2019 May;23(5):411-427. doi: 10.1007/s10151-019-01994-z. Epub 2019 May 2.
The clinical efficacy of stem cell therapy for complex perianal fistulas: a meta-analysis.
Choi S1, Jeon BG2, Chae G1, Lee SJ3.
Treatment of complex anal fistulas remains difficult. However, treatment with stem cells has had an encouraging success rate when applied to complex perianal fistulas. We systematically reviewed the current evidence through meta-analysis.
We performed an electronic literature search on PubMed, Embase, and the Cochrane Library and identified studies (published between January 1946 and August 2017) that used stem cells to treat patients with complex perianal fistula. Each paper was evaluated for treatment success rate, target patients, types of stem cells used, number of cells used, and criteria for complete healing. Potential publication bias was assessed via visual inspection of a funnel plot and Orwin's fail-safe N. Out of 171 papers, 16 were included in the meta-analysis.
The overall healing rate of stem cell injection therapy for patients with complex perianal fistulas was 62.8% (95% CI 53.5-71.2, I2 = 54.05%), whereas those for patients with Crohn's perianal fistulas alone and complex anal fistulas not associated with Crohn's disease were 64.1% and 61.5% (p = 0.840), respectively. Healing rates for autologous and allogenic stem cell treatment were 69.4% and 50.7% (p = 0.020), respectively. Four comparative studies out of 16 studies were analyzed separately. Stem cell therapy increased the healing rate compared to the control groups (OR 0.379, 95% CI 0.152-0.947).
Stem cell therapy is a good treatment option for complex perianal fistulas, which cannot be healed by conventional operative procedures. However, further research for additional supportive evidence, such as a large-scale randomized controlled trial, is required.
The clinical efficacy of stem cell therapy for complex perianal fistulas: a meta-analysis. - PubMed - NCBI
World J Clin Cases
. 2018 Oct 26; 6(12): 493–500.
Published online 2018 Oct 26. doi: 10.12998/wjcc.v6.i12.493
One more chance of fistula healing in inflammatory bowel disease: Stem cell therapy
Erica P Turse, Francis E Dailey, Maliha Naseer, Edward K Partyka, and Veysel Tahan
Patients with fistulizing inflammatory bowel disease are traditionally difficult to treat. This patient population often experiences delayed or insufficient healing of fistulas using current standard regimens including antibiotics, immunomodulators, anti-tumor necrosis factor-α drug, placement of setons, and surgical repair. Several studies over the last ten to fifteen years have been conducted using stem cell therapies with promising results in this patient population. These studies show stem cell therapy in fistulizing disease to be successful in healing between 60%-88% compared to currently 50% with infliximab. Moreover, remission was seen 24 wk to 52 wk in these studies. Further research with a multi-approach treatment using medications, stem cell therapy, and surgical interventions will likely be the future of this innovative treatment approach.
World J Transplant
. 2018 Aug 9; 8(4): 97–101.
Published online 2018 Aug 9. doi: 10.5500/wjt.v8.i4.97
Review of stem cells as promising therapy for perianal disease in inflammatory bowel disease
Francis E Dailey, Erica P Turse, Maliha Naseer, Jack D Bragg, and Veysel Tahan
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Those patients with perianal Crohn’s disease or ulcerative colitis experience a difficult to treat disease process with a delayed state and often inability to heal despite current therapies. The approaches currently used to treat these patients with corticosteroids, antibiotics, immunomodulators, anti-tumor necrosis factor-α drug, and surgical repair are limited in their healing ability. This review presents all current literature since emergence in the early 2000s of stem cell therapy for patients with perianal inflammatory bowel disease and analyzes the efficacy, outcomes and safety within these studies.
Dis Colon Rectum.
2018 May;61(5):629-640. doi: 10.1097/DCR.0000000000001093.
A Systematic Review and Meta-analysis of Mesenchymal Stem Cell Injections for the Treatment of Perianal Crohn's Disease: Progress Made and Future Directions.
Lightner AL1, Wang Z2, Zubair AC3, Dozois EJ1.
There has been a surge in clinical trials studying the safety and efficacy of mesenchymal stem cells for the treatment of perianal Crohn's disease.
The purpose of this work was to systematically review the literature to determine safety and efficacy of mesenchymal stem cells for the treatment of refractory perianal Crohn's disease.
Sources included PubMed, Cochrane Library Central Register of Controlled Trials, and Embase.
Studies that reported safety and/or efficacy of mesenchymal stem cells for the treatment of perianal Crohn's disease were included. Two independent assessors reviewed eligible articles.
The study intervention was delivery of mesenchymal stem cells to treat perianal Crohn's disease.
MAIN OUTCOMES MEASURES:
Safety and efficacy of mesenchymal stem cells used to treat perianal Crohn's disease were measured.
Eleven studies met the inclusion criteria and were included in the systematic review. Three trials with a comparison arm were included in the meta-analysis. There were no significant increases in adverse events (OR = 1.07 (95% CI, 0.61-1.89); p = 0.81) or serious adverse events (OR = 0.53 (95% CI, 0.28-0.98); p = 0.04) in patients treated with mesenchymal stem cells. Mesenchymal stem cells were associated with improved healing as compared with control subjects at primary end points of 6 to 24 weeks (OR = 3.06 (95% CI, 1.05-8.90); p = 0.04) and 24 to 52 weeks (OR = 2.37 (95% CI, 0.90-6.25); p = 0.08).
The study was limited by its multiple centers and heterogeneity in the study inclusion criteria, mesenchymal stem cell origin, dose and frequency of delivery, use of scaffolding, and definition and time point of fistula healing.
Although there have been only 3 trials conducted with control arms, existing data demonstrate improved efficacy and no increase in adverse or serious adverse events with mesenchymal stem cells as compared with control subjects for the treatment of perianal Crohn's disease.
A Systematic Review and Meta-analysis of Mesenchymal Stem Cell Injections for the Treatment of Perianal Crohn's Disease: Progress Made and Future D... - PubMed - NCBI
2019 Jun;156(8):2208-2216.e1. doi: 10.1053/j.gastro.2019.02.005. Epub 2019 Feb 14.
Efficacy of Injection of Freshly Collected Autologous Adipose Tissue Into Perianal Fistulas in Patients With Crohn's Disease.
Dige A1, Hougaard HT2, Agnholt J3, Pedersen BG4, Tencerova M5, Kassem M5, Krogh K3, Lundby L2.
BACKGROUND & AIMS:
Perianal fistulas are common in patients with Crohn's disease (CD). Injections of cultured autologous and allogeneic adipose tissue-derived stem cells have been shown to heal CD-associated fistulas. Unfortunately, this treatment is time consuming and expensive. We investigated the effects of injecting freshly collected autologous adipose tissue into perianal fistulas in patients with CD.
In a prospective interventional study, freshly collected autologous adipose tissues were injected into complex perianal fistulas of 21 patients with CD, from March 2015 through June 2018. The primary endpoint was complete fistula healing (no symptoms of discharge, no visible external fistula opening in the perineum, and no internal opening detected by rectal digital examination) 6 months after the last injection. We performed pelvic magnetic resonance imaging to confirm fistula resolution in patients with intersphincter and transsphincter fistulas who showed complete healing at clinical examination. Patients without complete fistula healing after 6 weeks and those with later relapse were offered additional injections. No control individuals were included.
Six months after the last adipose tissue injection, 12 patients (57%) had complete fistula healing. Three patients (14%) had ceased fistula secretion, and 1 patient (5%) reported reduced secretion. Among 10 patients with trans-sphincter or inter-sphincter fistulas, magnetic resonance imaging showed complete fistula resolution in 9 patients and a markedly reduced gracile fistula in the remaining patient. Of the 12 patients with complete fistula healing, 9 (43%) required 1 injection, 2 (10%) required 2 injections, and 1 (5%) required 3 injections. The predominant adverse effect was postprocedure proctalgia lasting a few days. Two patients developed small abscesses, 1 had urinary retention, and 1 had minor bleeding during liposuction.
In a study of 21 patients with CD and perianal fistulas, we found injection of recently collected autologous adipose tissue to be safe and to result in complete fistula healing in 57% of patients. ClinicalTrials.gov, Number: NCT03803917.
Efficacy of Injection of Freshly Collected Autologous Adipose Tissue Into Perianal Fistulas in Patients With Crohn's Disease. - PubMed - NCBI
Stem Cell Therapy: A Compassionate Use Program in Perianal Fistula
M. D. Herreros,1 D. Garcia-Olmo,1,2,3 H. Guadalajara,1,3,4 T. Georgiev-Hristov,4 L. Brandariz,1 and M. Garcia-Arranz2,3
Received 15 October 2018; Accepted 26 February 2019; Published 5 May 2019
Aim. To report our experience in a compassionate use program for complex perianal fistula. Methods. Under controlled circumstances and approved by European and Spanish laws, a compassionate use program allows the use of stem cell therapy for patients with nonhealing diseases, mostly complex fistula-in-ano, who do not meet criteria to be included in a clinical trial. Candidates had previously undergone multiple surgical interventions that had failed. The intervention consisted of surgery (with closure of the internal opening or a surgical flap performance), followed by stem cell injection. Three types of cells were used for implant: stromal vascular fraction, autologous expanded adipose-derived, or allogenic adipose-derived stem cells. Healing was evaluated at 6th month follow-up. Outcome was classified as partial response or healing. Relapse was evaluated 1 year later. Maximum follow-up period was 48 months. Results. 45 patients (24 male) were included; the mean age was 45 years, which ranged from 24 to 69 years. Since some of them received repeated doses, 52 cases were considered (42 fistula-in-ano, 7 rectovaginal fistulas, 1 urethrorectal fistula, 1 sacral fistula, and 1 hidradenitis suppurativa). Regarding fistula-in-ano, there were 18 Crohn’s-associated and 24 cryptoglandular. 49 cases (94.2%) showed partial response starting 6.5 weeks of follow-up. 24 cases (46.2%) healed in a mean time of 5.5 months. A year later, all patients cured remained healed. No adverse effects related to stem cell therapy were reported. Conclusion. Stem cells are safe and useful for treating anal fistulae. Healing can be achieved in severe cases.
. Author manuscript; available in PMC 2018 Jul 1.
Published in final edited form as:
Gastroenterology. 2017 Jul; 153(1): 59–62.e2.
Published online 2017 Apr 9. doi: 10.1053/j.gastro.2017.04.001
Autologous Mesenchymal Stem Cells, Applied in a Bioabsorbable Matrix, for Treatment of Perianal Fistulas in Patients With Crohn’s Disease’
Allan B. Dietz,*,1 Eric J. Dozois,2 Joel G. Fletcher,3 Greg W. Butler,1 Darcie Radel,1 Amy L. Lightner,2 Maneesh Dave,4 Jessica Friton,5 Asha Nair,6 Emily T. Camilleri,7 Amel Dudakovic,7 Andre J van Wijnen,7 and William A. Faubion*,5
Author information Copyright and License information Disclaimer
In patients with Crohn’s disease (CD), perianal fistulas frequently recur, causing substantial morbidity. We performed a 12 patient, 6 month phase I trial to determine whether autologous mesenchymal stem cells (MSCs), applied in a bioabsorbable matrix, can heal the fistula. Fistula repair was not associated with any serious adverse events related to MSCs or plug placement. At 6 months, 10/12 patients (83%) had complete clinical healing and radiographic markers of response. We found placement of MSC-coated matrix fistula plugs in 12 patients with chronic perianal fistulas to be safe and lead to clinical healing and radiographic response in 10 patients.
Autologous Mesenchymal Stem Cells, Applied in a Bioabsorbable Matrix, for Treatment of Perianal Fistulas in Patients With Crohn’s Disease’
Utilizing the innate potential of the stem cell, or modulating the body’s own regenerative capacity to heal disease, is an exciting and active area of research in many diseases including inflammatory bowel disease. Despite many inherent challenges to this type of therapy, advances are being made at a fast pace. It is likely that regenerative medicine will become a powerful and prominent tool for many disease states including inflammatory bowel disease.
Stem cell therapy (SCT) for inflammatory bowel disease is beginning to emerge as a potentially viable treatment option for some patients. There are numerous clinical trials either published or registered with Clinicaltrials.gov for use of stem cells in CD and UC. Therapies may include stem cells that are hematopoietic, bone marrow-derived, adipose-derived, or mesenchymal. Both autologous and non-autologous stem cells have been studied. The route of administration can be either systemic or locally injected/delivered.
In March of 2018, the European Commision approved Alofisel (formerly Cx601) (Takeda, TiGenix), the allogeneic expanded, adiposederived stem cell therapy for the treatment of complex perianal fistulas in adult patients with Crohn’s disease who have shown inadequate response to at least one conventional or biologic therapy. Approval was based on a randomized, double-blind, parallel-group, placebo-controlled phase III trial (ADMIRE-CD) of Cx601 injection for complex perianal fistulas in adult patients with Crohn’s disease demonstrating safety and efficacy. Display footnote number: 17 In this study 202 patients received a single injection of either Cx601 or placebo (saline solution) into the lesion. The primary endpoint was combined remission, defined as clinical closure of all treated external openings that were draining at baseline, and no collections of greater than 2 cm of treated fistulas on MRI. This was achieved in 50% of the treatment group compared to 34% of the placebo (p = 0.024). This study was also continued for a 52-week period evaluating efficacy endpoints of combined remission (as above), and clinical remission (absence of draining fistulas). At 52 weeks 56.3% of the treatment group achieved combined remission compared to 38.6% in the control group (p = 0.021); and 59.2% of the treatment group compared to 41.6% of the control group achieved clinical remission (p = 0.013). Cx601 also proved to be safe, with similar rates of adverse events in both groups. Display footnote number: 17 A large, multicenter, phase III trial (ADMIRE-CD II) in underway to gain FDA approval (NCT03279081).
Additional promising stem cell therapies in the pipeline include Furestem-CD (Kangstem Biotech) (NCT02000362, NCT02926300) in phase I and II trials for CD, PROCHYMAL (NCT00482092, NCT00543374, NCT01233960) in phase III trials for CD, and MultiStem (NCT01240915) in a phase II trial for UC.
A recent meta-analysis of stem cell therapy (SCT) for CD analyzed 21 studies that included 514 patients. Display footnote number: 18 This study found that systemic infusion of SCT resulted in 56% of patients achieving clinical response using random-effects meta-analysis (95% confidence interval [CI] 33-76, n=150). Efficacy was also demonstrated when evaluating clinical and endoscopic remission, and for patients with perianal CD. This analysis suggests that SCT may be effective, however the rate of severe adverse events (SAEs) was also significant. In this metaanalysis, the overall pooled rate of SAEs was 12%. The pooled rate of SAEs related to SCT was 8%. Severe adverse effects of SCT could be a significant obstacle to the use of these therapies. The use of adipose-derived mesenchymal stem cells as intralesional injection therapy for perianal fistulae in CD is perhaps closest to mainstream clinical use in the US. These studies, combined with the meta-analysis previously discussed, enabled the use of this therapy in Europe, and suggests that intra-fistula injection of adipose-derived stem cells may soon become a readily available treatment options for these patients in the US. In addition to therapies that utilize administration of actual stem cells, several emerging therapies aim to modulate or induce the regenerative capacity of a patient’s own stem cells.
Preliminary evidence suggests that regenerative therapies hold great promise as treatments for IBD. While many barriers to their widespread use remain, this is an area that is likely to occupy a significant role in the treatment of IBD in the future.
Jeffrey A. Berinstein, MD, Calen A. Steiner, MD, MS, Peter D.R. Higgins, MD, PhD, MSc Department of Internal Medicine, Division of Gastroenterology,
Mesenchymal stem cells
Stem cell therapy has not been successful in IBD until the advent of mesenchymal stem cell therapy to treat perianal Crohn’s disease. Cx-601, Alofisel (Tigenix/Takeda) has proven to be efficacious to induce and maintain fistula closure, when applied locally close to the tract in conjunction with surgical preparation of the fistula track . Of note, a high placebo effect was noted in this trial, which could have been due to the background therapies including anti-TNFs and the surgical preparation of the fistula track with closing of the internal orifice in both treatment arms. The drug received approval in Europe and a second phase III trial is being conducted.
Darvadstrocel is an expanded human allogeneic mesenchymal adult stem cells extracted from adipose tissue (expanded adipose stem cells - eASC).
Qualitative and quantitative composition
Each vial contains a suspension of 30 million cells (eASC) in 6 mL solution, corresponding to a concentration of 5 million cells/mL.
Alofisel 5 million cells/mL suspension for injection - Summary of Product Characteristics (SmPC) - (eMC)
Alofisel 5 million cells/mL suspension for injection - Summary of Product Characteristics (SmPC) by Takeda UK Ltd
The European Commission has approved Alofisel (darvadstrocel), a stem cell therapy to treat complex perianal fistulas — one of the most disabling complications of Crohn’s disease. The cell therapy represents an alternative to multiple surgeries for patients with Crohn’s that have shown an inadequate response to at least one conventional biologic therapy.
This medicine is authorised for use in the European Union.
Gastroenterology. 2018 Apr;154(5):1334-1342.e4. doi: 10.1053/j.gastro.2017.12.020. Epub 2017 Dec 24.
Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn's Disease.
Panés J1, García-Olmo D2, Van Assche G3, Colombel JF4, Reinisch W5, Baumgart DC6, Dignass A7, Nachury M8, Ferrante M3, Kazemi-Shirazi L9, Grimaud JC10, de la Portilla F11, Goldin E12, Richard MP13, Diez MC13, Tagarro I13, Leselbaum A14, Danese S15; ADMIRE CD Study Group Collaborators.
BACKGROUND & AIMS:
Therapies for perianal fistulas in patients with Crohn's disease are often ineffective in producing long-term healing. We performed a randomized placebo-controlled trial to determine the long-term efficacy and safety of a single local administration of allogeneic expanded adipose-derived stem cells (Cx601) in patients with Crohn's disease and perianal fistulas.
We performed a double-blind study at 49 hospitals in Europe and Israel, comprising 212 patients with Crohn's disease and treatment-refractory, draining, complex perianal fistulas. Patients were randomly assigned (1:1) to groups given a single local injection of 120 million Cx601 cells or placebo (control), in addition to the standard of care. Efficacy endpoints evaluated in the modified intention-to-treat population (randomly assigned, treated, and with 1 or more post-baseline efficacy assessment) at week 52 included combined remission (closure of all treated external openings draining at baseline with absence of collections >2 cm, confirmed by magnetic resonance imaging) and clinical remission (absence of draining fistulas).
The study's primary endpoint, at week 24, was previously reported (combined remission in 51.5% of patients given Cx601 vs 35.6% of controls, for a difference of 15.8 percentage points; 97.5% confidence interval [CI] 0.5-31.2; P = .021). At week 52, a significantly greater proportion of patients given Cx601 achieved combined remission (56.3%) vs controls (38.6%) (a difference of 17.7 percentage points; 95% CI 4.2-31.2; P = .010), and clinical remission (59.2% vs 41.6% of controls, for a difference of 17.6 percentage points; 95% CI 4.1-31.1; P = .013). Safety was maintained throughout week 52; adverse events occurred in 76.7% of patients in the Cx601 group and 72.5% of patients in the control group.
In a phase 3 trial of patients with Crohn's disease and treatment-refractory complex perianal fistulas, we found Cx601 to be safe and effective in closing external openings, compared with placebo, after 1 year. ClinicalTrials.gov no: NCT01541579.
Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn's Disease. - PubMed - NCBI
BioDrugs. 2018 Dec;32(6):627-634. doi: 10.1007/s40259-018-0311-4.
Darvadstrocel: A Review in Treatment-Refractory Complex Perianal Fistulas in Crohn's Disease.
Darvadstrocel (Alofisel®) consists of a suspension of expanded human allogeneic adipose-derived mesenchymal stem cells (eASCs). It is the first mesenchymal stem cell (MSC) advanced therapy approved in the EU for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn's disease, when fistulas have shown an inadequate response to ≥ 1 conventional or biologic therapy. In the pivotal phase 3 ADMIRE-CD trial in this difficult-to-treat patient population, after standard-of-care fistula conditioning, add-on therapy with a single dose of darvadstrocel (120 million eASC) administered into the tissue surrounding complex perianal fistulas was significantly more effective than placebo (saline), with the darvadstrocel group having a higher combined remission rate (i.e. clinically-assessed fistula closure plus MRI-assessed absence of abscesses) at 24 weeks in intent-to-treat (ITT primary analysis), modified ITT and per-protocol analyses. Clinical remission was maintained in > 50% of patients at 52 weeks' follow-up. Given the very limited treatment options available for this difficult-to-treat rare condition, darvadstrocel is a promising, novel, minimally invasive therapy that represents an important advance in the therapeutic options for complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn's disease when fistulas have shown an inadequate response to ≥ 1 conventional or biologic therapy.
Darvadstrocel: A Review in Treatment-Refractory Complex Perianal Fistulas in Crohn's Disease. - PubMed - NCBI
Drugs Today (Barc). 2019 Feb;55(2):95-105. doi: 10.1358/dot.2019.55.2.2914336.
Darvadstrocel for the treatment of patients with perianal fistulas in Crohn's disease.
Kotze PG1, Spinelli A2, Warusavitarne J3, Di Candido F4, Sahnan K3, Adegbola SO3, Danese S5.
Despite significant advances in medical and surgical therapy for perianal fistulas in Crohn's disease (CD), treatment results are still modest, and a specific need for more effective therapies is a reality. Darvadstrocel is composed of expanded human allogeneic mesenchymal adult stem cells extracted from adipose tissue and constitutes the first stem cell therapy for perianal fistulizing CD to receive approval from the European Medicines Agency (EMA). This therapy is injected in both internal and external openings, as well as inside the fistula tracks, to induce fistula healing. In this monograph, the authors review the preclinical pharmacology of darvadstrocel, as well as pharmacokinetics and metabolism, and cover the main indications and detailed information on the efficacy and safety profile of the agent. Possible interactions with other agents used to treat CD are also explored. Darvadstrocel is a safe and effective therapy for perianal complex fistulas in CD, and represents the beginning of a new era of mesenchymal stem cell therapy in this difficult phenotype of the disease.