Treatment of Patients with Therapy-Refractory Acute GvHD with the Novel MSC Product MSC-Ffm Resulted in Excellent Response and Low Mortality: Post-Approval Observational Data from 69 Consecutive Patients

Abstract Abstract We developed a new MSC expansion protocol (Kuci 2016) ensuring strict equipotency of therapeutic doses of the product MSC-FFM, which has received a national marketing authorization by the national regulatory authority Paul-Ehrlich-Institute (Number: PEI: A.11748.01.1) and is thus available for routine clinical use in patients with steroid refractory (SR) aGvHD. We here report outcomes of 69 consecutively treated patients (pts) with MSC-FFM as compassionate use in six countries. Patients and methods: 69 pts with steroid or treatment refractory aGvHD from 19 allogeneic transplant services from Germany, Hungary, Israel, Norway, Saudi-Arabia and UK were treated with MSC-FFM. Pts were aged between 0.5 and 66 years, with a preponderance of children Conditioning regimens were based on TBI in 15 pts (22%), Busulfan in 15 pts (22%), Treosulfan in 21 pts (30%), and other chemotherapies in 18 pts (26%). For in vivo T cell depletion, ATG or Campath were used in 34 (49%) and 14 pts (20%), respectively. GvHD prophylaxis was administered to 86% of all pts (n=62); in two-third of all pts with Cyclosporine A alone (16%) or in combination with Methotrexate (38%) or MMF (10%). Stem cell donors were MSD (n=14; 20%), MUD (n=45; 65%) or MMFD (n=10; 15%). Grafts were derived from BM (n=35; 51%) and peripheral blood (n=33; 48%) (cord blood: n=1). At the time of MSC-FFM treatment, 66 pts (96%) were suffering from either aGvHD grade III (n=26; 38%) or grade IV (n=40; 58%), 4% had aGvHD grade II. Acute GvHD occurred at a median time of 30 days (5-280 days) after transplant. MSC-FFM treatment was requested after pts had failed to respond to steroids (n=20, 29%), (SR pts) or if pts have failed to three (n=23, 33%), four (n=12, 17%), or ≥ five (n=14, 20%) lines of immune suppressive drugs (treatment refractory pts). Response was defined as either complete response (CR), i.e. complete resolution of all signs of GvHD, partial response (PR), i.e. GvHD reduction by at least one grade according to the Glucksberg criteria, or non-response (NR) at day 28 after first MSC transfusion. Results: At day 28, 33% of pts (n=23) achieved CR and 52% PR (n=36), resulting in an overall response rate (ORR) of 85%. 12% of pts (n=8) failed to respond and in 2 pts (3%) no data were available at day +28. As best response, 59% of pts (n=41) had a CR and 28% of pts (n=19) a PR, while 9 pts (13%) did not benefit from MSC transfusion. These response rates resulted in a cumulative incidence of non-relapse mortality (NRM) of 30±7% and relapse mortality (CIRM) of 2±2%. The overall survival (OS) probability was 68±6% at 12 months. MSC transfusions were equally effective in pts with aGvHD °III (n=26) or °IV (n=40), who had an estimated OS survival probability at 1 year of 72±10% and 64±8% (p=0.822), respectively. CR, PR and NR rates on day 28 were 42%, 50% and 8% for aGvHD °III vs. 27.5%, 52.5% and 15% (5% no response) for aGVHD °IV. Clinical responsiveness did not differ between children ( 0.085 for all comparisons). Only 29% of our pts (n=20) belonged to the group of SR pts, who all (100%) responded to MSC treatment: 65% with a CR and 35% PR at the day 28 and 75% (n=15) with CR and 25% (n=5) PR at last follow-up. In pts with treatment refractory aGVHD (n=49; 71%); at day 28 10 pts (20%) achieved CR, 29 pts (59%) PR, 8 pts (16%) NR, 2 pts did not reach this time point, resulting in an ORR of 79%. At last follow-up, 26 pts (53%) were in CR, 14 pts (29%) in PR and only 9 pts (18%) did not respond. Comparison of outcomes for SR vs. treatment-refractory pts also did not reveal statistically significant differences. Predicted one-year OS was 67±12% vs. 69±7% for SR vs. treatment-refractory pts (p=0.969, n.s.), with a CIRM of 0% vs. 3±3% and an NRM of 33±12% vs. 28±7% (p≥0.350, n.s.) Conclusion: MSC-FFM offers an excellent chance to survive for pts with steroid or even treatment refractory aGvHD. This warrants further clinical evaluation. Disclosures Bader: Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding. Bug: Jazz Pharmaceuticals: Other: Travel Funding; Astellas: Other: Travel Funding; Celgene: Honoraria, Other: Travel funding; Novartis: Honoraria, Research Funding; Janssen: Other: Travel Funding; Amgen: Honoraria. Lang: Miltenyi Biotec GmbH: Patents & Royalties, Research Funding. Lucchini: Alexion: Membership on an entity's Board of Directors or advisory committees. Buchner: Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Consultancy. Jarisch: Novartis: Consultancy.