Review
Copyright ©The Author(s) 2016.
World J Gastroenterol. Nov 7, 2016; 22(41): 9057-9068
Published online Nov 7, 2016. doi: 10.3748/wjg.v22.i41.9057
Table 2 Synopsis of published clinical studies using mesenchymal stromal cells in perianal fistulizing and/or refractory Crohn’s disease
Ref.Study designPatientsDisease duration and characteristicsAssessment and follow-upSource of cellsDoseSafety outcomes (terminology)Key safety results
García-Olmo et al[84] (2005)Phase 19 patients aged 32-46Diagnosis of CD at least 5 years before, unresponsive to medical treatment and unsuccessfully treated by classic surgery at least twiceWeekly follow-up for the first 8 wk, then monthly follow-up up max 30 moAutologous ASC3-30 × 106Not specifiedNo immediate adverse reactions (e.g., anaphylaxis, allergic reactions) were observed in any of the cases studied
Garcia-Olmo et al[85] (2009)Open-label, multicenter, phase 224 patients with mean age = 52 received ASC+fibrin glueComplex perianal fistula (either of cryptoglandular origin or associated with CD). In patients with CD, immunomodulators were used continuously for at least six months and stable for more than eight weeksWeek 8, 16 and then at 3-mo interval up to 12 monthsAutologous ASC2-4 × 107Incidence of adverse events and serious adverse events11 adverse events (at week 8), of which two were SAEs, but unrelated to ASC administration. In the following phase, 9 adverse event (perianal sepsis), unrelated to ASC administration
Ciccocioppo et al[86] (2011)Prospective study12 patients aged 16-44 (two drop outs)Patients with CD unresponsive to or unsuitable for all previous medical treatment including biological agents or unsuccessfully treated by surgery3, 6 and 12 moAutologous BM-MSCMedian 20 × 106Changes in vital signs and adverse reactions during the first 6 h after each cellular treatment, and during the following 12-month follow-upNo changes in vital signs and no adverse events were recorded during the procedure and up to the end of the 6-h observation time, or during the 12-mo follow-up period
Guadalajara et al[87] (2012)Retrospective follow up of phase 224 patients with mean age = 42Patients enrolled in previous phase 2 study receiving at least one ASC administration8 wk, 1 yrAutologous ASCNot specifiedNumber of adverse events since the final visit of the phase II study (serious or not, severity, causality)Ischiorectal abscess (patient treated with fibrin glue alone) and a perianal abscess (patient treated with ASCs plus fibrin glue), both toxicity grade I and unrelated to the study treatment. These events occurred at 13 and 21 mo after the original treatment, respectively
Herreros et al[88] (2012)Multicenter randomized single-blind Phase 3 + observational200 patients with mean age = 50Cryptoglandular complex fistula-in-ano (without CD)1, 4 and 12, 14 24, 26, 48 wkAutologous ASC2 × 107 (± fibrin glue)Incidence of adverse events and SAEsApproximately 85%-90% of patients experienced an adverse event, but most of these were nonserious. There were 17 different AEs reported in more than 5% of the cases. The most frequent AEs were proctalgia (43.7%), abscess drainage (22.4%), pain (13.7%), perianal abscess (13.1%), pyrexia (0.3%), swelling (6.6%), and pruritus (6.6%). There were no statistically significant differences within groups. There were 37 SAEs in 30 patients. All but 4 SAEs were unrelated to study treatment
Lee et al[89] (2013)Open-label phase 243 patients with mean age = 26Perianal fistulae with CD in patients not treated with infliximab within 3 mo prior to ASC4, 6 and 8 wk, 10 moAutologous ASCDepending on the fistula (mean from 15 to 19 × 107)Systemic tolerance, adverse events and SAEsPost-operative pain (60%), anal pain (19%) and anal bleeding (7%), unrelated to ASC administration. One hospitalization for vitamin B12 deficit; two grade 3/4 events (exacerbation of disease and peritonitis), unrelated to ASC administration
de la Portilla et al[90] (2013)Open-label phase 1/2a24 patients with mean age = 36Diagnosis of CD at least 12 mo before, presence of persistent and active complex perianal fistula with less than three fistulous tracts and/or external opening, non-active luminal CD; no treatment with infliximab or any other anti-TNF agent in the previous 8 wk or tacrolimus or cyclosporine in the previous 4 wk10, 12, 22, 24 wkAllogeneic ASC2 × 107 (up to 4 × 107 if no effect)Incidence of treatment emergent adverse events32 treatment-emergent adverse events during the study, the majority of which were of mild to moderate intensity. Five treatment-related AEs were reported: “anal abscess” (3 patients), “pyrexia” (1), and “uterine leiomyoma” (1). Only two SAEs: “pyrexia” and “perianal abscess”, considered to be possibly related to the study treatment and both patients were withdrawn from the study
Ciccocioppo et al[91] (2015)5-year follow up of an open-label phase 28 patients with median age = 37Refractory CD or inability to undergo standard therapies12 mo until 5 yrAutologous BM-MSCNot specifiedSystemic tolerance, adverse events and SAEs, as specified in the Medical Dictionary for Regulatory Activities terminology23 adverse events, mainly consisting of abdominal pain, headache, anal inflammation, diarrhea, erythema, nausea, and fever. All AEs were consistent with exacerbation of the primary disease, but cholecystectomy due to the presence of gallstones. None was attributed to MSC therapy, and no evidence of tumor development or opportunistic infection
Cho et al[92] (2013)Open-label, multicenter, dose-escalation phase 110 patients with mean age = 26Perianal fistula associated with CDWeeks 8, months 4,6 and 8Autologous ASC1, 2 and 4 × 107 to 40 × 107Adverse events reported after injection with ASCs, serious adverse events during study period, and laboratory toxicity observed after injection with ASCs. (CTCAE version 3.0)13 adverse events were reported in seven patients (70%). The adverse events, which were mild or moderate in severity, were not related to study drug. There were no grade 3 or 4 adverse events and no laboratory toxicity greater than grade 3 in this study. Adverse events reported in two or more patients included pain (n = 3) and diarrhea (n = 2). During the study period, two patients reported three SAEs of grade 2 (enterocolitis, seton application, and infliximab administration for new fistulas unrelated to the target fistula) requiring hospitalization
Cho et al[93] (2015)Retrospective analysis of 1-year follow up phase 242 patients with mean age = 26Average duration of CD of 58 mo2 yrAutologous ASCAverage 16.4 × 107Systemic tolerance, adverse events, SAEs53 adverse events were reported in 30 patients (73.2%), the most common being abdominal pain (17.1%); eczema and exacerbation of disease (9.8%) and anal inflammation, diarrhea, and fever (7.3%). None was related to MSC administration
Garcia-Olmo et al[62] (2015)Observational28-76Recurrent perianal fistulae who previously undergone at least three surgical interventionsWeek 8 and year 1Autologous ASCNot specifiedNot specifiedNo adverse reactions or complications related to MSC administration
Molendijk et al[66] (2015)Phase 2, double-blind, placebo-controlled, randomized study> 18Actively draining perianal fistulizing CD (diagnosis at least 3 months before enrollment) refractory to conventional therapies6, 12, and 24 wkAllogeneic BM-MSC1, 3 and 9 × 107Primary endpoint: incidence of serious adverse events at week 12. (CTCAE, version 3.0). Secondary end point: incidence of surgical intervention and infections at week 12 and 24No infusion reactions; one patient 2 developed fever 6 h after surgery. One patient in each group developed a perianal abscess that required surgical drainage. Reported adverse events: n = 17 (group 1, n = 5), 9 (group 2, n = 5), 10 (group 3, n = 5), 14 (placebo, n = 5). One patient (1 × 107) developed an adenocarcinoma of the cecum with peritoneal carcinomatosis > 15 mo after the surgical intervention
Dhere et al[52] (2016)Phase 1 safety trial18-52Established CD for at least 3 mo refractory to conventional therapies (lack of response to immunomodulators and/or biologics for at least 3 mo)1, 5 and 9 wk after infusionAutologous BM-MSC2, 5 and 10 × 106Changes in respiratory or cardiovascular parameters during the 1 h infusion and for 4 h after. Temperature, heart rate, mean arterial pressure and respiratory rate assessed at 15 min, 30 min, 1 h, 2 h, 3 h and 4 hNo patient developed significant infusion reaction. SAEs in 7 patients, of which 2 likely to be related to MSC administration: appendicitis (with appendectomy 9 d after infusion and complete colectomy for medically refractory CD after 120 d) and C. difficile colitis (30 d after infusion)
Panés et al[63] (2016)Phase 3, randomized, placebo-controlled trial107 patients, mean age = 39Actively draining perianal fistulizing CD refractory to conventional therapies24 wk after local injectionAllogeneic ASC12 × 106TEAEs (MedDRA version 17.0)18 patients of the ASC treated group vs 30 of 107 in the placebo group developed treatment-related adverse events, (anal abscess and proctalgia)