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DOP024 Allogeneic bone marrow-derived mesenchymal stromal stem cells for the treatment of refractory perianal Crohn fistulas: a dose-escalating placebo-controlled study

Molendijk I1, Bonsing BA2, Roelofs H3, Peeters KCMJ2, Wasser MNJM4, Dijkstra G5, van der Woude CJ6, Veenendaal RA1, Zwaginga JJ3, Verspaget HW*1, Fibbe WE3, van der Meulen-de Jong AE1, Hommes DW1,5.

1Dept. Gastroenterology and Hepatology, 2Dept. Surgery, 3Dept. Immunohematology and Blood Transfusion and 4Dept. of Radiology, Leiden University Medical Center, Leiden, The Netherlands. 5Dept. Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands. 6Dep. Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands. 7Div. Digestive Diseases, University of California Los Angeles, USA.

Background

Mesenchymal stromal cells (MSCs) have potential as cellular treatment for perianal Crohn’s disease (pCD), because of their ability to regenerate damaged tissue and to regulate immune responses.

Methods

Patients and methods: In a prospective double blind phase I-II trial 21 CD patients with draining perianal fistulas (total 32 fistulas, max 3 external and max 2 internal openings), but without active luminal disease and not responding to current therapy modalities, were randomized (5:2) to receive either protocolized local injections of 10, 30 or 90x10^6 (cohort 1, 2 or 3) allogeneic bone marrow-derived MSCs (bmMSC) or placebo. Treatment, preceded by endoscopy, MRI and removal of the seton, consisted of curettage and closure of the internal opening of the fistulous tract and standardized local injection of the study drug at the internal opening. Follow-up visits were at 6, 12 and 24 weeks. Primary endpoints were safety and preliminary efficacy of bmMSC treatment. Secondary objectives were a.o. the changes in CRP, disease activity (PDAI), and quality of life scores (sIBDQ and SF-36). A complete healed fistula (CHF) was defined as no discharge upon pressure at physical examination.

Results

Local infusion of bmMSC was safe as no serious adverse events were detected. After bmMSC therapy CHF was reached in 60% of the patients at week 6, in 40% at week 12 and in 80% at week 24 in cohort 1, and in 67% (6/9) of the fistulas. In cohort 2, 80% of patients had CHF at all three follow-up visits, and in 86% (6/7) of the fistulas. In cohort 3 this was 20% and 29% (2/7), respectively, at any time point. Placebo resulted in CHF in 17% of the patients at week 6 and in 33% at week 12 and 24, for the fistulas this was 22% (2/9) and 33% (3/9) resp. Seton drainage was needed in 2 patients after bmMSC therapy (1 in cohort 1; 1 in cohort 3) and in 1 patient after placebo. Abscess drainage was needed in 1 patient in cohort 2 at 16 weeks after bmMSCs, however, this fistula was completely healed at week 24. PDAI scores at week 0, 12 and 24 coincided perfectly with therapy efficacy: in cohort 1 changing from 4.4 to 3.0 and 2.0, respectively. In cohort 2 from 3.8, 0.8 to 1.3, and in cohort 3 from 5.0, 3.8 to 4.2 as opposed to 5.2, 5.5 and 3.8 in the placebo group. No major differences were observed in other secondary endpoints.

Conclusion

Local administration of allogeneic bmMSC is safe and feasible in patients with refractory pCD. Local treatment with bmMSC showed superior fistula healing compared to placebo with 30x10^6 bmMSC dose having the best response rates, a low dose had good and the highest dose rather poor CHF results.