusion of MSC can enhance hematopoietic recovery. For these reasons, we elaborate a phase II pilot study of MSC infusion in patients (pts) with poor hematopoietic recovery after allogeneic transplantation.
Objectives: to evaluate the safety of infusion of ex vivo amplified MSC after allogeneic transplantation. Secondly, to assess the improvement of hematopoietic recovery after MSC infusion in pts with poor engraftment at the day 30 or more after an allogeneic HSCT after informed consent.
Methods: MSC were amplified from the bone marrow (BM)-mononuclear cells of the HSC donors. MSC expansion was made in a commercial serum-free medium (UltraCulture, Cambrex, Walkersville, MD) supplemented with a serum substitute (Ultroser, Pall Biosepra, Cergy-Saint-Christophe, France) as previously reported by our group (Eur J Haematol, 2006). Ex vivo expanded allogeneic MSC were intravenously infused at the dose of 1×106 MSC/kg of recipient body weight.
Results: six patients (pts) were enrolled in this study. Three were fully related and 3 had haploidentical sibling donors. Median time from transplantation to MSC infusion was 112 (92–186). In two of these pts we observed a normalisation of the platelet level, the white blood cell count and an increase in the reticulocytosis 16 and 21days after MSC infusions. Four were unevaluable due to many interfering patches. Pts were closely monitored during the MSC infusion and over several hours. No immediate side effects were observed. Patients were monitored by PCR for viral reactivation. In one pt the PCR CMV became positive on the day 12 of the MSC infusion. This pt had an haploidentical HSCT (CMV+/+) and at the time of infusion had no GVHD, no corticoid treatment or previous CMV reactivation. A preemptive treatment with gancyclovir was given. However 15 days after the start of the treatment, we observed an increase of the level of the PCR, treatment was switched for foscavir and the PCR became negative. At the day 53 positive EBV PCR was efficiently treated by four injections of rituximab. 77 and 102 days after MSC infusion the pt needed new preemptive treatments with foscavir for new CMV reactivation. Unfortunately the pt developed encephalitis and died from CNS CMV infection. No other complications linked to the MSC infusion were observed in this pilot study.
Conclusions: we did not observed immediate side effects linked to the infusion of ex vivo expanded allogeneic MSC. However one of our pts died from CMV infection. It is difficult to assess that the immunosuppressive effects of MSC and not those of the transplantation were responsible of this fatal infection. Nevertheless future studies have to closely monitor infectious complications and pts with active infection or viral reactivation should not receive MSC infusion.