Response and Long-Term Outcome After Treatment With Third-Party Mesenchymal Stromal Cells - Updated Results In 58 Patients With Steroid-Refractory Acute Graft-Versus Host Disease -
Authors: von Dalowski Felix , Kramer Michael , Wermke Martin , Röllig Christoph , Alakel Nael , Stölzel Friedrich , Parmentier Stefani , Sockel Katja , Krech Mathias , Schmitz Marc , Platzbecker Uwe , Schetelig Johannes , Bornhauser Martin , von Bonin Malte 
Published: October 2019

Introduction
Acute Graft-versus-Host Disease (aGvHD) remains the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). So far, corticosteroids are the only first-line treatment proven to be effective. Steroid-resistance is associated with poor outcome and no commonly accepted second-line salvage therapy is available until now. Mesenchymal stromal cells (MSC) have shown promising immunomodulatory effects and have been suggested as cell-based treatment option in patients with steroid-refractory acute GvHD. Here, we report our experience from a large cohort of patients treated with MSC.

Patients, Materials and Methods
Fifty-eight patients with steroid-refractory acute GvHD after HSCT were treated with MSC at our centre between 2007 and 2012. MSC were obtained from volunteer third-party donors and expanded in platelet-lysate containing medium. Median age at transplantation was 55 years (range 19-71). In 25 patients AML was diagnosed initially. Further diagnoses were CLL (n=9), ALL (n=5), MDS (n=5) and others (n=14). For transplantation, patients received peripheral blood stem cells (n=56) or bone marrow (n=2) from HLA-identical (n=43) or HLA mismatched donors (n=15) after varying reduced-intensity conditioning regimens (n=50) or myeloablative conditioning (n=8). Eight-teen patients received anti-thymocyte globulin as part of their conditioning. GvHD prophylaxis consisted mostly of cyclosporine A (CsA) plus methotrexate, CsA alone or CsA plus mycophenolate mofetile.
The majority of patients suffered from aGvHD grade IV (79%), median interval from HSCT to onset of GvHD was 36 days. Involvement of gastrointestinal tract, liver and skin was observed in 91%, 43% and 41% of patients, respectively. Most patients (64%) had involvement of 2 or 3 organs at the same time. Besides corticosteroids, 48 patients (83%) received at least one additional immunosuppressive agent before the first MSC infusion. Response was assessed 28 days after initiation of MSC treatment and overall survival of the MSC treated cohort was compared to a historic patient cohort (n=36) with steroid-refractory aGvHD not receiving MSC.

Results
Median time between onset of aGvHD and first application of MSC was 12 days (range 6-62). Altogether 139 doses of MSC were transfused at a median dosage of 0.99x106cells/kg bodyweight (range 0.448 -2.077). A median number of 2 MSC infusions were given per patient (range 1-6). During MSC treatment, 39 patients needed further escalation of immunosuppression due to persistence or progression of GvHD. No side-effects directly related to MSC infusions were observed.
Four weeks after first MSC application, 9% (n=5) of patients showed a complete response (CR), 9% (n=5) exhibited a very good partial response (VGPR), 29% (n=17) experienced partial response (PR) whereas 53% (n=31) were classified as non-responders. There were no significant differences in organ specific response. One-year and 2-year-survival after onset of aGvHD was 19% [95% CI: 9-29%] and 17% [95% CI: 7-26%], respectively. Median survival was 69 days [95% CI: 38-100 days]. Causes of death were aGvHD (54%), infectious complications (29%), relapse of the underlying disease (4%) and others (13%). Median follow up was 1689 days and at the end of follow-up, 8 patients were still alive (median survival after HSCT 58 months). Of those eight, 6 were initially classified as responders (CR n=4, VGPR n=1, PR n=1). Responders showed higher survival compared to non-responders (hazard ratio 0.38; p=0.004). Overall survival in the MSC treated cohort did not differ significantly to that of the historic cohort not receiving MSC.

Conclusions
MSC in combination with further immunosuppressive strategies resulted in a response rate of 47% in patients with steroid-refractory aGvHD and should therefore be considered as a valuable treatment option in a difficult clinical situation. However, compared to our historic cohort, treatment with MSC did not lead to an improvement of survival. Future studies need to define which patient subsets are likely to benefit from MSC therapy and whether certain MSC preparations from specific donors may have a more pronounced and long-lasting immunosuppressive effect. Therefore, further insights into MSC biology are urgently needed to optimize the translation into clinical practice.

Disclosures:
No relevant conflicts of interest to declare.