Affiliation
- Cytopeutics Sdn Bhd, Cyberjaya, Selangor, Malaysia
- M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman – Kampus Sungai Long, Kajang, Selangor, Malaysia
- Hospital Ampang, Ampang,Selangor, Malaysia
- Sunway Medical Centre, Bandar Sunway, Selangor, Malaysia
- Universiti Kebangsaan Malaysia, Cheras, Selangor, Malaysia
- Hospital Sultanah Aminah, Johor Bahru, Johor Bahru, Johor, Malaysia. Ampang Hospital, Ampang, Selangor, Malaysia
Background
In spite of advancements in the acute graft-versus-host disease (aGVHD) management, the prognosis remains unfavorable, highlighting an ongoing, unmet need for satisfactory treatment. Previously, we outlined preliminary results of administering allogenic human umbilical cordderived mesenchymal stem cells (UC-MSCs) infusion alongside corticosteroids in aGVHD patients. UC-MSCs demonstrated a quicker and sustained complete response, and a superior 3month survival rate when compared to the placebo group.
Aim
We provide an in-depth analysis with a prolonged follow-up and subgroup assessment based on immune cell subsets findings.
Methodology
In this phase I/II trial, patients with grade II-IV aGVHD were randomized to receive up to three upfront infusions of UC-MSC (5×106 cells/kg bw) or placebo (ClinicalTrials.gov: NCT03847844). Informed consent was obtained from each participant. The measurements were taken at 14 and 28 days for the overall response (OR), and 3 and 12 months for the overall survival (OS). Based on the initial levels of circulating CD4+ terminally differentiated effector memory T (TEMRA) and CD8+TEMRA in the patients, subgroup analyses were conducted.
Results
A total of 22 patients participated in the study, with 14 receiving UC-MSCs and 8 receiving placebo. No adverse events related to the treatment were reported. Those who received UCMSCs exhibited improved OR rates at Day 14 (78.6% vs 75%) and Day 28 (78.6% vs 62.5%), as well as higher OS rates at 3 months (85.1% vs 62.5%) and 12 months (56.7% vs 37.5%) compared to the placebo group. Subgroup analysis based on baseline CD4+TEMRA >35% or CD8+TEMRA >70% demonstrated elevated OS at 3 months (100% vs 80%; 100% vs 80%) and 12 months (83.3% vs 60%; 71.4% vs 60%) for UC-MSCs recipients versus the placebo group. Correlation analysis revealed that OS at 12 months was positively related to OR at Day 28 (r=0.67, p<0.001), baseline CD4+TEMRA (r=0.54, p=0.009), and CD8+TEMRA (r=0.45, p=0.036).
In the severe grade III-IV group, individuals with >35% baseline CD4+TEMRA and received UCMSCs had a higher likelihood of surviving up to 12 months compared to those in the placebo group (83% vs 50%). Conversely, those with <35% CD4+TEMRA in the placebo group had 0%survival regardless of aGVHD grade (p=0.01). Notably, all patients with grade III-IV aGVHD who had baseline CD8+TEMRA >70% and received UC-MSCs were alive at 12 months, while none of the patients with CD8+TEMRA <70% in the placebo group survived (p=0.01).
Conclusion
OR at day 28 predicts survival at 3 months and 12 months. Our findings demonstrate that the administration of upfront UC-MSCs led to enhanced OR at Day 28 and increased survival rates at both 3- and 12-month in aGVHD patients, specifically those in grade III-IV with baseline CD4+TEMRA exceeding 35% or CD8+TEMRA surpassing 70%, as opposed to the placebo group. CD4+TEMRA or CD8+TEMRA are potential predictive markers that could be used to identify subsets of patients who experience significant benefits from upfront application of UC-MSCs, promising precision of patient selection and a cost-effective strategy.