Effective Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease with Human Induced Pluripotent Stem Cell Derived Mesenchymal Stromal Cells (iMSC) in a Clinical Setting

Background: Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The response rates to first-line treatment with steroids are low as 30%~50% and the mortality remains high in patients with steroid-refractory aGvHD (SR-aGVHD). Ruxolitinib is the only second-line agent approved in China for SR-aGVHD, but still around 40% of patients fail to reach a complete remission (CR) or partial remission (PR) by day 28 in a published Ruxolitinib phase III study, not excluding concomitant medication with other agents. iMSC holds promise to treat SR-aGVHD due to its immune regulatory ability and minimal interference with the marrow function.

Subjects and Methods: Patients with grade II-IV SR-aGvHD were enrolled in an investigator initiated trial to study the safety, tolerability, and efficacy of iMSC infusion added to routine treatment. iMSC infusion was administrated at 1 or 2 × 10⁶ cells/kg body weight weekly or twice a week for 4 weeks. Patients with PR after first 4 weeks treatment received further infusions for an additional 4-8 weeks. Response was defined as CR in patients who showed complete remission of aGvHD, and PR in patients who showed GvHD reduction by at least one grade according to the MAGIC criteria, or non-response (NR) by day 28 since the first iMSC infusion.

Results: 5 children and 12 adults with SR-aGvHD grade II (23.5%), III (23.5%) or IV (53.0%) received a total of 171 doses of iMSC infusion, 64.7% were male. The median age and weight were 35 years old (range, 7-60) and 50 kg (range, 15-78) respectively. Prior to HSCT, all 17 patients suffered haematological malignancies: acute lymphoblastic leukemia (35.3%), acute myeloid leukemia (35.3%), myelodysplastic syndrome (17.6%), aplastic anemia (5.9%), and lymphoma (5.9%). 41.2% of patients were ≥2 organs involved and 94.1% had lower gastrointestinal involvement. Patients were refractory to steroids and additional lines of treatment, including calcineurin inhibitors, anti-thymocyte globulin (ATG), mycophenolate mofetil (MMF), Basilixumab, Ruxolitinib and human umbilical cord-derived mesenchymal stem cells. The maximum dosing for a single patient was 24 and the longest follow-up was 180 days. Of all patients the best overall response rate (ORR, including CR and PR) was 88.2%, with 13 (76.5%) patients achieved CR status. All 5 pediatric patients achieved aGVHD remission (4CR, 1PR). 8 Grade IV patients had bloody stools and 87.5% (7/8) were resolved after iMSC treatment. No significant difference in response rate was observed between doses of 1× 10⁶ cells/kg (n=12) vs. 2× 10⁶ cells/kg (n=5). No adverse effects related to iMSC infusions were observed.

Conclusion: Our clinical study results suggest iMSC could offers a salvage solution for SR-aGvHD with promising efficacy and safety outcomes.