A phase IB/IIA study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulizing Crohn's disease.

BACKGROUND: Crohn-related rectovaginal fistulas are notoriously difficult to treat. Studies of mesenchymal stem cells for the treatment of perianal Crohn fistulizing disease have largely excluded rectovaginal fistulas. The aim of this study was to determine the safety and efficacy of mesenchymal stem cells for refractory rectovaginal fistulizing Crohn disease. METHODS: A phase IB/IIA randomized control trial was performed in a 3:1, single-blinded study. Patients included were adult women with an anovaginal/rectovaginal fistula in the setting of Crohn disease. Seventy-five million mesenchymal stem cells were administered with a 22G needle after curettage and primary closure of the fistula tract at day 0 and month 3. Adverse and serious adverse events were recorded at post-procedure day 1, week 2, week 6, month 3, month 6, and month 12, along with clinical healing, magnetic resonance imaging, and patient-reported outcomes. RESULTS: A total of 19 patients were enrolled and treated-15 treatment and 4 control. There were no adverse or serious adverse events related to mesenchymal stem cell therapy. At 6 months, 50% of the treatment group and 0% of the control had complete clinical and radiographic healing; 91.7% of the treatment group had improvement at 6 months with only one patient having a lack of response, whereas only 50% of the control group had improvement at 6 months. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe alternative treatment approach for rectovaginal fistulas in the setting of Crohn disease. Complete healing was achieved in half of the patients.

Treatment effect of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of fistulizing Crohn's disease are durable at 12 months.

BACKGROUND: Mesenchymal stem cells have been administered via direct injection to treat perianal Crohn's fistulizing disease. We herein sought to determine the safety and durability of treatment response to 12 months with 3 individual phase IB/IIA clinical trials of mesenchymal stem cells for refractory perianal, rectovaginal, and ileal pouch fistulas in the setting of Crohn disease. METHODS: Three phase IB/IIA randomized placebo-controlled single-blinded clinical trials were performed for (1) perianal fistulas, (2) rectovaginal fistula, and (3) ileal pouch in situ with anovaginal and/or perianal fistulas. Bone marrow-derived mesenchymal stem cells (75 million in 7.5 mL) were injected at the time of exam under anesthesia on day 0 and month 3. Outcome measures were adverse events and combined clinical and pelvic magnetic resonance imaging healing at month 6 and month 12. RESULTS: Across all 3 trials, 64 patients were enrolled; 49 were treatment and 15 were control. At 6 months, combined clinical and radiographic healing was achieved in 83.3%, 33.3%, and 30.8% of the perianal, rectovaginal, and pouch fistula treatment cohorts, respectively. At 12 months, the treatment response was durable, with 67.7% of perianal, 37.5% of rectovaginal, and 46.2% of peripouch fistulas maintaining complete clinical and radiographic healing. Two patients in the perianal fistula control cohort achieved combined clinical and radiographic healing at 12 months, whereas 0% of rectovaginal and pouch control patients healed. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal, rectovaginal, and peripouch fistulizing Crohn's disease. Treatment results are durable at 12 months.

A Phase IB/IIA Study of Allogeneic, Bone Marrow-derived, Mesenchymal Stem Cells for the Treatment of Refractory Ileal-anal Anastomosis and Peripouch Fistulas in the Setting of Crohn's Disease of the Pouch.

BACKGROUND AND AIMS: Mesenchymal stem cells [MSCs] have been used for the treatment of perianal Crohn's fistulising disease by direction injection. No studies to date have included patients with an ileal pouch-anal anastomosis [IPAA] in situ. METHODS: A phase IB/IIA, randomised, control trial of bone marrow-derived, allogeneic MSCs via direct injection to treat adult patients with a peripouch fistula[s] was conducted; 75 million MSCs were administered with a 22 G needle, with repeat injection at 3 months if complete clinical and radiographic healing was not achieved. Adverse and serious adverse events at post-procedure Day 1, Week 2, Week 6, Month 3, Month 6, and Month 12 were assessed. Clinical healing, radiographic healing per pelvic magnetic resonance imaging [MRI], and patient-reported outcomes were assessed at the same time points. RESULTS: A total of 22 patients were enrolled and treated; 16 were treated and six were controls. There were no adverse or serious adverse events related to MSC therapy. At 6 months, 31% of the treatment group and 20% of the control had complete clinical and radiographic healing. When stratifying the treatment group into perianal [n = 7] and ano-vaginal [n = 8] fistulas, 6-month healing in the treatment groups was 57% and 0%, respectively. The perianal Crohn's disease activity index [PCDAI], Wexner incontinence score, and van Assche score all significantly decreased in treatment patients at 6 months; only the PCDAI decreased in the control group. CONCLUSION: Bone marrow-derived, allogeneic MSCs offer a safe and effective alternative treatment approach for peripouch fistulas in the setting of a Crohn's like phenotype of the pouch [ClinicalTrials.gov Identifier: NCT04519684.].