Background

A major challenge after allogeneic haematopoietic stem cell transplantation for haematologic malignancies is the management of acute graft-versus-host disease (aGVHD), which remains associated with poor prognosis despite therapeutic advancements. We conducted a randomized, double-blinded, placebo-controlled Phase I/II clinical trial to assess the safety and efficacy of umbilical cord-derived mesenchymal stem cells (Cyto-MSC) as an upfront treatment in patients with grade II-IV aGVHD.

Methods

In this multicentre trial, 22 grade II-IV aGVHD patients were randomized to receive up to three infusions of Cyto-MSC (n = 14) or placebo (n = 8), alongside standard corticosteroid therapy. The primary endpoints were overall response (OR) at Day 28 and overall survival (OS) at 12 months. The secondary endpoints included correlation between responses at Day 28 with 12-month OS and exploratory analyses of immune cell subsets.

Results

No treatment-related adverse events were observed. There were no significant differences between Cyto-MSC and placebo in the OR at Day 28 and 12-month OS. Among patients with severe grade III-IV aGVHD who achieved OR by Day 28, those treated with Cyto-MSC had significantly improved 12-month OS compared to placebo (100% vs 50%, p=0.039). Furthermore, in patients with severe aGVHD and baseline CD4+ TEMRA >35% or CD8+ TEMRA >70%, the survival benefit was pronounced in the Cyto-MSC group (83.3% and 100%, respectively). In contrast, none of the placebo-treated patients with baseline CD4+ TEMRA <35% (p=0.007) or CD8+ TEMRA <70% (p=0.005) survived at 12 months. OS was significantly associated with OR at Day 28 (p<0.001), baseline CD4⁺ TEMRA (p=0.004), and baseline CD8⁺ TEMRA (p=0.004).

Conclusion

Patients with severe grade III-IV aGVHD, particularly those who respond early or have elevated baseline CD4+ TEMRA (>35%) or CD8+ TEMRA (>70%) levels, may have an overall survival advantage when treated with Cyto-MSC as an upfront therapy in combination with standard corticosteroids.

Keywords

CD4+/CD8+; TEMRA cells; acute graft-versus-host disease; mesenchymal stem cells; predictors; upfront treatment.

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