Efficacy of cx601 (darvadstrocel) for the treatment of perianal fistulizing Crohn’s disease—A prospective nationwide multicenter cohort study

Perianal fistulas are common and occur in up to 40% of Crohn’s disease (CD) patients [1, 2]. In the first two decades after initial CD diagnosis, about 28% suffer from this complication [1], causing substantial morbidity and reduced the quality of life in those affected. The vast majority of fistulas in CD are classified as complex and are therefore difficult to treat as they are particularly refractory to conventional medical treatment strategies [3‐5]. Furthermore, up to 70% of patients relapse after stopping conservative treatment, with only a few patients achieving long-term remission [6, 7].

Infliximab is currently the only approved anti-tumor necrosing factor (TNF) for fistulizing CD, which has shown efficacy in a randomized controlled clinical study [8]; however, after 1 year of treatment with infliximab, complete closure of draining fistula was demonstrated in only 23% of patients [9].

Although several surgical procedures to treat complex CD fistulas exist, they are associated with an increased risk of recurrence and incontinence [10].

As a new therapeutic option, allogeneic-expanded adipose-derived mesenchymal stem cells (Cx601) were introduced to manage perianal fistulizing CD. Mesenchymal stem cells are considered to promote anti-inflammatory and immunomodulatory effects and thereby support fistula healing [11, 12].

A placebo-controlled prospective phase III study by Panés et al. reported the efficacy of allogeneic adipose-derived mesenchymal stem cells in 51% of CD patients treated with Cx601-darvadstrocel [13], compared to 36% in the placebo group. Notably, further clinical data are still lacking, thus, its definite clinical efficacy still needs to be confirmed.

Therefore, the purpose of the present prospective nationwide study was to evaluate the efficacy of darvadstrocel in clinical practice.

Between 2018 and 2021, 14 patients (3 male, 11 female) were prospectively enrolled to the study and treated with an injection of darvadstrocel in 3 different tertiary hospitals in Austria and 21 patients did not meet the inclusion criteria and were excluded. The most common reasons for exclusion were rectovaginal fistulas, stomas and anal abscesses larger than 2 cm.

One patient underwent repetitive stem cell therapy due to failure after the first treatment session. The time interval between the 2 operations was 23 months.

Demographic data are outlined in Table 1. The median duration of an active anal fistula disease was 47 months (range 23–109 months).

All fistulas showed a transsphincteric course and were treated with seton drainage prior to stem cell therapy. The mean number of anal fistulas treated per patient was 1.4 with a maximum of 2 fistulas.

The median operation time was 20 min (range 6–50 min). The median length of hospital stay was 2 days (range 2–3 days). We observed neither intraoperative nor postoperative complications.

The follow-up ranged from 52 to 156 weeks (median 92.0 weeks).

We observed 8 patients (57.1%) with complete fistula healing, demonstrated by a closure of the external opening and no secretion by external compression. One patient required two injections of darvadstrocel after initial treatment failure. The other patients, who did not show successful fistula closure, received a reapplication of a loose seton.

Due to incomplete MRI data, no systematic evaluation was performed.

The immunomodulatory medication was changed during the follow-up period in 4 patients (40%) to another biological treatment. None of those patients showed fistula healing after darvadstrocel injection.

The PDAI changed significantly at weeks 12 and 26 compared to the baseline scores (see Fig. 2) (baseline to week 12: p = 0.042; baseline to week 26: p = 0.039); however, PDAI did not change significantly from baseline to week 52 (baseline to week 52: p = 0.495).

The postoperative HBIs did not show a significant difference to the preoperative results (see Fig. 3) (baseline to week 12: p = 0.655; baseline to week 26: p = 0.564; baseline to week 52: p = 0.739).

Complex perianal fistulas are challenging to treat and debilitating for those patients who are affected. The main goal of surgical treatment is to achieve long-term fistula closure by preserving anal sphincter function. The finding of our nationwide cohort study showed that in a difficult to treat patient population with refractory complex perianal fistula, a 57.1% healing rate was achieved using allogeneic-expanded adipose-derived mesenchymal stem cells in combination with immunomodulatory medication. Additionally, our data confirmed the safety of this treatment with no observed serious adverse events in the perioperative period. Noteworthy, one patient developed an early abscess at the surgical site soon after the operation requiring incision with new placement of a loose seton. We defined this as an early treatment failure, rather than a side effect following stem cell application.

As the exact mechanism of mesenchymal stem cells in treating Crohn’s disease remains unknown, it is believed that due to their intrinsic immunomodulatory properties, a reduction of exacerbated inflammation can be achieved [15]. The immunomodulatory characteristics of mesenchymal stem cells have already found application in treatment of various diseases such as multiple sclerosis, graft-versus-host disease, myocardial infarction and Crohn’s disease [16‐19]. The attributes of the cells result from three significant steps: migration to sites of active inflammation/tissue injury, secretion of anti-inflammatory molecules and paracrine signalling to nearby cells to maintain the local anti-inflammatory environment [15, 20‐24].

The first successful treatment with mesenchymal stem cells was reported by Garcia-Olmo et al. [25]. A patient with a refractory rectovaginal fistula due to CD was treated by autologous stem cell transplantation with a lipoaspirate as the source of stem cells. After a follow-up of 3 months, the rectovaginal fistula appeared to be healed.

Notably, there is a lack of studies evaluating the role of perianal fistula remission after darvadstrocel therapy. Our fistula closure rate was in line with the results of the ADMIRE trial [13, 26]. In addition, we observed a significant improvement of the PDAI until the second postoperative control, while the HBI remained unchanged.

Cabalzar-Wondberg et al. included 11 patients with Crohn’s disease and described a healing rate of 72.7% after a median of 41.5 weeks (range 12–81 weeks) [27]. The short follow-up period and the missing radiological data could explain the surprisingly increased healing rate in contrast to the literature.

However, Schwandner reported in a single-centre cohort study a similar fistula healing rate of 66.7% in 12 CD patients treated with darvadstrocel [28]. The internal openings were closed by simple suture and there was one patient in which a mucosal flap was created to close the internal fistula opening before administration of the stem cells.

Nikolic et al. assessed the efficacy of darvadstrocel in the treatment of rectovaginal fistula in 4 patients after a follow-up of 6 months. Noteworthy, they reported a successful fistula healing in one patient (25%) only [29]. None of the patients had a stoma at the time of surgery which could explain the disappointing outcome. Further studies are necessary to clarify the role in this specific group of affected patients.

A phase I study by Dietz et al. investigated autologous mesenchymal stem cells applied in a bioabsorbable matrix to treat perianal fistulizing Crohn’s disease [30]. After 6 months, 10 of 12 patients (83%) showed clinical healing.

Patient selection is crucial to achieving optimal clinical outcomes. So far, the ideal patient for stem cell therapy has not been identified. Thus, we still need to obtain more data to predict treatment outcome more accurately. The use of concomitant immunosuppressive therapies, the grade of proctitis or the number of existing fistula tracts remain important influencing parameters, which need to be addressed in future trials.

The main limitation of our study is the low number of patients; however, considering the high cost of the stem cell therapy and the lack of clinical data, we still believe that we can further provide important results to more clearly define the role of stem cells in perianal CD.

The study demonstrated the feasibility and safety of the application of mesenchymal stem cells in CD patients with complex anal fistulas. Clinical fistula closure can be expected in about half of the patients, treated with darvadstrocel.