Still 'dwelling in the possibility' - critical update on stem cell therapy for acute on chronic liver failure

Table 1 Summary and salient features of clinical studies on acute on chronic liver failure utilizing stem cell therapy and/or growth factor therapy

Ref.	Country	Etiology of ACLF	Type of study	Therapy used	Outcome
Shi et al[23], 2012	China	Hepatitis B virus	Open label, randomized controlled trial (n = 24 treated, 19 controls)	Umbilical cord derived mesenchymal stem cells; cubital vein infusion; 3 times 4 weeks apart	Follow up at 72 wk; partial improvement in MELD score and liver function; 12-wk survival better in stem cell group; no long-term survival benefit
Lin et al[24], 2017	China	Hepatitis B virus	Open label, non-blinded randomized controlled trial (n = 56 treated, 54 controls)	Allogenic bone marrow derived mesenchymal stem cells; peripheral vein infusion; once weekly for 4 wk	Follow up at 24 wk; survival better in stem cell group; bilirubin reduction and MELD score improved significantly in stem cell group
Chen et al[25], 2018	China	Hepatitis B virus	Systematic review and metanalysis of three studies (n = 91 treated with MSC, 107 on SMT)	Bone marrow derived and umbilical cord derived mesenchymal stem cells; one study included patients on plasma exchange along with stem cell therapy (not ideal for inclusion)	Significant reduction of bilirubin at 4 wk and not beyond; improved survival at 12 wk (short term) only; safety profile of peripheral infusion confirmed
Xue et al[26], 2018	China	Multiple	Systematic review and metanalysis of four randomized controlled trials and six non-randomized controlled trials; poor inclusion, decompensated cirrhosis patients, alcoholic cirrhosis and acute liver failure due to hepatitis B virus also included	Bone marrow mononuclear cells, peripheral blood derived stem cells, bone marrow derived stem cells, umbilical cord derived mesenchymal stem cells; peripheral vein and hepatic artery	Significant reduction in bilirubin at 12 mo; improvement in albumin level in long term (confounders not controlled); short term survival at 12 wk; bone marrow mononuclear cells associated with adverse events; no long-term clinical efficacy or safety could be assessed
Engelmann et al[27], 2019	European multicenter	Multiple (mostly alcoholic hepatitis and bacterial sepsis)	Interim analysis of a prospective, controlled, open-label 2-armed study (n = 163)	Granulocyte-colony stimulating factor (5 µg/(kg·d); 12 injections in total, 5 d consecutively, then 3 d apart)	No survival benefits; no clinical improvement; adverse events more with therapy; futility confirmed and study prematurely stopped
Sharma et al[28], 2020	India	Paediatric population (aged > 1 yr); multiple etiology (including Wilsons disease and autoimmune hepatitis)	Open-label randomised pilot study	Granulocyte-colony stimulating factor (5 µg/(kg·d); once daily for 5 d)	Improvement in Child Pugh scores at 2 wk, not thereafter; no clinical improvement in the short-term; no survival benefit at 30-d and 60-d follow up

ACLF: Acute on chronic liver failure; SMT: Standard medical treatment; MSC: Mesenchymal stem cells; MELD: Model for end stage liver disease.