Bone Marrow Mesenchymal Stem Cells in Acute-on-Chronic Liver Failure Grades 2 and 3: A Phase I-II Randomized Clinical Trial

Fernando Comunello Schacher, Annelise Martins Pezzi da Silva, Lucia Mariano da Rocha Silla, Mario Reis Álvares-da-Silva, Fernando Comunello Schacher, Annelise Martins Pezzi da Silva, Lucia Mariano da Rocha Silla, Mario Reis Álvares-da-Silva

Abstract

Introduction: Acute-on-chronic liver failure (ACLF) is an acute liver decompensation in cirrhotic patients, which leads to organ failures and high short-term mortality. The treatment is based on the management of complications and, in severe cases, liver transplantation. Since specific treatment is unavailable, we aimed to evaluate the safety and initial efficacy of bone marrow mesenchymal stem cells (BM-MSC) in patients with ACLF Grades 2 and 3, a population excluded from previous clinical trials.

Methods: This is a randomized placebo-controlled phase I-II single center study, which enrolled 9 cirrhotic patients from 2018 to 2020, regardless of the etiology. The control group (n = 5) was treated with standard medical therapy (SMT) and placebo infusion of saline. The intervention group (n = 4) received SMT plus 5 infusions of 1 × 106 cells/kg of BM-MSC for 3 weeks. Both groups were monitored for 90 days. A Chi-square test was used for qualitative variables, and the t-test and Mann-Whitney U test for quantitative variables. The Kaplan-Meier estimator was used to build survival curves. In this study, we followed the intention-to-treat analysis, with a significance of 5%.

Results: Nine patients with a mean Child-Pugh (CP) of 12.3, MELD of 38.4, and CLIF-C score of 50.7 were recruited. Hepatitis C and alcohol were the main etiologies. The average infusion per patient was 2.9 and only 3 patients (2 in control and 1 in the BM-MSC group) received all the protocol infusions. There were no infusion-related side effects, although one patient in the intervention group presented hypernatremia and a gastric ulcer, after the third and fifth infusions, respectively. The survival rate after 90 days was 20% (1/5) for placebo versus 25% (1/4) for the BM-MSC. The patient who completed the entire MSC protocol showed a significant improvement in CP (C-14 to B-9), MELD (32 to 22), and ACLF (grade 3 to 0).

Conclusion: BM-MSC infusion is safe and feasible in patients with ACLF Grades 2 and 3.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Copyright © 2021 Fernando Comunello Schacher et al.

Figures

Figure 1
Figure 1
Kaplan–Meier survival curves (n = 9).
Figure 2
Figure 2
Changes in liver and inflammatory laboratory tests from three days before the first dose of MSC through the seventh day after the first infusion. PT, prothrombin time; TB, total bilirubin; Alb, albumin; CRP, C-reactive protein. (a) PT evolution. (b) TB evolution. (c) Alb evolution. (d) Leukocytes evolution. (e) CRP evolution.
Figure 3
Figure 3
Variations regarding Child–Pugh, MELD and ACLF scores before and after the infusion of 5 doses of the intervention group ((a); n = 1) and in the placebo group after 90 days ((b); n = 2). MELD, Model for end-stage liver disease; ACLF, acute-on-chronic liver failure.

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