Phase II Trial of Prochymal™ (Ex-Vivo Cultured Adult Human Mesenchymal Stem Cells) and Corticosteroids as Primary Treatment for Acute Graft-Vs-Host Disease (aGVHD).

AGVHD is a major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). Primary treatment of aGVHD with corticosteroids achieves a complete response (CR) rate of 20–40%. Mesenchymal stem cells (MSC) derived from adult bone marrow have immunomodulatory effects. Preclinical and clinical data suggest that MSC inhibit T-cell alloreactivity. Thus, we initiated a trial to investigate the use of Prochymal, ex-vivo cultured adult human MSC derived from unrelated donors, added to conventional steroid therapy for the primary treatment of aGVHD.

Patients (pts) and Methods: Pts must have had newly clinically diagnosed aGVHD, grades II-IV using standard grading criteria, after undergoing a related or unrelated allogeneic SCT, or donor lymphocyte infusion (DLI). Endpoints of the study included safety of administration of Prochymal and response rates of aGVHD by day 28 after Prochymal infusion. Treatment with steroids (2mg/kg) and Prochymal, randomized to 2 (low) or 8 million (high) cells/kg, was initiated at the time of GVHD diagnosis. Pts were kept at therapeutic levels of tacrolimus, cyclosporine, or MMF for GVHD prophylaxis. 2 doses of Prochymal were given 3–5 days apart, with the first given within 72 hrs of steroid initiation. Corticosteroids were maintained at 2 mg/kg for at least 1 week. Pts were monitored for response and toxicity weekly for 4 weeks, and then followed for safety on a 2 year long-term follow-up study.

Results: 32 pts were enrolled with interim data available for 30 pts (21 males, 9 females) with median age 52 (range 34–67). AGVHD developed following matched sibling (n=15), matched unrelated (n=11), or DLI (n=4) infusions. Overall aGVHD was noted to be grade II (n=20), grade III (n=7), and grade IV (n=3), and involved GI (n=13), skin (n=11), GI and skin (n=4), and GI and liver (n=2). Prochymal dose was low in 17 pts and high in 13 pts. All pts received both Prochymal infusions. 26 of 29 evaluable pts (90%) initially responded to treatment of their aGVHD: 19 achieved CR with no evidence for GVHD, and 7 achieved PR as documented by a reduction in 1 organ stage. Nine pts (31%) eventually required a second line agent to control aGVHD. No infusional toxicities were noted. One pt developed atrial fibrillation 1 day following the second Prochymal infusion. No unexpected ectopic tissue formation was noted in any pt by CT scans at day 28. Currently, 8 pts have died from progression of aGVHD (n=2), intracranial bleed following fall (n=1), relapse (n=1), and infection (n=4) at a median of 44 days (range 13–58) following Prochymal infusion.

Conclusions: The addition of Prochymal to corticosteroids resulted in a high response rate with minimal added toxicity when used for the primary treatment of aGVHD, and suggests that MSC have unique biological properties that may be effective for treatment of GVHD. Longer follow-up is necessary to determine if Prochymal has any impact on survival. Phase III studies are warranted, including studies in steroid refractory GVHD.